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Hierarchical accumulation of histone variant H2A.Z regulates transcriptional states and histone modifications in early mammalian embryos [ChIP-seq]

ABSTRACT: Early embryos undergo extensive epigenetic reprogramming to achieve gamete-to-embryo transition, which involves the loading and removal of histone variant H2A.Z on chromatin. Although the H2A.Z landscapes in sperm have been investigated, its dynamics during early development remain unrevealed. Here, by using ultra-low-input native chromatin immunoprecipitation and sequencing (ULI-NChIP-seq), we map the genome-wide distribution of H2A.Z in mouse oocytes and early embryos. We find that paternal H2A.Z is removed upon fertilization, followed by unbiased accumulation on parental genomes during zygotic genome activation (ZGA). More importantly, H2A.Z exhibits hierarchical accumulation as different peak types at promoters. We identify that double H2A.Z peaks co-localizes with H3K4me3 and facilitates transcriptional activation, bivalent markers (H3K4me3+H3K27me3) prefer to occupy single H2A.Z peak and inhibits developmental gene expression, while promoters with no H2A.Z accumulation exhibit gene silencing in early embryos. Remarkably, H2A.Z depletion changes the enrichments of histone modifications and RNA polymerase II (Pol II) binding at promoters, resulting in abnormal gene expression and developmental arrest during lineage commitment. Hence, H2A.Z plays dual roles in regulating the epigenomes required for proper gene expression during preimplantation development.

ORGANISM(S): Mus musculus Sus scrofa

PROVIDER: GSE188588 | GEO | 2022/06/24

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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Hierarchical accumulation of histone variant H2A.Z regulates transcriptional states and histone modifications in early mammalian embryos [ChIP-seq]

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