Abstract
BackgroundPluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew. These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Recently, several chromatin-related proteins have been shown to regulate ESC pluripotency and/or differentiation, yet the role of the major heterochromatin proteins in pluripotency is unknown.ResultsHere we identify Heterochromatin Protein 1β (HP1β) as an essential protein for proper differentiation, and, unexpectedly, for the maintenance of pluripotency in ESCs. In pluripotent and differentiated cells HP1β is differentially localized and differentially associated with chromatin. Deletion of HP1β, but not HP1α, in ESCs provokes a loss of the morphological and proliferative characteristics of embryonic pluripotent cells, reduces expression of pluripotency factors and causes aberrant differentiation. However, in differentiated cells, loss of HP1β has the opposite effect, perturbing maintenance of the differentiation state and facilitating reprogramming to an induced pluripotent state. Microscopy, biochemical fractionation and chromatin immunoprecipitation reveal a diffuse nucleoplasmic distribution, weak association with chromatin and high expression levels for HP1β in ESCs. The minor fraction of HP1β that is chromatin-bound in ESCs is enriched within exons, unlike the situation in differentiated cells, where it binds heterochromatic satellite repeats and chromocenters.ConclusionsWe demonstrate an unexpected duality in the role of HP1β: it is essential in ESCs for maintaining pluripotency, while it is required for proper differentiation in differentiated cells. Thus, HP1β function both depends on, and regulates, the pluripotent state.Electronic supplementary materialThe online version of this article (doi:10.1186/s13059-015-0760-8) contains supplementary material, which is available to authorized users.
Highlights
Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew
Heterochromatin Protein 1β (HP1β), but not HP1α, is essential to maintain pluripotency and cell proliferation in ESCs In order to determine whether HP1α and/or HP1β isoforms have any role in stem cell pluripotency and early differentiation, we took advantage of the recently generated HP1α−/− and HP1β−/− knockout (KO) mice and of the derived pluripotent ESCs, the differentiated embryoid bodies (EBs), and the mouse embryonic fibroblast (MEF) cells from these KO strains [34, 52]
To explore whether HP1α or HP1β has a specific function in pluripotent/undifferentiated cells, we analyzed the morphology of HP1α−/− and HP1β−/− ESCs, their cell growth, and differentiation potential compared with their wild-type (WT) counterparts at identical passages under identical conditions
Summary
Pluripotent embryonic stem cells (ESCs) have the unique ability to differentiate into every cell type and to self-renew These characteristics correlate with a distinct nuclear architecture, epigenetic signatures enriched for active chromatin marks and hyperdynamic binding of structural chromatin proteins. Embryonic stem cells (ESCs), derived from the blastocyststage embryo, are capable of generating all cell types of the mammalian body (pluripotency) and of maintaining the capacity for indefinite self-renewal without compromising their genomic integrity. This unique duality makes them an attractive system for potential regenerative medicine and cell therapies, and for differentiation studies in vitro and for modeling diseases. Condensed heterochromatin, which can be observed by both light and electron microscopy, is less frequently observed [16,17,18], and Heterochromatin Protein 1 (HP1)α-enriched heterochromatin foci are less compact and less numerous in ESCs [2, 13]
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