Discovery and Characterization of the Polycomb Repressive Complex 1 of C. Elegans




Karakuzu, Ozgur

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unc-3 encodes the Caenorhabditis elegans homolog of the Olf-1/Early B cell factor family of transcription factors, which in vertebrates regulate development and differentiation of B lymphocytes, adipocytes, and cells of the nervous system. In the first chapter I analyze the role of unc-3 in determining the fates of neurons in ventral nerve cord (VNC). unc-3 mutants are uncoordinated in locomotion. I show that unc-3 represses a VC-like motor neuron program in the VA and VB motor neurons, which in wild-type animals control backwards and forwards locomotion, respectively. Our lab identified a physical interaction between UNC-3 and the C2H2 zinc finger transcription factor PAG-3, the mammalian homologs of which are coexpressed in olfactory epithelium and hematopoietic cells. Our data explain the locomotory defects of unc-3 mutants and suggest that interactions between unc-3 and pag-3 homologs in other species may be functionally important. The second chapter of the thesis is about the analysis of MIG-32 a RING protein similar to some Polycomb proteins that were identified in a yeast two hybrid screen with UNC-3 as bait. The Polycomb repression complex 2 (PRC2) methylates histone H3 lysine 27 at target genes to modify gene expression, and this mark is recognized by PRC1, which ubiquitylates histone H2A. In Caenorhabditis elegans, a complex of the MES-2, MES-3, and MES-6 proteins is functionally analogous to the PRC2 complex, but the functional analog of PRC1, and indeed whether C. elegans has such a complex, has been unclear. I describe here that MIG-32 is a homolog of BMI-1, a core component of PRC1. I also identify SPAT-3A as a homolog of Ring1B, a partner protein of BMI-1 in the PRC1 core complex. Mig-32 and spat-3 mutants have some defects that overlap with those of mes mutants. However, unlike the mes mutants, mig-32 and spat-3 mutants are fertile, despite lacking apparent H2A ubiquitylation. Migration and axon guidance of specific neurons were defective in mig-32 and spat-3 mutants. Our data suggest that mig-32 and spat-3 encode core components of a PRC1-like complex in C. elegans.

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