The preservation of cell identity depends on the maintenance of gene expression programs through mitosis. Generally, this is mediated by epigenetic systems of repression involving Polycomb proteins and H3K9 and DNA methyltransferases. Pluripotent Embryonic Stem (ES) cells constitute an exception as abrogation of these systems does not lead to detrimental consequences, with defects appearing only during differentiation. This is particularly surprising since ES cells maintain their transcriptome and developmental potential over long periods of frequent divisions. Understanding how ES cells identity is mitotically maintained is the focus of this application.
An unconventional view will be adopted in which the mitotic stability of pluripotency depends on the memory of gene activation (rather than repression). These so-called “bookmarking mechanisms” rely on transcription factors whose binding at specific genomic locations is mitotically stable, preserving and instructing gene activity from mother to daughter cells. The major hypothesis driving this proposal is therefore that memory of active transcription in ES cells is maintained by retention of one or several pluripotency transcription factors on mitotic chromatin. We have identified one such “bookmarking” factor and we propose to study its potential function on the intergenerational maintenance of ES cells identity.
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