Seminar "Epigenetic regulation of imprinted gene expression in mammals.” by Prof. Robert Feil

Title：Epigenetic regulation of imprinted gene expression in mammals.

Speaker：Robert Feil, Institute of Molecular Genetics (IGMM), CNRS and the University of Montpellier, France.

Abstract:
Genomic imprinting is an important epigenetic phenomenon that induces mono-allelic gene expression that is entirely parent-of-origin dependent. It evolved independently in insects, plants and mammals, for different biological reasons. In eutherian mammals, imprinted genes play diverse roles in development, homeostasis and behavior. They are clustered in large chromosomal domains that are controlled by parental DNA methylation imprints at ‘differentially methylated regions’ (DMRs). Almost all imprinted domains express one or more long non-coding RNAs (lncRNAs), whose precise functions remain often unknown. In humans, (epi)genetic deregulation of imprinted gene expression causes complex congenital diseases (‘imprinting disorders’), and is often observed in cancer as well. Our laboratory has explored the somatic maintenance of allelic DNA methylation at DMRs –a process which is linked to specific chromatin features– and how these epigenetic marks mediate imprinted gene expression during development. In my presentation I will focus on our recent studies on the developmental, disease-associated Dlk1-Dio3 domain on mouse chromosome 12. At this conserved, disease-associated imprinted domain, a paternally-methylated intergenic DMR activates a large ncRNA polycistron on the maternal chromosome. This, in turn, leads to the repression of developmental genes on the maternal chromosome. Using CRISPR-modified hybrid mouse ES cells (mESCs) as a model system, we found that this cis-regulatory process requires a nuclear lncRNA produced by the polycistron, and also involves repressive histone methylation and CTCF-mediated long-range chromatin interactions. In my talk, I will also present ongoing work on DNA replication timing in mono-parental and hybrid mESCs. We find that at specific imprinted chromosomal domains, there are pronounced replication timing differences between the parental chromosomes. Our replication timing, DNA methylation, 3D chromatin structure and gene expression data highlight how parental methylation imprints and lncRNA control asynchronous replication and can override domain organization. The novel insights from our model systems may help to understand the etiology of human imprinting disorders.