Robustness and plasticity in the Caenorhabditis elegans endoderm gene regulatory network

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. 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. 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 97 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. Hence, our findings reveal the basis for the extensive genetic redundancy in the regulatory circuitry for endoderm development, as well as the remarkable plasticity in the GRN even within a single species.