CHARACTERIZATION OF THE PR-DOMAIN PROTEIN PRDM15: ROLE IN DEVELOPMENT AND CANCER

Abstract

Members of the PR domain containing family of proteins (PRDMs) have, lately, emerged as master regulators of key cellular processes. Several PRDM proteins play important roles during development and cell fate decisions, through regulation of multiple epigenetic mechanisms. Here, we investigate the role of PRDM15, a previously uncharacterized member of this family, in both settings. We first derived mouse Embryonic Stem Cells (mESCs) in which we could induce PRDM15 depletion (Rosa26 CRE-ERT2), and characterize a fundamental role for PRDM15 in regulating ESCs homeostasis, self-renewal and cell fate decisions. At the molecular level, we established a comprehensive transcriptional map for PRDM15 in mESCs and demonstrate a direct regulation of Nodal/Activin and WNT/ß-Catenin signallings, two major developmental pathways. Then we relied on Knockout mouse models to demonstrate that PRDM15 is essential during mammalian development, but not in the postnatal life. Deletion of PRDM15 induces severe brain defects during early developmental stages and hence embryonic lethality.