Pairing of competitive and topologically distinct regulatory modules enhances patterned gene expression

Abstract

Biological networks are inherently modular, yet little is known about how modules are assembled to enable coordinated and complex functions. We used RNAi and time series, whole-genome microarray analyses to systematically perturb and characterize components of a Caenorhabditis elegans lineage-specific transcriptional regulatory network. These data are supported by selected reporter gene analyses and comprehensive yeast one-hybrid and promoter sequence analyses. Based on these results, we define and characterize two modules composed of muscle-and epidermal-specifying transcription factors that function together within a single cell lineage to robustly specify multiple cell types. The expression of these two modules, although positively regulated by a common factor, is reliably segregated among daughter cells. Our analyses indicate that these modules repress each other, and we propose that this cross-inhibition coupled with their relative time of induction function to enhance the initial asymmetry in their expression patterns, thus leading to the observed invariant gene expression patterns and cell lineage. The coupling of asynchronous and topologically distinct modules may be a general principle of module assembly that functions to potentiate genetic switches.

Gene transcription is coordinated with, but not dependent on, cell divisions during C. elegans embryonic fate specification

“…Clonal commitment to the body wall muscle fate occurs in the D lineage from its birth, in the C lineage at the 4C stage, and in the MS lineage approximately at the 16MS stage (Sulston et al, 1983). In the C lineage, muscle versus epidermal clonal commitment at the 4C stage is thought to occur by the activity of POP-1 in response to an anterior-posterior Wnt signaling gradient (Sugioka et al, 2011;Yanai et al, 2008). Our data shows substantial unc-120 mRNA accumulation in div-1 mutants before even the 2C→4C (Fig.…”

Caudal-like PAL-1 directly activates the bodywall muscle module regulator hlh-1 in C. elegans to initiate the embryonic muscle gene regulatory network

“…Both HLH-1 and UNC-120 are detectable within posterior, PAL-1-positive muscle lineages within 60 minutes of somatic lineage establishment (Fukushige et al, 2006). Similarly, expression array analysis reveals that ectopically expressed pal-1 in early embryos results in the activation of both hlh-1 and unc-120 within 2 hours (Fukushige and Krause, 2005), and that both genes are temporally downstream of PAL-1 activity in wild-type development (Baugh et al, 2005a;Baugh et al, 2005b;Yanai et al, 2008). Thus, PAL-1 sits at the top of a hierarchy of gene function in posterior embryonic bodywall muscle development, although the molecular details of this transcriptional cascade remain unknown.…”

“…In the presence of high nuclear POP-1, PAL-1 drives hypodermal (skin) cell fate, whereas in the presence of low or absent POP-1, PAL-1 directs bodywall muscle development (Baugh et al, 2005a;Fukushige and Krause, 2005). In the case of myogenesis, PAL-1 is required genetically to activate key transcriptional regulators of myogenesis, including HLH-1/MRF and UNC-120/SRF (Baugh et al, 2005a;Baugh et al, 2005b;Fukushige et al, 2006;Yanai et al, 2008).…”

Collaborative Regulation of Development but Independent Control of Metabolism by Two Epidermis-specific Transcription Factors in Caenorhabditis elegans

“…A loss of function mutation in elt-1 produced excess neurons and muscle cells at the expense of epidermis, whereas ectopic expression of ELT-1 in early embryonic cells was sufficient to convert the entire embryo into epidermis (5). Transcription of elt-1 is dependent on a caudal-like maternal protein, PAL-1, in C lineage (6,7), whereas its upstream regulators in AB have not been identified. Functional genomic analysis combined with RNAi identified another two epidermis-specific transcription factors, NHR-25 and ELT-3, as its direct targets (7).…”