Abstract
Caenorhabditis elegans is a powerful model for studying gene regulation, as it has a compact genome and a wealth of genomic tools. However, identification of regulatory elements has been limited, as DNA-binding motifs are known for only 71 of the estimated 763 sequence-specific transcription factors (TFs). To address this problem, we performed protein binding microarray experiments on representatives of canonical TF families in C. elegans, obtaining motifs for 129 TFs. Additionally, we predict motifs for many TFs that have DNA-binding domains similar to those already characterized, increasing coverage of binding specificities to 292 C. elegans TFs (∼40%). These data highlight the diversification of binding motifs for the nuclear hormone receptor and C2H2 zinc finger families and reveal unexpected diversity of motifs for T-box and DM families. Motif enrichment in promoters of functionally related genes is consistent with known biology and also identifies putative regulatory roles for unstudied TFs.
Highlights
Transcription factors (TF) are sequence-specific DNA binding proteins that control gene expression, often regulating specific biological processes such as pluripotency and differentiation (Takahashi and Yamanaka 2006), tissue patterning (Lemons and McGinnis 2006), the cell cycle (Evan et al 1994), metabolic pathways (Blanchet et al 2011), and responses to environmental stimuli (Benizri et al 2008)
The key goal of this project was to expand our knowledge of DNA sequence specificities of C. 108 elegans TFs. To do this we analyzed a diverse set of TF DNA-binding domains (DBDs) with Protein Binding Microarrays (PBMs) assays (Berger et al 2006; Weirauch et al 2014)
It is believed that identity in the recognition helix corresponds to identity in sequence preference (Van Gilst et al 2002); surprisingly, we found that TFs with identical RH sequences can bind very different DNA sequences
Summary
Transcription factors (TF) are sequence-specific DNA binding proteins that control gene expression, often regulating specific biological processes such as pluripotency and differentiation (Takahashi and Yamanaka 2006), tissue patterning (Lemons and McGinnis 2006), the cell cycle (Evan et al 1994), metabolic pathways (Blanchet et al 2011), and responses to environmental stimuli (Benizri et al 2008). C. elegans contains major expansions of several specific TF families, with Nuclear Hormone Receptor (NHR), Cys2His (C2H2) zinc finger, homeodomain, bHLH, bZIP, and T-box together comprising 74% of the TF repertoire (Reece-Hoyes et al 2005; Haerty et al 2008). The lineage-specific expansion of C2H2 zinc finger TFs is similar to that observed in many animals, including diversification of DNA-contacting “specificity residues”, suggesting diversification in DNA binding specificity (Stubbs et al 2011). Extensive variation in the DNA-contacting recognition helix or “P-box” suggests that C. elegans NHRs, like C2H2 and bHLH families, have diversified DNA sequence specificities, and that many will recognize novel motifs (Van Gilst et al 2002). Four have known binding motifs, and unlike most other TFs, T-box binding motifs are virtually identical across the metazoa (Sebe Pedros et al 2013; Weirauch et al 2014); the diversification of TFs is often associated with changes in DNA sequence specificity, and alteration in protein-protein interactions and expression of the TF gene itself (Grove et al 2009; Reece-Hoyes et al 2013)
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