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Transcriptional regulation*

Peter G. Okkema §
Laboratory of Molecular Biology, University of Illinois at Chicago, Chicago, IL 60607, USA

Michael Krause§
Laboratory of Molecular Biology/NIDDK, Bethesda, MD 20892-0510, USA

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Table of Contents

1. Introduction
2. Tools to study transcriptional regulation
3. Locating cis-acting regulatory elements
4. Simple promoters
5. Complex promoters
5.1. myo-2: activation of a terminal differentiation gene by the combined activities of organ- and cell type-specific regulatory elements
5.2. hlh-1: activation of gene expression by lineage-preference regulatory elements.
5.3. lin-26: activation of gene expression by tissue-specific regulatory elements.
6. Trans-acting factors
7. Spatial specificity
7.1. Organ specificity: control of pharyngeal gene expression by a master regulator
7.2. Tissue specificity: regulation of gut gene expression by a cascade of redundant GATA factors.
7.3. Cell type specificity: regulation of AIY neuronal expression by a single core motif
8. Future
9. Acknowledgements
10. References


The regulation of transcription in C. elegans shares many similarities to transcription in other organisms. The details of how specific transcription factors bind to target promoters and act as either activators or repressors are still being examined in many cases, but an increasing number of factors and their binding sites are being characterized. This chapter reviews the general concepts that have emerged with regards to promoter function in C. elegans. Included are the methods that have been successfully employed as well as limitations encountered to date. Specific cis-acting promoter elements from myo-2, hlh-1 and lin-26 are discussed as examples of complex promoters regulated by multiple sequence elements. In addition, examples of organ-, tissue-, and cell type-specific mechanisms for generating spatial specificity in gene expression are discussed.

1. Introduction

Regulation of Polymerase II (Pol II) transcription in C. elegans can be described as typical for eukaryotes. Pol II appears to act in concert with TATA Binding Protein (TBP) and TBP-Associated Factors (TAFs) at the promoter of protein coding genes (Dantonel et al., 2000; Kaltenbach et al., 2000; Lichtsteiner and Tjian, 1993; Walker et al., 2004). Active Pol II is phosphorylated on the C-terminal domain (CTD) at serine 2 and 5 like other eukaryotes (Seydoux and Dunn, 1997; Wallenfang and Seydoux, 2002; Zhang et al., 2003). The functions of these proteins at the core of transcription are beginning to be defined and are reviewed in Transcription mechanisms. However, there are many things about transcription in C. elegans that we do not yet know for sure. For example, putative TATA and CAT boxes upstream of the coding region are often described, but this is largely done subjectively without any firm experimental evidence for the function of these elements. We also have not fully explored the role of histone modifications and chromatin organization in somatic cell transcription. Progress on these fronts has primarily been made in the areas of dosage compensation (see X-chromosome dosage compensation) and germline chromatin organization (see Germline chromatin). For these cases, the evolutionary conservation suggests that somatic cell transcription will similarly be influenced by typical eucaryotic mechanisms of chromatin organization. In many ways then, our understanding of transcription in C. elegans is still in its infancy, reflecting the fact that C. elegans, as a model biological system, is still a growing field that has primarily been exploited for its genetics.

The purpose of this chapter is to provide an overview of transcriptional regulation in C. elegans. It is geared towards an audience that is naïve in the ways of C. elegans gene regulation, but, it also includes information that should be helpful even to the seasoned veteran. The tools for studying transcription in C. elegans will be described in an effort to illustrate successful approaches and highlight techniques that, while useful in other systems, are challenging in the nematode. A review of the general trends in regulatory elements is followed by specific examples of spatial and temporal regulatory strategies. The hope is that this information will serve as both a useful review and an entry point into literature appropriate for specific applications.

2. Tools to study transcriptional regulation

Reporter genes are the most commonly used method to study transcriptional regulation in C. elegans. It is straightforward to generate transgenic lines (see Transformation and microinjection), and, as C. elegans is transparent throughout its life, it is easy to visualize reporter gene expression in all cells. Early studies of gene expression relied on lacZ reporter genes and were aided by the development of a set of vectors by the Fire lab (Fire et al., 1990). These lacZ reporters were very useful for determining cis-acting transcriptional control elements (Fire and Waterston, 1989; MacMorris et al., 1994; Okkema et al., 1993) and lacZ continues to be a robust marker that can be pushed to detect even low levels of expression (Wilkinson and Greenwald, 1995).

More recently, Green Fluorescent Protein (GFP), or one of its variants, serves as the common reporter. A GFP coding cassette can be inserted in different locations within a large genomic clone (tens of kilobases) to generate transcriptional and/or translational fusions. These constructs provide the greatest chance of capturing required cis-acting regulatory elements. However, it is more common to make the assumption that genomic sequences 5 to the coding region represent the core promoter. This region, usually a few kilobases in length, can be PCR amplified and easily cloned into the reporter gene backbone of choice. Alternatively, the Promoterome Project can serve as a source for many promoter regions and is useful if the reporter gene cloning strategy is Gateway (Invitrogen) compatible (Dupuy et al., 2004). These constructs are commercially available through Open Biosytems.

There are several considerations to take into account when making reporter genes. One is the distinction between transcriptional and translational reporters; often one would like to have both. For transcriptional reporters, expression can be engineered to highlight the cytoplasm, nucleus or other cellular compartments in the expressing cell. Nuclear localized reporters are useful for embryonic cell identification whereas cytoplasmic reporters are often more useful for larval cells, particularly in neurons where they highlight the axonal and dendritic tracks. The Chalfie lab is developing a two-part fluorescent expression system that has the potential to simplify cell type identification (Zhang et al., 2004). Translational reporter genes can provide information on the subcellular localization of the endogenous gene product. In this case, it is advisable to use the fusion protein to rescue a mutant phenotype, thus demonstrating that some or all aspects of the expression pattern and subcellular localization are biologically relevant.

Once a pattern of expression is determined, promoter analyses can be used to home in on important regulatory elements. Sequential deletions of putative promoter regions linked to a GFP reporter gene are easily made by traditional cloning or Splicing by Overlap Extension (SOEing) Polymerase Chain Reaction (PCR) amplification (Horton et al., 1990). The latter technique allows high throughput and convenience as PCR reactions can be injected directly into animals without purification or cloning (Hobert, 2002). As the control elements become localized to small genomic regions (several hundred base pairs or less), they can be placed upstream of “basal” promoters to assay for enhancer activity. These approaches are common in the C. elegans literature and can be very successful in defining important cis-acting regulatory sequences.

The use of reporter genes has several important caveats. First and foremost is that they are artificial and can easily misrepresent the pattern of gene expression. Important positive- and negative-acting control elements can be excluded by assuming promoter location leading to mosaicism, loss of expression, or ectopic expression (Krause et al., 1994). For example, reporter genes that lack sufficient control elements for fidelity are often expressed in the anterior and posterior intestinal cells or a small set of head neurons. Moreover, small changes in promoter regions can dramatically alter expression patterns as illustrated by the studies of the ges-1 gene (Egan et al., 1995). It is critical to confirm reporter gene expression patterns with an independent technique such as in situ hybridization, antibody staining, or mutant phenotype.

A second concern of reporter genes is the nature of any additional modules in the construct or in a co-injected marker that may have an effect on expression. For example, many of the standard constructs available from the Fire Lab have a 3 untranslated region (UTR) derived from the unc-54 gene encoding muscle myosin heavy chain. These sequences may not be neutral when combined with promoters from other cell types. There are also reports of dramatic effects of co-transformation markers on expression levels suggesting that you should not rely on a single co-transformation marker when exploring the expression of a novel gene (Fukushige and Siddiqui, 1995). Similarly, “basal” promoters (e.g., pes-10) may be biased in working with certain types of genomic elements. This may cause them to fail to respond in certain cell types resulting in false information about a particular enhancer element (Natarajan et al., 2004). As long as you keep these limitations in mind, reporter genes can be very helpful in characterizing transcriptional control elements for the gene of interest.

Genome-wide approaches provide a more global assessment of transcriptional regulation and have begun to become more common in C. elegans. The availability of both spotted cDNA (see Kim Lab) and oligonucleotide microarrays (e.g., Affymetrix) for C. elegans has given birth to a large amount of gene expression data in response to tissue type (e.g., germline-enriched; Reinke et al., 2004), growth conditions (e.g., dauer; Liu et al., 2004), or mutant background (e.g., DAF-16; McElwee et al., 2003). Much of this data is available on web sites (e.g., http://genome-www5.stanford.edu/cgi-bin/login.pl) or is linked in Wormbase to individual genes. A second global approach for gene expression profiling is Serial Analysis of Gene Expression (SAGE) that has recently been combined with tissue isolation or cell type sorting (McKay et al., 2003; http://elegans.bcgsc.ca/home/sage.html). These approaches give an overview of expression. For specific genes, this data should be validated by an independent method, such as reverse transcriptase (RT)-PCR or reporter genes.

Bioinformatics provides another way to study gene regulation, either alone or in combination with other methods. Currently, the genome sequence of two Caenorhabditis species are finished (elegans and briggsae), one is in draft (remanei), and two are planned (japonica and CB5161). Interspecific comparisons of non-coding regions provides a powerful tool in identifying important cis-acting regulatory elements controlling gene expression, as functional elements will remain constrained through evolution. Comparisons between C. elegans and C. briggsae revealed important cis-acting sequences controlling the vitellogenin genes and helped to identify GATA-type transcription factors as likely regulators (MacMorris et al., 1994; Spieth et al., 1991; Winter et al., 1996; Zucker-Aprison and Blumenthal, 1989). Such comparison continue to provide valuable information about cis-acting sequences within gene promoter regions with many examples in the literature (Culetto et al., 1999; Kirouac and Sternberg, 2003; Marshall and McGhee, 2001; Natarajan et al., 2004; Teng et al., 2004). The power of these comparisons is increased as the number of species is increased and will thus become more informative as sequences of additional species are finished. Recently developed programs, such as FamilyJewels, provide methods for sophisticated multiple alignments (Brown et al., 2002). This approach will become widely exploited in coming years to pinpoint regulatory promoter elements.

Bioinformatic analysis of known transcription factor binding sites upstream of coding regions has also been successful. Given a known binding consensus site of sufficient length, the CisOrtho program can be used to ferret out a list of potential genes sharing expression patterns (Bigelow et al., 2004). Bioinformatic comparisons of promoters from genes with the same or overlapping expression patterns can also be informative to home in on potential regulatory elements (for example, see Chang et al., 2004; Guhathakurta et al., 2004). A nice combination of bioinformatics and in vitro studies used the DNA binding properties of DAF-12, a regulator of dauer development and lifespan, to define potential binding sites and gene targets (Shostak et al., 2004). Regardless of the method used, candidate elements and gene targets should be validated experimentally by an independent means.

There are also several techniques for studying gene expression that, while commonplace in other organisms, are not routinely used in the worm. For example, one would ideally isolate pure populations of cells and tease apart transcriptional regulation at a biochemical level. At only 1mm in length as an adult, C. elegans makes tissue dissections tedious or impossible for generating enough homogeneous tissue for biochemical analysis. The recent development of cell culture techniques (see Methods in Cell biology), coupled with cell sorting, may make biochemical approaches more feasible in the future. However, the technique is still challenging enough that most researchers have opted for other methods to study transcription.

In situ hybridization is another common technique for cataloging transcriptional profiles in many organisms but it is less often used in C. elegans studies. The impermeable egg shell of C. elegans embryos and the cuticle of larvae and adults often lead to background hybridization or partially permeabilized animals, making it difficult to get in situ hybridization signals that are reproducible or trustworthy. Despite these difficulties, a genome-scale effort to catalog gene transcription profiles using in situ hybridization by the Kohara group is now underway. Their protocols and data are useful and can be accessed at http://nematode.lab.nig.ac.jp/db2/index.php.

3. Locating cis-acting regulatory elements

The majority of protein coding genes in C. elegans are within gene-dense regions of the genome. Consequently, cis-acting regulatory regions are usually close to the coding region. The minimal promoter region required for proper expression of most Pol II transcripts lies within a couple of kilobases upstream of the start codon. There are notable exceptions to this compact view of cis-acting sequences. For example, egl-1 expression is controlled, in part, by an element located greater than 2 kb downstream of the coding region and beyond an unrelated, intervening gene (Thellmann et al., 2003). For lin-39, proper reporter gene expression required inclusion of ~30 kb of genomic DNA that extended upstream and downstream of the protein coding region (Wigmaister and Eisenmann, personal communication). Clearly C. elegans genes can have complex and distant control regions. However, a rule-of-thumb of 2 kb upstream of the ATG works well as a starting point in the search for cis-acting control elements.

It is important to remember that the minimal promoter region is not synonymous with the natural promoter. The natural promoter may span a much larger region due to redundancy in the function of regulatory elements that ensure proper and robust regulation of the endogenous gene. One common site of additional control elements is within introns. Most C. elegans introns are small (e.g., <100 bp; see Alternative splicing in C. elegans) and are thus unlikely to contain elements controlling expression. However, introns larger than several hundred base pairs do often have such elements (e.g., Nam et al., 2002; Okkema et al., 1993). Therefore, intron size can provide a clue in searching for transcriptional control sequences. Large introns, particularly at the beginning of a coding region, may also provide a clue to promoter organization and the presence of multiple transcriptional initiation sites. For example, nhr-23 has a 1.8 kb intron at the start of the gene that is included in one transcript and absent in a second (Kostrouchova et al., 1998). In cases such as this, the presence of a trans-spliced leader (see Trans-splicing and operons) on two or more different transcripts from a single gene can be an indicator of multiple messages, possibly encoding different protein isoforms.

4. Simple promoters

A simple promoter is defined here as one in which the cis-acting control elements necessary for proper expression are confined to a small region (a few hundreds of bp) of the genome. Housekeeping genes expressed in all tissues might be good candidates for regulation by simple promoters, Unfortunately, few housekeeping genes in C. elegans have been characterized. Among the best characterized simple promoters are those of the hsp-16 family of genes. This family consists of pairs of divergently transcribed genes with promoter regions sufficient for heat-regulated expression contained within the short (~350 bp) intragenic regions (Jones et al., 1986; Russnak and Candido, 1985; Stringham et al., 1992). Despite these compact promoters, distinct tissue expression patterns are induced from different hsp-16 promoters (Stringham et al., 1992), suggesting the presence of multiple regulatory sites within these simple promoters. Another excellent example of simple promoters are in the vitellogenin (vit) genes, which exhibit stage-, tissue- and sex-specific expression controlled, in the case of vit-2, by a 247 bp promoter (MacMorris et al., 1992; MacMorris et al., 1994). vit-2 promoter activity depends on GATA-factor binding sites and a novel VPE2 site (TGTCAAT) conserved in vit gene promoters in C. elegans and C. briggsae (Spieth et al., 1985; Zucker-Aprison and Blumenthal, 1989). Certain cell cycle promoters have also been shown to be remarkably simple. Analysis of several genes expressed only in proliferative cells and encoding G1 phase regulators (e.g., cyclin D) revealed that proper regulation minimally required a 67 bp region of the promoter (Brodigan et al., 2003; Park and Krause, 1999). How could genes with such dynamic expression profiles throughout development be regulated in an apparently simple way? The answer is likely that they are end effectors of a cell's decision to divide rather than integrating lineage or temporal information governing proliferation.

5. Complex promoters

The term complex is used here to describe a promoter in which the overall pattern of gene expression is the result of the composite action of several dispersed elements, each influencing or contributing to the overall expression pattern. This piecemeal organization has been described for the promoter region of several genes, including myo-2, hlh-1 and lin-26. These studies reveal examples in which spatial control of transcription is regulated by elements active in groups of cells related by cell-, tissue- and organ-type and by lineage history.

5.1. myo-2: activation of a terminal differentiation gene by the combined activities of organ- and cell type-specific regulatory elements

myo-2 encodes a myosin heavy chain expressed exclusively in the pharyngeal muscles as these cells undergo terminal differentiation (Ardizzi and Epstein, 1987; Miller et al., 1983). Characterization of the myo-2 promoter region in transgenic C. elegans and identification of trans-acting regulators indicates expression is regulated by a combination of organ- and cell type-specific signals targeting distinct regulatory sequences.

High level activity of the myo-2 promoter requires a transcriptional enhancer located approximately 300 bp upstream of the transcriptional start (Okkema et al., 1993). The intact myo-2 enhancer is active exclusively in the pharyngeal muscles, but, surprisingly, its activity depends on distinct cell-type-specific and organ-specific subelements, termed B and C, that can separately activate gene expression either specifically in the pharyngeal muscles, or more globally in all pharyngeal cell types (Okkema and Fire, 1994). In their endogenous context within the myo-2 gene, these subelements synergistically activate pharyngeal muscle gene expression.

Consistent with their distinct activities, the B and C subelements are targeted by transcription factors expressed in different spatial patterns in the pharynx (Figure 1). The cell-type-specific B subelement binds and is activated by the pharyngeal muscle specific NK-2 family homeodomain factor CEH-22 (Okkema and Fire, 1994; Okkema et al., 1997), which is structurally and functionally related to factors controlling cardiac muscle development in other species (Haun et al., 1998). The organ-specific C subelement binds and is activated by the pan-pharyngeal FoxA family transcription factor PHA-4 (Kalb et al., 1998), which is required for formation of pharyngeal muscle and all other pharyngeal cell types during embryonic development (see below).

CEH-22 is not the only factor functioning with PHA-4 to activate myo-2 expression. CEH-22 is expressed in most, but not all, myo-2 expressing pharyngeal muscles (Okkema and Fire, 1994). Likewise a ceh-22 mutant expresses myo-2, although these animals exhibit defects in B subelement activity and pharyngeal muscle development and function (Okkema et al., 1997). Thus, other as yet unidentified factors must contribute to myo-2 expression, and the characterization of these factors will enhance our understanding of pharyngeal muscle development.

 figure 1

Figure 1. CEH-22 and PHA-4 function in combination to activate pharyngeal muscle expression of myo-2. myo-2 expression is activated by the pharyngeal muscle-specific CEH-22 and the pan-pharyngeal PHA-4, which bind the myo-2 enhancer B and C subelements, respectively. Micrographs indicate trangenic embryos expressing ceh-22::gfp in pharyngeal muscles and pha-4::gfp in all pharyngeal cells (top, delimited by arrowheads), and a transgenic adult expressing myo-2::lacZ in the pharyngeal muscles (bottom). Note pha-4::gfp is also expressed in the gut. GFP and β-galactosidase are targeted to nuclei to facilitate cell identification.

5.2. hlh-1: activation of gene expression by lineage-preference regulatory elements.

hlh-1 encodes a basic helix-loop-helix transcription factor expressed in all body wall muscle cells and their precursors (Krause et al., 1990). The body wall muscle cells are derived from multiple cell lineages. Of the 81 body wall muscle cells born during embryogenesis, 1 is from the AB lineage, 28 are from the MS lineage, 32 are from the C lineage and 20 are from the D lineage (Sulston et al., 1983). An additional 14 body wall muscle cells (and other cell types) are born postembryonically from the M mesoblast (Sulston and Horvitz, 1977).

Dissection of the hlh-1 promoter shows that gene expression can be properly regulated by multiple elements spanning ~3 kb upstream of the ATG (Figure 2; Krause et al., 1994). A core element required for all expression resides just upstream of the ATG. In addition, there are several individual elements that drive expression preferentially in one or more lineages. However, no single element is specific for expression in just one lineage. In addition, the expression during embryogenesis is controlled by a different region than that controlling postembryonic expression. The overall pattern of hlh-1 expression is thus a composite of the action of several lineage-preference elements with overlapping domains of action, working in concert with an essential core element. Superimposed on this spatial pattern of regulation are distinct temporal control elements regulating timing of expression during development. As yet, no trans-acting factors have been identified that bind to the defined cis-acting elements, illustrating the difficulty in using promoter analysis alone to identify trans-acting factors.

 figure 2

Figure 2. Regulation of hlh-1 expression by lineage-preference elements. A) A schematic of body wall muscle nuclei is super-imposed on an image of a comma stage embryo. Each of four different lineages of origin is color-coded as shown in (B) (adapted from (Sulston et al., 1983). C) The promoter and partial coding region (exons 1 and 2) of hlh-1 are shown (adapted from (Krause et al., 1990). All expression is dependent on a “core” element (star) located upstream of the ATG of exon 1. Below the gene structure diagram are color-coded elements that can direct lineage-preference expression of transgenes during embryogenesis; color coding as in (A) and (B). Mature body wall muscle is dependent on distinct temporal elements (purple boxes) that do not have lineage preferences.

5.3. lin-26: activation of gene expression by tissue-specific regulatory elements.

lin-26 encodes a predicted zinc-finger transcription factor expressed in a broad range of ectodermally derived epithelial tissues, the somatic gonad and uterus (Labouesse et al., 1996; Labouesse et al., 1994). Within these ectodermally-derived epithelial tissues are the major hypodermis surrounding the body of the animal, specialized hypodermal cells located at the anterior and posterior ends of the body, and interfacial cells such as rectal cells connecting the external epithelium to the endoderm. A recent characterization of the lin-26 promoter region revealed this gene is regulated by a core element required for all expression working in concert with tissue-specific elements, rather than lineage-preference elements as discussed above for hlh-1 (Landmann et al., 2004).

lin-26 is the downstream gene in an alternatively spliced operon including lir-1 (Dufourcq et al., 1999), and proper expression of lin-26 requires an 11 kb upstream region including most of the lir-1 gene itself (den Boer et al., 1998). Within this region are tissue specific regulatory modules that activate gene expression in subsets of lin-26 expressing tissues (Figure 3; Landmann et al., 2004). For example, separable modules control expression in the major hypodermal cells, in the minor hypodermal cells and sheath and socket support cells, in rectal cells, or in the somatic gonad. In some cases, redundant elements contribute to expression in particular tissues (e.g., major hypodermal cells), and, in the case of the minor hypodermis and support cells located at the worms anterior and posterior ends, separable elements active either in anterior or posterior ends were identified. Thus, the lin-26 promoter region contains cis-regulatory elements active in cells that belong to the same organ, are functionally related, or have similar positions along the body (Landmann et al., 2004), and these elements together produce the full lin-26 expression pattern in a piecemeal fashion.


 figure 3

Figure 3. Regulation of lin-26 by tissue-specific elements. A) A diagram of some of the cell types expressing lin-26 (adapted from (Landmann et al., 2004) is shown super-imposed on an image of a comma stage embryo. B) A partial embryonic lineage showing the origin of lin-26 expressing cells with color coding matching the cell types shown in (A)(adapted from (Landmann et al., 2004): major hypodermal cells include hyp 7 (green), seam cells (orange), and P cells (purple); support cells (red); somatic gonad precursors Z1 and Z4 (yellow). C) The promoter elements for lin-26. All expression is dependent on a “core” element (star) located in the intergenic region between lin-26 and its upstream neighbor lir-1. Tissue-specific control elements, located within a lir-1 intron, are shown below the gene structure diagram with color-coding as in (A) and (B). Most control elements function in cells related by tissue-type but not by lineage. Note also that temporal control is achieved by sequentially acting elements that are progressively further upstream from the ATG of lin-26.

One common theme to emerge from these three examples is redundancy of regulatory elements. In most cases, even when sub-elements are identified with specific tissue, lineage or organ activity, their loss does not prevent all expression in that region. Clearly endogenous gene regulation has evolved to include multiple and overlapping regulatory regions to ensure proper expression during development. The deconstruction of a promoter is most useful in showing a minimal set of cis-acting control elements. As studies employ more sophisticated techniques and assays, we may learn how extensive this redundancy is.

6. Trans-acting factors

The completion of the C. elegans genome makes it possible, in theory, to define all transcription factors in the worm. In practice, this effort is more difficult because of several uncertainties when surveying the properties of a given gene. For example, zinc finger motifs can bind DNA but also can serve other functions including RNA binding and protein-protein interactions. It is therefore difficult to conclude that a given gene product is indeed a transcription factor based solely on the presence of signature motifs. For factors that modify chromatin or participate in a transcription complex, the definition of a transcription factor often lies in the eyes of the investigator. A first-pass attempt at defining a list of C. elegans transcription factors is presented in Table 1. Originally compiled in the Sternberg Lab (courtesy of T. Ririe and J. Fernandes), we present a modified version of their list with the understanding that it will necessarily need refinement over time to correct inaccuracies and omissions. The current list includes 664 genes representing only about 3.5% of the predicted genes in C. elegans. This number is surprisingly low and about one half the number of transcription factors estimated previously (McGhee and Krause, 1997).


Table 1. C. elegans transcription factors

Gene Affy probe set Description
gfl-1 190531_at AF-9-like
taf-11.3 188157_at an ortholog of human TATA-binding protein associated factor TAF11
R07C12.4 185116_s_at AP-1-like
F28C6.1 191919_at AP-2-like
F28C6.2 191940_at AP-2-like
K06A1.1 191145_at AP-2-like
Y62E10A.17 186925_at AP-2-like
Y73E7A.2 176887_at Apoptosis antagonizing transcription factor
aha-1 172967_x_at, 172057_x_at bHLH
ahr-1 193149_at bHLH
C15C8.2 192573_at bHLH
cnd-1 187594_at bHLH
F38C2.8 172921_x_at bHLH
hif-1 183824_s_at bHLH
hlh-1 193759_at bHLH
hlh-10 189550_at bHLH
hlh-11 171841_x_at bHLH
hlh-12 186469_at bHLH
hlh-13 182960_at bHLH
hlh-14 192984_at bHLH
hlh-15 182141_at bHLH
hlh-16 192331_at bHLH
hlh-17 172921_x_at bHLH
hlh-19 193041_at bHLH
hlh-2 193176_s_at bHLH
hlh-21 183551_at bHLH
hlh-25 184961_s_at bHLH
hlh-26 183674_at bHLH
hlh-27 184961_s_at bHLH
hlh-28 179991_s_at bHLH
hlh-29 179991_s_at bHLH
hlh-3 192523_at bHLH
hlh-4 190064_at bHLH
hlh-6 193106_at bHLH
hlh-8 193985_at bHLH
hnd-1 192707_at bHLH
lin-32 188671_at bHLH
mdl-1 193723_s_at bHLH
ngn-1 176272_at bHLH
T01D3.2 190290_at bHLH
W02C12.3 190299_at bHLH
Y105C5B.29 172921_x_at bHLH
Y39A3CR.6 186966_at bHLH
mxl-1 193662_at bHLH/ZIP
mxl-2 184737_s_at bHLH/ZIP
mxl-3 192645_at bHLH/ZIP
bra-2 172599_x_at BMP receptor associated protein family
taf-3 177494_at bromodomain
atf-2 189943_at bZIP
atf-5 192027_s_at bZIP
atf-6 188462_at bZIP
atf-7 173892_s_at, 172407_x_at bZIP
C27D6.4 188956_at, 187831_at, 176715_at, 193833_s_at bZIP
C34D1.5 193844_at bZIP
C48E7.11   bZIP
ces-2 193437_s_at bZIP
crh-1 189423_s_at bZIP
F17A9.3 191134_at bZIP
F23F12.9 187591_at bZIP
F23F12.9 171733_x_at bZIP
F29G9.4 191088_at bZIP
F57B10.1 185841_s_at bZIP
K02F3.4 181230_at bZIP
mgl-2 173929_s_at, 193356_s_at bZIP
pha-1 188075_at bZIP
R07H5.10 181517_at bZIP
skn-1 188421_at bZIP
srx-41 183336_at bZIP
T24H10.7 180818_at, 188946_at bZIP
T27F2.4 179204_s_at bZIP
W02H5.7 182521_at bZIP
W07G1.3 179163_at, 179658_at bZIP
W08E12.1 184700_at bZIP
xbp-1 190863_at bZIP
Y75B8A.29 185348_at bZIP
ZC376.7 189598_s_at bZIP
ZC8.4a.1 191675_s_at bZIP
zip-1 173457_s_at bZIP
T05C1.4 179917_at, 182254_s_at calmodulin-binding transcription activator (CAMTA)
cbp-1 173017_at, 191123_s_at CBP/p300 homolog
lpd-2 182912_at CCAAT-binding
T08D10.1 189859_s_at CCAAT-binding
F23F1.1 174270_s_at CCAAT-binding, subunit C (HAP5)
Y51H1A.5 182089_at CCAAT-binding
F22F1.3 194040_at KIX domain, coactivator CBP
lag-1 175617_at, 192000_s_at CSL
cdk-8 190709_at cyclin C interactor
pqn-45 177704_at DEC-1-like
pqn-47 182066_s_at DEC-1-like
mab-23   DM DNA-binding
mab-3 192765_at DM DNA-binding
C27C12.6 173904_at DM DNA-binding
Y53F4B.3 181571_s_at DNA Polymerase epsilon, subunit C
F10C1.5 192453_at Doublesex
dpl-1 191593_s_at E2F/DP1
F49E12.6 175552_at, 189678_at E2F/DP1
elf-1(mex-2) 186476_s_at E2F/DP1
elf-2 186271_at E2F/DP1
C24A1.2 174325_at ETS domain
C33A11.4 188664_at ETS domain
C42D8.4 189894_at ETS domain
C50A2.4 183564_at ETS domain
C52B9.2 180922_at ETS domain
F19F10.1 190163_at ETS domain
F19F10.5 190230_at ETS domain
F22A3.1 192249_at ETS domain
lin-1 173446_s_at, 175607_s_at ETS domain
T08H4.3 188791_s_at ETS domain
Y73F8A.14   ETS-related
peb-1 188015_at Zn-finger, FLYWCH
C34B4.2 192149_at Forkhead
daf-16 188176_s_at, 181992_s_at Forkhead
pes-1 188273_at Forkhead
pha-4 193962_at Forkhead
T27A8.2 189248_at Forkhead
unc-130 190731_s_at Forkhead
fkh-10 190179_at Forkhead
fkh-2 193957_s_at, 174011_at Forkhead
fkh-3 190724_s_at Forkhead
fkh-4 172877_x_at Forkhead
fkh-5 187411_at Forkhead
fkh-6 191946_at Forkhead
fkh-7 187837_at Forkhead
fkh-8 181677_at Forkhead
fkh-9 188781_at Forkhead
let-381 175474_at Forkhead
lin-31 188600_at Forkhead
C18G1.2 191147_at, 183542_at, 174326_s_at GATA
egl-18 190079_at GATA
elt-1 192655_s_at GATA
elt-2 193259_at GATA
elt-3 193640_s_at GATA
elt-4   GATA
elt-6 185110_at GATA
elt-7   GATA
end-1 193618_at GATA
end-3 193616_at GATA
med-1 188376_at GATA
med-2   GATA
F55A3.3 171809_s_at, 190137_s_at global transcriptional regulator
F31F7.3 182888_at Golden2-like
unc-37 173188_s_at, 193614_s_at Groucho
egr-1 188149_s_at, 188166_s_at HDAC, GATA-like)
K08B5.2 182979_at heat shock
dro-1 192105_at histone-like
W10D9.4 180226_s_at histone-like
lin-22 175682_at HLH
ref-1 193898_at HLH
sbp-1 192735_s_at HLH
hmg-1.1 175799_at HMG box
hmg-1.2 175806_at HMG box
hmg-11 193301_at HMG box
hmg-12 188169_at HMG box
hmg-3 193484_s_at HMG box
hmg-4 188651_s_at HMG box
hmg-5 187989_at HMG box
pop-1 188002_at HMG box
gei-3 178044_at, 192981_at HMG-box
C02F12.5 192268_at homeobox domain
C07E3.6 189406_at, 178029_at homeobox domain
C09G12.1 189632_at homeobox domain
C12D12.4 184383_at homeobox domain
C12D12.5 184573_at homeobox domain
C17H12.9 189669_at homeobox domain
C18B12.3 189424_at homeobox domain
C36F7.1 189594_at homeobox domain
C49C3.5 189172_s_at homeobox domain
ceh-1 176628_at homeobox domain
ceh-10 176624_at homeobox domain
ceh-12 192019_at homeobox domain
ceh-13 176615_at homeobox domain
ceh-14 192631_s_at homeobox domain
ceh-16 188939_at homeobox domain
ceh-17 191721_at homeobox domain
ceh-19 192315_at homeobox domain
ceh-2 191750_at homeobox domain
ceh-22 175701_at, 193693_s_at homeobox domain
ceh-23 189145_at homeobox domain
ceh-24 193511_at homeobox domain
ceh-26 176620_at homeobox domain
ceh-27 192317_at homeobox domain
ceh-28 193479_at homeobox domain
ceh-30 189850_at homeobox domain
ceh-31 189951_at homeobox domain
ceh-32 193576_at homeobox domain
ceh-33 188645_at homeobox domain
ceh-34 192166_at homeobox domain
ceh-35 192928_at homeobox domain
ceh-36 173826_s_at homeobox domain
ceh-37 192014_s_at homeobox domain
ceh-40 192022_at homeobox domain
ceh-41 193249_at homeobox domain
ceh-43 193833_at homeobox domain
ceh-5 191117_at homeobox domain
ceh-6 194028_s_at homeobox domain
ceh-7 191844_at homeobox domain
ceh-8 193515_at homeobox domain
ceh-9   homeobox domain
egl-5 175712_s_at homeobox domain
F17A9.6 189546_s_at homeobox domain
F22A3.5 190371_at homeobox domain
F42G2.6 181119_s_at homeobox domain
F45C12.15 186689_s_at homeobox domain
K02F3.8 181123_at homeobox domain
lin-39 189637_at homeobox domain
M6.3 189007_at homeobox domain
mab-18 194012_s_at homeobox domain
mab-5 173387_at, 176579_s_at homeobox domain
mls-2 173754_at, 189498_s_at, 182023_at homeobox domain
nob-1 191468_s_at homeobox domain
pal-1 193341_at, 193342_s_at homeobox domain
pax-1 192418_at homeobox domain
pax-3 193866_at homeobox domain
php-3 191509_at homeobox domain
R04A9.5 193949_s_at homeobox domain
R06F6.6 189665_at homeobox domain
T13C5.4 189464_at homeobox domain
tab-1 189979_at homeobox domain
ttx-1 186833_s_at homeobox domain
unc-39 192928_at homeobox domain
unc-4 193581_at homeobox domain
unc-42 191585_at homeobox domain
vab-7 193846_at homeobox domain
Y38E10A.6 171992_x_at, 186209_s_at homeobox domain
Y80D3A.3 182349_s_at homeobox domain
zag-1 193363_at homeobox domain
ceh-20 177324_s_at homeobox domain, cofactor
ceh-21 190942_at homeobox domain, CUT
ceh-38 189668_at homeobox domain, CUT
ceh-39 174323_at homeobox domain, CUT
ceh-44 176483_at, 176499_at homeobox domain, CUT
ZK1193.5 185625_at homeobox domain, CUT
egl-13 188167_s_at, 193037_s_at homeobox domain, HMG
sox-2 191681_at homeobox domain, HMG
C25G4.4 188729_at homeobox domain, HMG, SAND domain
eat-1 174122_s_at, 188775_s_at homeobox domain, LIM
vab-15 192609_at homeobox domain, MSH
K03A11.5 180454_s_at homeobox domain, Nkx2
cog-1 189136_at homeobox domain, Nkx6.1
R08B4.2 192223_at homeobox domain, Paired domain
unc-30 174442_s_at, 193622_at homeobox domain, Paired domain
Y53C12C.1 192900_at homeobox domain, Paired domain
egl-38 193140_at homeobox domain, Paired domain
vab-3 194012_s_at homeobox domain, Paired domain
ceh-18 187890_at homeobox domain, POU
unc-86 187875_s_at homeobox domain, POU
unc-62 192045_s_at homeobox domain, TALE
B0496.7 181555_at LIM domain
B0496.8 189866_s_at LIM domain
C26C6.6 188741_at LIM domain
C28H8.6 189207_at LIM domain
C34B2.4 181869_at LIM domain
F20D12.5 184796_s_at LIM domain
F25H5.1 180879_at, 193411_s_at, 193324_at, 181484_s_at, 181483_at LIM domain
F28F5.3 181521_at LIM domain
F33D11.1 188952_at LIM domain
F42H10.4 176229_at LIM domain
lim-4 191102_at LIM domain
lim-6 187894_at LIM domain
lim-7 191686_at LIM domain
lin-11 194088_at LIM domain
ltd-1 188644_at LIM domain
mec-3 194097_s_at LIM domain
ttx-3 172067_x_at, 194096_s_at LIM domain
unc-115 190640_s_at LIM domain
unc-95 176968_s_at LIM domain
unc-97 193526_s_at LIM domain
Y1A5A.1 193268_at LIM domain
Y57G11A.1 192213_s_at LIM domain
Y57G11A.3 192211_at LIM domain
Y65B4A.7 176112_at, 176123_at LIM domain
ZK381.5 180400_at, 181271_s_at LIM domain
ZK622.4 187981_at LIM domain
zyx-1 192073_at LIM domain
pin-2 189051_at LIM domain (Focal adhesion protein PINCH-1)
B0379.4a 193257_at, 178388_at LIM domain, (basal component)
grh-1 186593_at LSF/GRH-like
unc-120 188706_at MADS box
mef-2 190718_s_at MADS-box
dpy-22 187986_s_at, 173764_at mediator
sur-2 172005_x_at, 190922_s_at mediator
Y62F5A.1 172520_x_at, 185066_s_at mediator
F58H1.2 179510_at Metencephalon-mesencephalon-olfactorystra- nscription factor 1
C50F4.12 183467_at Mitochondrial transcription termination factor, mTERF
egl-27 188531_s_at, 188530_at, 187748_s_at, 175679_at Myb-like DNA binding, GATA Zn finger
K11H12.8 184428_at, 184429_s_at Myb-related
F40F9.7 190650_at NC2-like transcriptional repressor
R11H6.5 190505_at NFAT-like
C13C4.1 194101_at NHR
C14C6.4 190050_at NHR
C17A2.1 190255_s_at NHR
C25E10.1 192196_at NHR
C26B2.4 190868_at NHR
C33G8.10 190253_at NHR
C33G8.12 191187_at NHR
C33G8.7 190077_at NHR
C33G8.8 190084_at NHR
C41G6.5 192406_at NHR
C49D10.9 190255_s_at NHR
C50B6.8 194133_at NHR
C54E10.5 192526_at NHR
dpr-1 192538_at NHR
F16B4.1 190004_at NHR
F16B4.11 190260_at NHR
F16H9.2 194105_at NHR
F38H12.3 191042_at NHR
F41D3.3 192456_at NHR
F44A2.4 190088_at NHR
F44E7.8 189031_at NHR
F47C10.1 186434_at NHR
F47C10.3 191031_at NHR
F47C10.4 185749_at NHR
F47C10.7 185192_at NHR
F47C10.8 191126_at NHR
F59E11.10 190380_at NHR
F59E11.11 1872090_at NHR
fax-1 175757_s_at NHR
M02H5.5 176016_at NHR
nhr-1 192168_at NHR
nhr-10 191884_s_at NHR
nhr-100 194112_at NHR
nhr-101 172572_x_at NHR
nhr-102 173975_s_at NHR
nhr-103 190850_at NHR
nhr-104 190875_at NHR
nhr-105 189902_at NHR
nhr-106 189964_at NHR
nhr-107 191205_s_at NHR
nhr-108 192601_s_at NHR
nhr-109 175463_at, 182895_at NHR
nhr-11 174023_at, 192634_at NHR
nhr-110 188585_at, 188586_s_at NHR
nhr-111 192431_at NHR
nhr-112 173159_s_at NHR
nhr-113 192511_s_at NHR
nhr-114 177144_at NHR
nhr-115 189980_at NHR
nhr-116 190812_at NHR
nhr-117 190287_at NHR
nhr-118 189855_at NHR
nhr-119 187893_s_at, 190018_at, 176194_at NHR
nhr-12 193687_at NHR
nhr-120 180497_at NHR
nhr-121 181125_at NHR
nhr-122 176072_at NHR
nhr-123 175973_at NHR
nhr-124 190854_at NHR
nhr-125 182971_at NHR
nhr-126 188808_at NHR
nhr-127 192488_at NHR
nhr-128 189920_at NHR
nhr-129 194133_at NHR
nhr-13 176625_at NHR
nhr-130 190001_at NHR
nhr-131 189948_at NHR
nhr-132 190237_at NHR
nhr-133 189999_at NHR
nhr-134 190842_at NHR
nhr-135 177337_at NHR
nhr-136 194102_at NHR
nhr-137 185968_at NHR

Gene Affy probe set Description
nhr-138 NHR
nhr-14 193175_at NHR
nhr-15 192935_at NHR
nhr-16 190172_at NHR
nhr-17 192635_at NHR
nhr-18 192777_at NHR
nhr-19 193637_at NHR
nhr-2 193015_s_at NHR
nhr-20 193638_s_at NHR
nhr-21 194090_s_at NHR
nhr-22 193245_s_at NHR
nhr-23 194130_s_at NHR
nhr-25 193001_s_at NHR
nhr-28 173241_at NHR
nhr-3 193679_s_at NHR
nhr-31 192541_s_at NHR
nhr-32 192460_at NHR
nhr-34 174018_at, 193049_at NHR
nhr-35 190373_at NHR
nhr-38 193582_at NHR
nhr-4 194123_s_at NHR
nhr-40 175720_at, 194035_s_at NHR
nhr-41 176582_at, 186589_at NHR
nhr-42 192603_at NHR
nhr-43 193483_at NHR
nhr-44 192173_s_at NHR
nhr-45 193486_at NHR
nhr-46 192835_at NHR
nhr-47 192271_s_at NHR
nhr-48 193671_at NHR
nhr-49 194120_at NHR
nhr-5 188223_at NHR
nhr-50 172035_x_at NHR
nhr-51 193556_at NHR
nhr-52 193670_at NHR
nhr-53 193701_s_at NHR
nhr-54 193559_s_at NHR
nhr-55 192136_at NHR
nhr-56 192231_at NHR
nhr-57 192189_at NHR
nhr-58 192282_at NHR
nhr-59 172034_x_at, 172722_x_at NHR
nhr-6 194121_s_at NHR
nhr-60 194128_s_at NHR
nhr-61 193603_s_at NHR
nhr-62 192819_at NHR
nhr-63 193566_at NHR
nhr-64 193768_at NHR
nhr-65 173003_s_at, 193567_at NHR
nhr-66 192260_at NHR
nhr-67 192717_at NHR
nhr-68 192782_at NHR
nhr-69 194132_at NHR
nhr-7 192920_s_at NHR
nhr-70 193658_at NHR
nhr-71 193513_s_at NHR
nhr-72 192209_at NHR
nhr-73 192748_s_at NHR
nhr-74 192640_at, 192641_s_at NHR
nhr-75 192291_at NHR
nhr-76 182867_at, 192270_at NHR
nhr-77 193530_at NHR
nhr-78 188348_at NHR
nhr-79 193540_s_at NHR
nhr-8 193749_at NHR
nhr-80 190236_s_at, 191574_at NHR
nhr-81 193507_at NHR
nhr-82 193508_at NHR
nhr-83 192858_at NHR
nhr-84 193542_at NHR
nhr-85 193753_at NHR
nhr-86 176830_s_at NHR
nhr-87 176042_s_at NHR
nhr-88 189858_at, 190898_at NHR
nhr-89 193577_at NHR
nhr-9 188454_at NHR
nhr-90 189961_at NHR
nhr-91 193433_at NHR
nhr-92 174019_s_at, 176050_at NHR
nhr-94 184113_at NHR
nhr-95 183502_at NHR
nhr-96 187786_at NHR
nhr-97 194122_at NHR
nhr-98 175979_at NHR
nhr-99 176003_at NHR
R11G11.12 190367_at NHR
R13D11.8 185889_at NHR
sex-1 172940_x_at, 188033_s_at, 171736_x_at NHR
T01G6.5 189965_at NHR
T01G6.6 191004_at NHR
T03E6.3 189871_at NHR
T09D3.4 190944_at NHR
Y116A8C.18 186548_at NHR
Y17D7A.1 192543_at NHR
Y17D7B.1 192565_s_at NHR
Y22F5A.1 192564_at NHR
Y41D4B.21 176108_at NHR
Y54F10AM.1 176503_at NHR
Y80D3A.4 182290_at NHR
ZK455.6 192466_at NHR
ZK488.4 189947_at NHR
ZK697.2 190022_at NHR
lin-14 193913_s_at novel nuclear protein
unc-3 193538_s_at HLH
F21A10.2 180693_at p53-like
Y51H4A.19 184538_s_at p53-like
pax-2 192273_at homeobox domain, Paired domain
C28H8.9 187205_at PHD-finger
C36C5.13 185704_at PHD-finger
C44B9.4 193372_at PHD-finger
F17A2.3 188658_at PHD-finger
lin-49 175774_at, 192161_s_at PHD-finger
lin-59 188202_s_at PHD-finger
phf-5   PHD-finger
T06A10.4 174921_s_at, 186168_at PHD-finger
T23B12.1 185082_at PHD-finger
Y51H1A.4 188811_s_at PHD-finger
Y51H4A.12 184300_s_at PHD-finger
Y53G8AR.2 174165_at, 187052_at PHD-finger
ZC132.2 179825_at PHD-finger
K04C1.2 182794_s_at Polycomb-group
mes-2 190261_s_at Polycomb-group
mes-6 187971_at Polycomb-group
sop-2 185770_at, 186277_at Polycomb-group
mix-1 173070_s_at, 193889_at possible T.F.
T12A7.6 175158_s_at possible T.F.
arx-6 187615_at possible T.F., ARp2/3 complex component
cdk-9 193890_s_at P-TEF-b component
lin-35 188392_s_at RB-like
daf-19 190486_s_at RFX
lin-41 187703_s_at RING finger
C36E8.1 186636_s_at RNA polymerase I transcription factor
C15H11.8 192503_at RNA polymerase I transcription factor TFIIS
icd-1 174688_at, 192927_s_at RNA polymerase II BTF3 (basal component)
Y73B3A.8 175882_at RNA polymerase II subunit 9
R03D7.4 186827_s_at RNA polymerase II transcription elongation factor
spt-5 193747_s_at RNA polymerase II transcription elongation factor DSIF/SUPT5H/SPT5
pqn-51 185179_s_at RNA polymerase II transcription initiation factor TFIIA, large chain
T16H12.4 174400_s_at RNA polymerase II transcription initiation TFIIH
ZK1128.4 180510_s_at RNA polymerase II transcription initiation TFIIH, subunit TFB4
ZK856.13 189860_s_at RNA polymerase III transcription factor TFIIIC
C01B12.2 186210_at SAND domain
C44F1.2 188653_at SAND domain
T21B10.5 192141_at SET domain
dac-1 189843_at SKI/SNO domain
elc-1 192714_at SKP1 component
daf-14 175659_at, 190867_s_at SMAD
daf-3 188906_s_at SMAD
daf-8   SMAD
R05D11.1 188788_at SMAD
Y113G7B.14 187096_at SNF2-related
R07E5.3 175088_at, 188857_at SWI/SNF
taf-11.2 192267_at TAFII28-like protein
Y37E11B.2 186683_at TATA binding factor
mab-9 192729_at T-box
mls-1 186222_at T-box
tbx-11 187486_at T-box
tbx-18 185577_s_at T-box
tbx-2 188633_at T-box
tbx-30 186686_s_at T-box
tbx-31 182311_at T-box
tbx-32 188373_at, 188374_s_at T-box
tbx-33 176669_at T-box
tbx-34 186275_s_at T-box
tbx-35 187661_at T-box
tbx-36 178364_at T-box
tbx-37 186121_at T-box
tbx-38 188023_at T-box
tbx-39 184577_at T-box
tbx-40 184249_at, 184250_s_at T-box
tbx-41 189631_at T-box
tbx-7 188450_at T-box
tbx-8 190477_at T-box
tbx-9 190539_s_at T-box
Y59E9AR.5   T-box
taf-5 193468_at TBP-associated T.F.
taf-6.1 188098_s_at TBP-associated T.F.
taf-7.1 188233_at TBP-associated T.F.
taf-8   TBP-associated T.F.
egl-44 193230_at TEA/ATTS domain
Y73F8A.24 184394_s_at Tfb2 T.F.
B0336.13 176733_at TFIIA, (basal component)
taf-10 188274_at TFIID
taf-13 190935_at TFIID
tbp-1 188606_at TFIID
tlf-1 187785_s_at, 193370_s_at, 193369_at TFIID
taf-4 174570_s_at, 187952_at TFIID component
taf-9 178055_at TFIID; TAFII-31
cdk-7 172068_x_at, 176484_s_at TFIIH complex (basal component)
brf-1 193633_s_at TFIIIB (basal component)
Y77E11A.6 186842_at TFIIS
Y97E10AR.5 176591_s_at TFIIS
F10D7.4 180109_at Transcription elongation factor (basal component)
F59E12.9 185204_s_at Transcription elongation factor S-II, central region
sqt-4 188021_at Transcription elongation factor SPT4
T24H10.1 191738_at Transcription elongation factor TFIIS
Y51B9A.5 182001_at Transcription factor 21-related motif
Y38E10A.1 185362_at Transcription factor Sp3
C25H3.6 175492_at Transcription factor TFIIS elongin A-like
Y38F2AR.13 176361_at Transcription factorsIIIC-alpha subunit
Y38F2AR.5 176179_at, 176323_at Transcription factorsIIIC-alpha subunit
Y111B2A.13 193715_at Transcription initiation factor IIA, gamma subunit
F54D5.11 193310_s_at Transcription initiation factor IIE, beta subunit
C01F1.1 190074_s_at, 173313_s_at Transcription initiation factor IIF, alpha subunit
Y39B6A.36 183088_at Transcription initiation factor IIF, small subunit (RAP30)
ttb-1 172103_x_at, 192210_at Transcription initiation factor TFIIB
Y56A3A.4 183864_s_at transcription initiation factor TFIID 20/15 kDa subunits
taf-1 193610_s_at Transcription initiation factor TFIID, subunit TAF1
taf-12 183864_s_at Transcription initiation factor TFIID, subunit TAF12
F01G4.1 174598_s_at trithorax family
sdc-2 173447_s_at X chromosome transcription repressor
eor-1 189910_s_at Zn finger
eor-2 177725_at Zn finger
F22D6.2 179366_at Zn finger
arc-1 194111_at Zn-finger
asc-1 184727_s_at Zn-finger
C03G6.12 191749_at Zn-finger
C06E1.8 176000_at Zn-finger
C09F5.3 187378_at Zn-finger
C28G1.6 192344_at Zn-finger
C38D4.7 178513_at Zn-finger
C55C2.1 192307_at Zn-finger
ces-1 192612_at Zn-finger
che-1 188612_at Zn-finger
D1046.2 189843_at Zn-finger
daf-12 187714_at, 192797_s_at Zn-finger
dpy-20 191799_at Zn-finger
egl-43 193452_at Zn-finger
egl-46 192272_at Zn-finger
egl-9 187973_s_at Zn-finger
F33E11.2 174322_s_at, 184231_at Zn-finger
F36F12.8 190224_at Zn-finger
F45H11.1 190574_at Zn-finger
F47H4.1 173993_s_at Zn-finger
F53B3.1 182205_s_at Zn-finger
F53B3.1 182204_at Zn-finger
F53F8.1 192448_at Zn-finger
F56F11.3 190273_at Zn-finger
ham-2 190176_at Zn-finger
hbl-1 192791_s_at Zn-finger
K01H12.1 180815_at Zn-finger
K11D2.4 192478_at Zn-finger
lin-13 189214_s_at Zn-finger
lin-26 190309_at Zn-finger
lin-28 172855_x_at, 191973_s_at Zn-finger
lin-29 193019_s_at Zn-finger
lin-36 172020_x_at, 176610_s_at Zn-finger
lin-48 175830_at, 192611_s_at Zn-finger
lir-1 176605_s_at Zn-finger
lir-2 193382_at Zn-finger
lir-3 192263_s_at Zn-finger
mex-1 194039_s_at Zn-finger
mex-5 193943_at Zn-finger
mex-6 192002_at Zn-finger
mua-1 186941_at Zn-finger
ncl-1 176869_s_at Zn-finger
nhl-2 184111_s_at Zn-finger
nhl-3 175228_at, 190138_at Zn-finger
odd-1 187380_at Zn-finger
oma-1 189867_s_at Zn-finger
oma-2 173110_at Zn-finger
pag-3 193449_at Zn-finger
pie-1 175605_s_at Zn-finger
pos-1 175810_at, 192079_s_at Zn-finger
pqm-1 192333_at Zn-finger
R02E12.4 193931_at Zn-finger
R06C7.9 175549_s_at Zn-finger
R08E3.4 190402_at Zn-finger
ref-2 190155_at Zn-finger
sdc-1 174953_s_at, 193642_at Zn-finger
sdc-3 192294_s_at Zn-finger
sem-4 175707_s_at, 193521_s_at Zn-finger
spr-3 190210_at Zn-finger
spr-4 192576_s_at Zn-finger
T05G11.1 192021_at Zn-finger
T10B11.9 185854_s_at Zn-finger
T22C8.5 192372_at Zn-finger
tlp-1 187904_at Zn-finger
tra-1 175693_at, 188843_s_at, 175694_s_at Zn-finger
unc-55 192833_at Zn-finger
unc-98 188814_s_at Zn-finger
Y37E11B.1 175198_at, 190343_at, 175531_s_at Zn-finger
Y40B1A.4 190543_at Zn-finger
Y53H1A.2 182098_at Zn-finger
Y55F3AM.7 186536_at Zn-finger
Y5F2A.4 192396_at Zn-finger
Y66D12A.12   Zn-finger
Y6G8.3 192301_at Zn-finger
Y75B8A.6 179697_at Zn-finger
ZC328.2 189940_at Zn-finger
ZK1240.1 186412_at Zn-finger
ZK1240.3 185446_at Zn-finger
ZK1240.8 186272_at Zn-finger
ZK337.2 192490_at Zn-finger
ZK856.9 174049_s_at Zn-finger
ZK867.1 188821_at Zn-finger
ZK945.5 188263_at Zn-finger
F56F3.4 189303_at Zn-finger, AN1-like
C16A3.7 193714_at Zn-finger, RING domain
let-418 189004_at Zn-finger, RING domain, PHD finger
ZC123.3 189909_at Zn-finger; homeobox domain
F19B2.6 178024_at  
pha-4 193963_s_at  

The goal in studying transcription is to make the link between transcription factors and their target genes. For a small number of genes in C. elegans, this connection has been made and a chart showing some of these is presented in Table 2. Notice that most transcription factors have been defined as either activators or repressors. However, for some, both modes of action have been described highlighting the importance of co-factors and promoter context within chromatin in determining the transcriptional outcome of DNA binding by these proteins. The list of potential target genes for several transcription factors will explode over the coming years with the application of microarray methods. However, most of these will not be specifically tested to determine if the regulation is direct and which cis-acting elements mediate the effect.

Table 2. Transcription factor target genes

Class Number of genes Factor type Factor Partner Activat- or Repress- or Putative target genes DNA binding sequence References
Homeo- domain 83               Ruvkun and Hobert, 1998
    HOX LIN-39 CEH-20 YES Possible hlh-8, egl-17, egl-18/ elt-5, elt-6, possible direct repressor of eff-1 TGATTAAT (G/T) (G/A) Cui and Han, 2003; Koh et al., 2002; Liu and Fire, 2000; Shemer and Podbilewicz, 2002
    Paired- like CEH-10 TTX-3 YES N.D. ceh-23 and 38 other AIY terminal genes AATTGG (C/T) TT (A/C) (G/A) TTA (G/A) Wenick and Hobert, 2004
      UNC-4 UNC-37   YES VB motor neuron genes TAATY-NR- ATTA Winnier et al., 1999
      UNC-30 N.D. YES N.D. unc-25, unc-47 TAATCC Eastman et al., 1999; Jin et al., 1994
      EGL-38 N.D. YES N.D. lin-48 TGNNG-CG- TGAC (C/G) Johnson et al., 2001
    Even- skipped VAB-7 N.D. N.D. YES unc-4 (may be indirect) N.D. Esmaeili et al., 2002
    LIM TTX-3 CEH-10 YES N.D. ceh-23 and 38 other AIY terminal genes AATTGG (C/T) TT (A/C) (G/A) TTA (G/A) Wenick and Hobert, 2004
      MEC-3 UNC-86 YES N.D. mec-4, mec-7; see also UNC-86 CATNNNN- AATGCAT Duggan et al., 1998; Way and Chalfie, 1988
    POU UNC-86 MEC-3 YES N.D. mec-3, 50 plus candidate genes from screen; snap-25 CATNNNN- AATGCAT Zhang et al., 2002; Hwang and Lee, 2003
    Zn-Fing- er CHE-1 N.D. YES N.D. cog-1, ceh-36, gcy-5 other undefined ASE genes N.D. Chang et al., 2003
    NK Class CEH-22 N.D. YES N.D. myo-1, myo-2 (B element) TNNAGTG Okkema and Fire, 1994; Okkema et al., 1997
    EXD CEH-20 LIN-39, UNC-62 (genetic evidence only) YES N.D. hlh-8 TGATTAAT Liu and Fire, 2000; Van Auken et al., 2002
Zn-Fing- er                  
    GATA ELT-1 N.D. YES N.D. msp-113 AAGATAA, AGATCT Shim, 1999; Shim et al., 1995
      ELT-2 N.D. YES N.D. ges-1, pho-1, mtl-1, mtl-2 WGATAR Egan et al., 1995; Fukushige et al., 1998; Moilanen et al., 1999
      END-1 N.D. YES N.D. elt-2 GATA Fukushige et al., 1998; Shoichet et al., 2000
      MED-1, MED-2 N.D. YES N.D. end-1, end-2 GATA Maduro et al., 2001; Maduro and Rothman, 2002; JHR unpublished
    SAL SEM-4 N.D. N.D. YES elg-5, mec-3 ACACAA Toker et al., 2003
    Snail CES-1 N.D. N.D. YES egl-1 CACCTG Thellmann et al., 2003
    Gli TRA-1A N.D. N.D. YES egl-1, mab-3 TGTGAGG- TC Zarkower and Hodgkin, 1993; Conradt and Horvitz, 1999; Yi et al., 2000
    DM domain MAB-3 N.D. N.D. YES vit-2 (probably all vits) AATGTTG- CGA (T/A) NT Yi and Zarkower, 1999
    O/E UNC-3 PAG-3? YES Possible acr-2 (indirect activator?) N.D. Prasad et al., 1998
    GFI PAG-3 UNC-3? N.D. YES pag-3 TAAATCAC (A/T) GCA McDermott and Aamodt, unpublished; Zweidler-Mckay et al., 1996
      LIN-29 N.D YES N.D. col-19 N.D. Rougvie and Ambros, 1995
NHR 284               Maglich et al., 2001
    FTZ-F1 NHR-25 N.D. YES N.D. lin-3 TCAGGGT- CA Hwang and Sternberg, 2004
    ROR/ RZR NHR-23 N.D. YES N.D. dpy-7? AGGTCAN- NNNNAG- GTCA Kostrouchova et al., 1998; Kostrouchova et al., 2001
    Vit D DAF-12 N.D. YES YES ceh-22, myo-2, many others CA(C/G)AC (A/G); AGT- GCANNNN- NAGTGCA Ao et al., 2004; Shostak et al., 2004
bHLH 39               Ledent et al., 2002
    MyoD HLH-1 HLH-1 YES N.D. N.D. CAGCTG Krause et al., 1992; Blackwell et al., 1994
    E/Daug- hterless HLH-2 HLH-2; HLH-3; LIN-32 YES N.D. lin-3, lag-2 CACCTG Hwang and Sternberg, 2004; Karp and Greenwald, 2003
    Achaete- scute HLH-3 HLH-2 YES N.D. egl-1 CACCTG Krause et al., 1997; Thellmann et al., 2003
    Twist HLH-8 HLH-8, HLH-2 YES N.D. ceh-24, egl-15, mls-1 CATATG; CAGGTG Corsi et al., 2000; Harfe and Fire, 1998; Harfe et al., 1998; Kostas and Fire, 2002
    Atonal LIN-32 HLH-2 YES N.D. N.D.; several genes identified that respond to overexpressi- on CACGTG Portman and Emmons, 2004
bZIP 19               Ruvkun and Hobert, 1998
    Cap'n' Collar SKN-1 N.D. YES N.D. med-1, med-2, end-1?, gcs-1 WWTRTC- AT An and Blackwell, 2003; Blackwell et al., 1994; Carroll et al., 1997; Maduro et al., 2001; Walker et al., 2000
Forkhe- ad 15               Hope et al., 2003
    FOXO DAF-16 N.D. YES YES microarray TTGTTTAC Furuyama et al., 2000; Lee et al., 2003; McElwee et al., 2003
      PHA-4 PEB-1 YES N.D. myo-2 (C element) TGTTTGC Gaudet and Mango, 2002; Kalb et al., 1998; Okkema and Fire, 1994; Vilimas et al., 2004
      UNC-1- 30 N.D. N.D. YES unc-129 WTRTTNN- NNY Nash et al., 2000
ETS 10               Hart et al., 2000
      LIN-1 N.D. N.D. N.D. N.D. GGA (A/T) (core only; ACCGGAA- GTAA was in oligo tested) Miley et al., 2004
T-box 20               Pocock et al., 2004
      TBX-30 N.D. N.D. YES vab-7 GGTGTGAA Pocock et al., 2004
Others   CSL LAG-1 N.D. YES N.D. lin-12, glp-1 RTGGGAA Christensen et al., 1996
    NOVEL PEB-1 PHA-4 YES N.D. myo-2 (C element) TGCCGT Beaster-Jones and Okkema, 2004; Thatcher et al., 2001
    ARID CFI-1 N.D. Possible Possible N.D. (some gfp reporters respond although could be indirect) TCAATTA- AATGA Shaham and Bargmann, 2002
    AHR AHR-1 AHA-1 YES N.D. N.D. TGCGTG Powell-Coffman et al., 1998
    LSF/Gr- ainyhead GRH-1 N.D. N.D. N.D. binds promoter element for dbl-1, mab-5, pcn-1 (A/T) CNGGTTT Venkatesan et al., 2003
    co-SM- AD DAF-3 N.D. N.D. YES myo-2 (C element) GTCTG Thatcher et al., 1999
    MADS Box MEF-2 had-7 N.D. N.D. N.D. CTAAAAA- TA Choi et al., 2002; Dichoso et al., 2000

7. Spatial specificity

Spatial specificity refers to a pattern of gene expression that is limited to one or a few organs, tissues, or cell types. Examples of control mechanisms governing these types of spatial restriction are presented to show the logic underlying these patterns. Our current understanding shows that spatial specificity can be achieved by multiple mechanisms, ranging from the combinatorial action of overlapping transcription factors to transcriptional cascades.

7.1. Organ specificity: control of pharyngeal gene expression by a master regulator

The C. elegans pharynx is a complex organ consisting of five very different cell types, including muscles, neurons, epithelia, glands and marginal cells (Albertson and Thomson, 1976). The pharynx initially forms as a primordium of undifferentiated cells around mid-embryogenesis, and these cells subsequently differentiate and express cell type-specific genes (Sulston et al., 1983).

Formation of the pharynx and differentiation of all pharyngeal cell types depends on a single FoxA family transcription factor PHA-4 (Horner et al., 1998; Kalb et al., 1998; Mango et al., 1994). PHA-4 is expressed in all pharyngeal cells beginning at the time these cells become committed to a pharyngeal cell fate, as well as in the hindgut and intestine (Horner et al., 1998; Kalb et al., 1998). PHA-4 is believed to directly regulate most or all genes specifically expressed in the pharynx, including both early genes specifying fate of different pharyngeal cell types and late genes expressed during terminal differentiation (Gaudet and Mango, 2002). A major question in understanding pharyngeal development is how does PHA-4 regulate genes expressed in different pharyngeal cell types and at different times in pharyngeal development.

The function of PHA-4 in cell-type specific differentiation is best understood in the pharyngeal muscles. As discussed above, PHA-4 functions with the pharyngeal muscle-specific homeodomain factor CEH-22 to activate myo-2 expression during muscle cell differentiation (Kalb et al., 1998; Okkema and Fire, 1994). PHA-4 and CEH-22 similarly target a late functioning auto-regulatory enhancer from ceh-22 itself (Gaudet and Mango, 2002; Kuchenthal et al., 2001), suggesting these factors function together to control many regulatory sequences that function during terminal differentiation of the pharyngeal muscles. Earlier in pharyngeal muscle development, PHA-4 is also required for the initiation of ceh-22 expression (Mango et al., 1994; Vilimas et al., 2004), but the mechanism by which PHA-4 initially activates ceh-22 in the pharyngeal muscles remains unknown.

Less is known of how PHA-4 regulates specific gene expression in other pharyngeal cell types, largely because other pharyngeal specific promoters have not been extensively characterized. This situation, however, appears soon to be changed based on pioneering microarray studies that have identified >300 genes preferentially expressed in the pharynx (Ao et al., 2004; Gaudet and Mango, 2002). Analyses of these genes' known expression patterns, in situ hybridization patterns, and placement on the Gene Expression Topo Map have identified clusters of genes expressed preferentially in subsets of pharyngeal cells, and comparisons of the promoters of genes within these clusters have identified conserved regulatory elements that likely impart positional or cell type specificity to PHA-4 target genes (Ao et al., 2004).

PHA-4 also regulates genes in temporally distinct patterns in the pharynx. This temporal regulation may involve both the affinity of PHA-4 for its binding sites in various gene promoters (Gaudet and Mango, 2002), and the presence of binding sites for additional factors functioning with PHA-4 (Gaudet et al., 2004). These mechanisms are likely not mutually exclusive and may be interdependent, as additional factors could affect PHA-4 binding affinity by cooperative binding.

7.2. Tissue specificity: regulation of gut gene expression by a cascade of redundant GATA factors.

The E blastomere is the clonal precursor of the gut, and the maternal factors specifying E blastomere identity are well understood. One effect of these maternal factors is to initiate zygotic gene expression, including expression of a series of sequentially functioning GATA family transcription factors expressed exclusively in the gut lineage (reviewed in Maduro and Rothman, 2002; Figure 4). These GATA factors bind WGATAR motifs required in many gut specific genes and directly activate gut gene expression (e.g., Britton et al., 1998; Egan et al., 1995; MacMorris et al., 1992; Nam et al., 2002)


 figure 4

Figure 4. Sequentially functioning GATA factors regulate gut gene expression. Genetic pathway indicating genes encoding gut-specific GATA factors and the terminal differentiation gene ges-1, the stage at which their expression begins, and the proposed function of these genes in promoting gut differentiation. An arrow indicates an autoregulatory mechanism that maintains elt-2 expression.

The first of these gut-specific GATA factors is END-1, which is expressed transiently in the E lineage, beginning in the E cell itself and continuing until approximately the 8E stage (Figure 4; Zhu et al., 1997). ELT-2 is then expressed one cell division later, beginning at the 2 E-cell stage (Fukushige et al., 1998). elt-2 expression is activated by END-1 (Zhu et al., 1998), but, unlike end-1, elt-2 remains expressed in the gut throughout the life of the worm through an autoregulatory mechanism (Fukushige et al., 1998; Fukushige et al., 1999). Interestingly, both end-1 and elt-2 appear to be members of redundant gene families. While ectopic expression of either of these genes activates widespread gut differentiation, loss-of-function studies reveal surprisingly mild defects in gut gene expression (Fukushige et al., 1998; Zhu et al., 1998; Zhu et al., 1997). Indeed, end-1 loss-of-function produces no phenotype. In comparison, elt-2 loss produces gut defects and lethality, while the effect on gene expression varies from promoter to promoter (Fukushige et al., 2005; Fukushige et al., 1998; Oskouian et al., 2005). In both cases, the likely suspects for redundant genes encode additional GATA factors. end-1 may be redundant with the linked gene end-3, while elt-2 may be partially redundant with elt-7 (Maduro and Rothman, 2002). Thus, end-1 and end-3 are believed to establish endoderm fate in the E lineage, while elt-2 and elt-7 are likely the direct regulators of most genes expressed in the gut (Figure 4).

While most gut-specific promoters contain WGATAR motifs, their accurate regulation depends on more than simply turning on ELT-2. Gut genes are expressed under distinct temporal, sex-specific, and environmental controls, indicating other factors must contribute to gut gene regulation. In the case of the vit-2 gene, which encodes a yolk protein expressed only in the gut of adult hermaphrodites, repression in males requires the MAB-3 DM-domain protein (Yi and Zarkower, 1999). Likewise, ges-1, which encodes a gut-specific esterase, is activated in the gut by ELT-2 while being repressed in other regions of the digestive system by an unknown factor binding near the WGATAR motifs (Fukushige et al., 1996; Marshall and McGhee, 2001). In most cases, the identity of factors functioning with ELT-2 remain unknown, and there remains much to be learned about gut transcription.

7.3. Cell type specificity: regulation of AIY neuronal expression by a single core motif

Cell type specificity of gene expression is best exemplified by studies of neuronal gene expression (for example Chang et al., 2004; Zhang et al., 2004). Hobert and colleagues have studied the mechanism that regulates gene expression in a single pair of bilateral interneurons in the head called AIY left and right (AIYL & AIYR) that function in sensory input processing, learning, and memory (Ishihara et al., 2002; Mori and Ohshima, 1995; Tsalik et al., 2003). Differentiation of these interneurons is dependent on the transcription factors ceh-10 (Paired homeobox) and ttx-3 (LIM homeobox; Altun-Gultekin et al., 2001). Analysis of several promoters of genes expressed in AIY, including ceh-10 and ttx-3, revealed a consensus 16 bp AIY motif responsible for proper expression and comprising the core of an element that functions as an AIY-specific enhancer (Wenick and Hobert, 2004). This enhancer element is active in combination with some non-neuronal cell type promoters but not others demonstrating that promoter context is an important aspect of transcriptional regulation. Both ceh-10 and ttx-3 are part of an autoregulatory loop that activates their own expression, explaining the presence of an AIY motif within each of their promoters.

Control of AIY gene expression by ceh-10 and ttx-3 provides some insight into the logic of cell type-specific gene regulation (Wenick and Hobert, 2004). Cell type specificity is generated by using a combination of transcription factors that are unique to AIY interneurons in concert with a modular AIY response element upstream of target genes. Although some of the identified ceh-10/ttx-3 target genes were AIY specific, others were generally expressed in neurons or non-neuronal tissues. However, in most cases, expression in AIY was dependent on the AIY motif demonstrating that widespread expression may often be the composite action of several cell type-specific cis-acting elements. Finally, cis-acting control of gene targets encoding terminal differentiation products in AIY appeared to lack repressive elements. This suggests that the integration of positive and negative signals influencing cell type specificity is carried out by upstream transcription factors, ceh-10 and ttx-3 in this case. Once these upstream factors are activated, the downstream target gene battery will ensue largely independent of other influences.

8. Future

There is little doubt that the field of transcriptional regulation is on the verge of an information explosion. The combination of genome sequences from multiple Caenorhabditis species, microarray transcriptional profiling, and improved methodology will soon lead to a wealth of information on transcriptional activators and downstream target genes. One challenge will be the experimental verification of the mountains of data that will become available about upstream activators and downstream targets. Can these relationships be confirmed by independent approaches and are the interactions direct or indirect? We are entering an age in which the connections between most trans-acting factors and cis-acting regulatory target elements will be defined. Understanding how these connections regulate development will add an exciting chapter in the study of the worm and for transcriptional regulation in general.

9. Acknowledgements

This research was supported in part by the Intramural Research Program of the NIH, National Institute of Diabetes, Digestive and Kidney Diseases, and by grants from the NIH (GM053996) and the American Heart Association (03505487).

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*Edited by Thomas Blumenthal. Last revised April 12, 2005. Published December 23, 2005. This chapter should be cited as: Okkema, P. G. and Krause, M. Transcriptional regulation (December 23, 2005), WormBook, ed. The C. elegans Research Community, WormBook, doi/10.1895/wormbook.1.45.1, http://www.wormbook.org.

Copyright: © 2005 Peter G. Okkema and Michael Krause, This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

§To whom correspondence should be addressed. E-mail: okkema@uic.edu or mwkrause@helix.nih.gov

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