Thesis Title: CHARACTERIZATION OF THE PR-DOMAIN PROTEIN
PRDM15: ROLE IN DEVELOPMENT AND CANCER
Supervisor: Ernesto GUCCIONE
Members of the PR domain containing family of proteins (PRDMs) are master regulators of key cellular processes ranging from DNA recombination to transcriptional regulation, both in physiological (development and cell differentiation) and pathological (cancer) conditions. Here, we characterize a poorly studied member of the PRDM family, PRDM15, to uncover its role in mammalian development. We first derived conditional PRDM15 KO mouse Embryonic Stem Cells (mESCs) and characterized a fundamental role for PRDM15 in regulating ESCs homeostasis, self-renewal and cell fate decisions. At the molecular level, using high-throughput technologies (ChiP-seq, RNA-seq and quantitative Mass Spectrometry), we uncover both PRDM15 binding partners and direct transcriptional targets. Overall, our data suggest a role of PRDM15 in transcriptional repression of key pathways regulating early lineage specification (e.g. Wnt and Nodal). Next, we relied on Knockout mouse models to demonstrate that PRDM15 is essential during mammalian development, but not in the postnatal life. Deletion of PRDM15 affects anterior/posterior patterning leading to severe brain defects during early developmental stages, and to embryonic lethality.
Collectively, our findings elucidate an essential role of PRDM15 in mouse development and in ESC homeostasis.
Figure legend: Schematic representation of the transcriptional targets of PRDM15 which are involved in i) regulation of the extended pluripotency network, Blue circles represent transcription factors co-occupying PRDM15 binding sites (e.g. STAT3, KLF4, TCFCP2L1 and ESRRB) ii) regulating key extracellular signaling pathways essential to ensure ESCs pluripotency and self-renewal as well as EMT, Anterior/Posterior patterning and forebrain development.
For more information on Ernesto GUCCIONE’s laboratory, please click here.