The Role of p130/DREAM in Silencing Self-renewal Genes in Post-mitotic Neurons.

Abstract

The recently identified DREAM complex assembles when Rb-like protein (p130, p107) recruits E2F4, DP (dimerization partner) and MuvB (multivulval complex B (Lin9, Lin37, Lin52, Lin54, and RbBp4)) during G0 and quiescence to repress cell cycle-dependent genes. DREAM assembly requires phosphorylation of the MuvB subunit Lin52 mediated by Dyrk1a, a kinase that has been linked to Down syndrome and neurodegenerative diseases. Our lab previously demonstrated an essential role for the Rb-like pocket proteins in the regulation of neural precursor population and that E2F4 is also involved in the regulation of the expression of the pluripotent gene Sox2. Here, we performed in utero electroporation experiments to overexpress the DREAM complex components and assess their roles during neurogenesis. Our results showed that the overexpression of DREAM components (Lin52 and p130) and Dyrk1a promotes commitment to differentiation at the expense of self-renewal. We also showed that Dyrk1a requires p130 or p107 to regulate neurogenesis. Furthermore, using harmine treatment which is an inhibitor of Dyrk1a the kinase that induces DREAM assembly, our results revealed that DREAM regulates the expression of self-renewal markers affecting the cell fate decision. Performing ChIP experiments, we detected a binding enrichment of the DREAM components on the promoters of not only classical cell cycle genes but on the self-renewal genes like Sox2 and EZH2. Taken together, our study confirmed that DREAM complex plays an important role in the cell fate determination during the regulation of neurogenesis through the control of the self-renewal genes.