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Genetic and epigenetic regulation of a core embryonic gene regulatory network

Abstract

Development is driven by progressive installation of transcriptional programs and complex interactions between genetic factors that constitute gene regulatory networks (GRNs). How are GRNs structured and deployed to avoid frequent catastrophic failure resulting from environmental and genetic variation? How are GRNs modified during evolution to engender Charles Darwin’s "endless forms most beautiful”? In the nematode C. elegans, the SKN-1/Nrf transcription factor activates a GATA transcription factor-driven cascade that modulates specification and differentiation of the endoderm. We found that six GATA factors (MED-1/2, END-1/3, and ELT-2/7) form a recursive series of interlocked feedforward loops to mediate robust lockdown of endodermal cell fate. We further found that the specification-to-differentiation transition is linked through END-1 that straddles the two processes. Further, we uncovered additional role for key GATA factors as transcriptional repressors in establishing spatial gene expression domains that appear to define the boundaries of the digestive tract (Chapter 2). With the molecular details of the endoderm GRN in hand, we subsequently explored the evolutionary diversification of the regulatory network by exploiting natural genetic variation in the C. elegans wild isotypes. Remarkably, we uncovered extensive intraspecies variation in SKN-1 requirement: some isotypes absolutely require SKN-1 during endoderm development, while in others most embryos differentiate endoderm in its absence. We showed that this polymorphism results from accumulation of cryptic genetic variations, including a missense variant in the transcriptional activator Pur-α homolog, PLP-1 (Appendix II). In addition to the genetic plasticity of the GRNs, we found that SKN-1 requirement can be further tuned by a heritable epigenetic effect triggered by nutritional stress. This transgenerational epigenetic inheritance involves Piwi Argonaute, the nuclear RNAi pathway, and H3K9 methyltransferases (Chapter 3). Our results therefore demonstrate that the substantial plasticity in C. elegans endoderm GRN is driven by both genetic and epigenetic mechanisms.

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