About
VIROLOGY DEPARTMENT SEMINAR
Prof. Alexander GIMELBRANT
Dana-Farber Cancer Institute
Harvard Medical School
Broad Institute of Harvard and MIT
“Mechanism of epigenetic variability in clonal cell lineages”
Mercredi 6 Novembre 2019 à 14h00
Auditorium du Centre François Jacob
Invited by: Dr Yves Jacob (yves.jacob@pasteur.fr)
Institut Pasteur – 28, rue du Dr. Roux – 75724 PARIS CEDEX 15
Abstract:
“In mammals, otherwise similar cells from distinct clonal lineages can maintain striking epigenetic differences, with profound impact on transcription and cell function. Inactivation of one copy of the X chromosome in female cells is the best understood example of such epigenetic mosaicism. Autosomal monoallelic expression (MAE) is another common example, with different clonal lineages maintaining distinct states of allele-specific expression. Despite its prevalence, no molecular mechanisms underlying MAE have been identified to date. We developed and applied a new screening-by-sequencing strategy to identify mechanism of mitotic memory of MAE in clonal mouse cells. Contrary to previous reports, DNA methylation plays key role in mitotic memory of MAE in multiple autosomal loci.
Building on this finding, we performed the first genome-wide analysis of changes in allele-specific gene-regulatory landscape in response to chemical perturbation. Unexpectedly, genome-wide changes were not limited to relaxation of MAE towards equal biallelic expression. Many genes showed paradoxical increase of allelic imbalance, even though it relaxed for DNA methylation and chromatin accessibility. These unexpected observations are explained by comparative analysis of multiple clonal lines, revealing a previously unappreciated interplay of genetic regulatory architecture with epigenetic control of allele-specific expression.”