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Abstract
An open and decondensed chromatin organization is a defining property of pluripotency. Several epigenetic regulators have been implicated in maintaining an open chromatin organization, but how these processes are connected to the pluripotency network is unknown. Here, we identified a new role for the transcription factor NANOG as a key regulator connecting the pluripotency network with constitutive heterochromatin organization in mouse embryonic stem cells. Deletion of Nanog leads to chromatin compaction and the remodeling of heterochromatin domains. Forced expression of NANOG in epiblast stem cells is sufficient to decompact chromatin. NANOG associates with satellite repeats within heterochromatin domains, contributing to an architecture characterized by highly dispersed chromatin fibers, low levels of H3K9me3, and high major satellite transcription, and the strong transactivation domain of NANOG is required for this organization. The heterochromatin-associated protein SALL1 is a direct cofactor for NANOG, and loss of Sall1 recapitulates the Nanog-null phenotype, but the loss of Sall1 can be circumvented through direct recruitment of the NANOG transactivation domain to major satellites. These results establish a direct connection between the pluripotency network and chromatin organization and emphasize that maintaining an open heterochromatin architecture is a highly regulated process in embryonic stem cells.
Highlights
The genome of eukaryotic cells is organized into euchromatin, which is generally permissive for gene transcription and activation, and heterochromatin, which is largely gene-poor
NANOG regulates heterochromatin in ESCs ery into distinct heterochromatin domains (Fig. 1A). These data were supported by the increased density of heterochromatin fibers in Nanog–/– ESCs compared with wild-type ESCs (Fig. 1B)
The altered heterochromatin organization observed in Nanog–/– ESCs could be rescued by restoring NANOG levels with a transgene (Fig. 1B,C; Supplemental Fig. S1D–F)
Summary
The genome of eukaryotic cells is organized into euchromatin, which is generally permissive for gene transcription and activation, and heterochromatin, which is largely gene-poor. Deletion of epigenetic regulators (including Suv39h1/2 and Dicer) in mouse somatic cells perturbs PCH identity, causes the transcriptional upregulation of major satellite sequences, and is associated with severe chromosome missegregation phenotypes (Peters et al 2001; Kanellopoulou et al 2005). Deletion of Suv39h1/2 and Dicer in ESCs can lead to increased major satellite transcription, as in somatic cells; the downstream response is different because the transcriptional up-regulation does not cause chromosome missegregation in ESCs (Peters et al 2001; Kanellopoulou et al 2005) These findings raise the possibility that ESCs can tolerate or perhaps even require a unique PCH identity and suggest the existence of key functional differences in heterochromatin regulation between pluripotent and somatic cells
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