Omics-based discovery reveals new functions of the transcription factor CEH-60/PBX in C. elegans

Transcription factors govern genetic regulation of most physiological processes in multicellular organisms, including reproduction. An important aspect of reproduction is maternal provisioning, in which parents provide resources to their offspring. Vitellogenesis or yolk protein production drives the supply of energy-rich nutrients to offspring. Transcription from vitellogenin genes is tightly regulated by a network of transcription factors, which allows time- and site-specific expression. In the nematode Caenorhabditis elegans, one of the most potent regulators of vitellogenesis described to date is CEH-60, ortholog of the TALE homeobox transcription factor PBX in vertebrates, but little is known about its mode of action. In this thesis, I provide evidence for the spatiotemporally defined interaction of two evolutionarily conserved TALE homeobox transcription factors, CEH‑60 and UNC-62, acting as a gateway to yolk protein production. I show that this interaction occurs in the intestine of animals at the onset of sexual maturity and suffices to support the reproductive program, elucidating the mode of action of CEH-60. I also tackle a long-standing question regarding the function of yolk proteins, showing that - while not necessary for embryonic development in C. elegans per se - abundant yolk does provide an evolutionary advantage to offspring. Because CEH-60's closest paralogs, as well as its here revealed in vivo interaction partner UNC-62 and their vertebrate homologs PBX and MEIS, show myriad other developmental functions, I sought to expand the scope of CEH-60's function through a double omics approach. I used differential proteomics to find changes in protein levels and DamID to identify direct gene targets of CEH-60. This combined omics approach suggests new functions for CEH-60 in neuronal development and muscle structure, as well as cuticle permeability, for which the lipid-rich epicuticle is causative. The discovery that PBX's interaction with MEIS can be extended to C. elegans CEH-60 and UNC-62, as well as the discovery of several new processes in which CEH-60 plays a role, open up new research questions in other organisms as well. This study highlights the importance of unbiased approaches, and shows that well-studied protein families, such as PBX and MEIS, still harbor hidden functions.status: publishe