Transcriptional regulation of gene expression in C. elegans

Abstract

Protein coding gene sequences are converted to mRNA by the highly regulated process of transcription. The precise temporal and spatial control of transcription for many genes is an essential part of development in metazoans. Thus, understanding the molecular mechanisms underlying transcriptional control is essential to understanding cell fate determination during embryogenesis, post-embryonic development, many environmental interactions, and disease-related processes. Studies of transcriptional regulation in C. elegans exploit its genomic simplicity and physical characteristics to define regulatory events with single-cell and minute-time-scale resolution. When combined with the genetics of the system, C. elegans offers a unique and powerful vantage point from which to study how chromatin-associated proteins and their modifications interact with transcription factors and their binding sites to yield precise control of gene expression through transcriptional regulation.

Figure 1. A hypothetical RNAPII elongation megacomplex

RNAPII (including the extended CTD with SerPO4 knobs) is purple; the globular and CTD portions are drawn approximately to scale for mammalian RNAPII. Orange DNA is wrapped around yellow nucleosomal histones; nucleosomes modified by Set2 are shaded darker. The nascent RNA transcript is green. Yeast names are used for PCAPs (e.g., Phatnani and Greenleaf, 2006; PMID 17079683), not all of which are shown. (CBC) cap-binding complex; (CRF) chromatin remodeling factor; (XF) processing/export factor. (Used with permission Phatnani and Greenleaf, 2006; PMID 17079683)

Figure 2. Metazoan regulatory modules controlling transcription

Shown is a diagram of a typical metazoan gene illustrating the complex interactions among cis-acting modules and trans-acting factors regulating gene expression. Note that both positive and negative control regions are interspersed with promoter modules, all of which can be further influenced by distal regions regulating chromatin configuration, such as insulators. (Used with permission Levine and Tjian, 2003; PMID 12853946)

Figure 3. Core promoter motif composition among Caenorhabditis promoters

Motif composition of the Caenorhabditis core promoter. (A) Five conserved motifs in each of the five examined Caenorhabditis species are shown as sequence logos. (*) In contrast to all other motifs that were found in the initial search, the Caenorhabditis japonica TATA box motif was detected only in sequences whose orthologs contained the “TATA” motif. (B) Distribution of motifs relative to the translational start codon. The gray box in each plot corresponds to the core promoter. The area under the curve is the total frequency of occurrence within the core promoter region with the line indicating the frequency at each position as indicated by the scale to the left. The C. japonica SL1 motif was normalized to the length of the other species. (C) Frequency table for each sequence motif. (Figure and data used with permission Grishkevich et al., 2011; PMID 21367940)

Figure 4. C. elegans transcription factor genes with clear orthologs in the human genome

The percentage of C. elegans genes from each DNA-binding domain family with clear orthologs in the human genome (Reece-Hoyes et al., 2005; PMID 16420670; Shaye and Greenwald, 2011; PMID 21647448). Only DNA-binding domain families with 3 or more C. elegans members are included.

Figure 5. Automated analyses of transcription factor gene expression

(A–D) Representative frames showing expression of mCherry reporters for the indicated transcription factors (red) ovelayed on ubiquitous histone::gfp reporter expression marking all nuclei. Anterior is left. (E) Embryonic lineage trees showing expression of the indicated transcription factor::mCherry transgenes (colored), or a merged image showing expression of all four transgenes. This data was acquired and visualized using StarryNite and AceTree (Murray et al., 2008; PMID 18587405). Panels A–D were acquired from movies at http://epic.gs.washington.edu/. Panel E was adapted with permission from Murray et al., 2008; PMID 18587405.

Figure 6. Examples of ChIP-chip data for RNA polymerase II (Pol II) and five different histone modifications

The X axis represents a stretch of Chr IV from nt 12,341,610 to 12,472,625. Coding genes are shown below, with arrows marking the direction of transcription 5'>3'. The Y axis represents the z-score of the log 2 ratios of IP/Input (mean centered and scaled to stdev=1). Note the opposing pattern of H3K27me, a mark associated with gene silencing, with that of activation marks such as H3K4me and H3K36me. Image courtesy of Susan Strome and Andreas Rechsteiner.

Figure 7. Outline of genes in each group of the SynMuv pathway

SynMuv A and SynMuv B are the major groups in this pathway that are redundantly required for vulval development. The relationship of these pathways with the SynMuv C pathway are less clear. Within the SynMuv B group, LIN-53, marked with an asterisk, is listed twice, as it is found in both NuRD and DRM complexes.