Final Report Summary - CELLREPROGRAMMING (Uncovering the Mechanisms of Epigenetic Reprogramming of Pluripotent and Somatic Cell States)
The ERC-StG grant has allowed us to make numerous seminal discoveries in the field of pluripotency and epigenetic-reprogramming including: (i) Identifying the role of several molecular regulators of pluripotency maintenance, induction and resolution like: Utx, C/EBPα, Gatad2a-Mbd3-NuRD complex and m6A mRNA methylation. Our research on Utx highlighted the connection between iPSC reprogramming and in vivo primordial germ cell (PGC) development. Our work on m6A methylation provided the first evidence for the importance of an mRNA epigenetic modification during in vivo development. (ii) We have uncovered interconvertability of murine naive and primed pluripotent states and epigenetic repressors opposingly regulating them. (iii) We have descirbed the first derivation of transgene-dependent and -independent human naïve pluripotent cells, with distinct functional and regulatory properties. These findings are revolutionizing the human pluripotency field and bare dramatic influence on cross-species molecular analysis of pluripotency. (v)v The latter discovery also enabled the first in vitro generation of PGCs from human iPSCs. Not stopping there, we have uncovered species-specific transcriptional regulators of PGC induction (SOX17) differing between human and mice. This authentic PGC differentiation platform is also being used for biochemical dissection of human in vitro reprogramming and toward advancing novel infertility treatments. Collectively, our ERC supported findings have facilitated deeper understanding of reprogramming mechanisms and established exacting platforms for enhanced utilization of pluripotent cells in basic and applied molecular research.