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Unique cell cycle-dependent variations in the pluripotent epigenetic landscape define novel cohorts of temporal expressed bivalent genes during hESCs differentiation

ABSTRACT: By mapping the genomic enrichments of H3K4me3 and H3K27me3 modifications in pure populations of hESCs during the G2, mitotic and G1 phases of the cell cycle, we characterize cell cycle-dependent variations in the epigenetic landscape of bivalent genes, altering the current view of mitotic inheritance in pluripotent cells. We identified novel classes of bivalent domains that are highly enriched with H3K4me3 during mitosis, depleted during G1 only, and ubiquitously bivalent. These bivalent domains are associated with specific genes and expression patterns during differentiation. These cell cycle-dependent epigenetic profiles are unique to hESCs and are not observed following initiation of phenotype commitment. Our results establish a new dimension in cell cycle-dependent chromatin regulation that advances understanding of contributions the pluripotent epigenetic landscape to hESC identity.

ORGANISM(S): Homo sapiens

PROVIDER: GSE55502 | GEO | 2015/12/23

SECONDARY ACCESSION(S): PRJNA239803

REPOSITORIES: GEO

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Project description:Epigenetic priming factors establish a permissive epigenetic landscape which is not required until a later developmental or physiological time point, temporally uncoupling the presence of these factors with their phenotypic effects. One classic example of epigenetic priming is in the context of bivalent chromatin, found in pluripotent stem cells and early embryos at key developmental gene promoters marked by both activating-associated H3K4me3 and repressive-associated H3K27me3 histone modifications. It is currently unknown how these bivalent domains are targeted, or precisely how they impact on lineage commitment. Here we show that the small heterodimerising non-enzymatic DNA binding proteins Developmental Pluripotency Associated 2 (Dppa2) and 4 (Dppa4) act as epigenetic priming factors to establish bivalency at a subset of developmental genes. Dppa2/4 localise to the +1 nucleosome position of bivalent genes and while they are not required for pluripotency in embryonic stem cells (ESCs), double knockout cells fail to exit pluripotency and to differentiate efficiently, with delays in upregulating bivalently marked lineage genes. Proteomics reveal that Dppa2/4 interact on chromatin with members of the COMPASS and Polycomb complexes important for H3K4me3 and H3K27me3 deposition, respectively. Epigenetic profiling reveals a striking loss of H3K4me3, H3K27me3, and their associated enzymatic machinery at a significant subset of bivalent promoters in Dppa2/4 mutants, in addition to loss of H2A.Z and chromatin accessibility. In wild-type ESCs, these “Dppa2/4-dependent” bivalent promoters are characterised by low H3K4me3 enrichment and breadth, near-absent expression levels and initiating but not elongating RNA polymerase. Notably, Dppa2/4-dependent promoters are less evolutionarily conserved suggesting that they lack additional safeguard measures to maintain bivalency at these genes in the absence of Dppa2/4. Concomitantly with the loss of bivalency, Dppa2/4-dependent bivalent promoters gain DNA methylation and consequently are no longer able to be effectively activated upon ESC differentiation, leading to defects in cell fate acquisition. Our findings reveal a targeting principle for bivalency to developmental gene promoters poising them for future lineage specific gene activation.

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Unique cell cycle-dependent variations in the pluripotent epigenetic landscape define novel cohorts of temporal expressed bivalent genes during hESCs differentiation

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