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Histone modifications and SP1 balance Pol II recruitment at bivalent promoters during gastrulation

ABSTRACT: Progressive activation of bivalent genes is crucial for promoting cell differentiation and embryonic development. However, the mechanisms governing RNA polymerase II recruitment at bivalent promoters remain poorly understood. Here, we unveiled the dynamic landscape of Pol II in mouse post-implantation embryos. Our findings indicated that imprinting genes are selectively activated in embryonic and extra-embryonic lineages. Pseudotranscribed genes exhibit significant dynamism across embryonic germ layers, with transcriptional events preceding substantial mRNA production. The recruitment of Pol II to bivalent promoters is synergistically regulated by KMT2B/H3K4me3, EED/H3K27me3, and SP1 in a dose-dependent manner. Specifically, the absence of H3K4me3 and SP1 reduces Pol II recruitment at promoters, while the loss of H3K27me3 increases Pol II occupancy and derepresses developmental gene expression. Our in vivo study not only elucidated the mechanism of Pol II recruitment at bivalent promoters in mammals, but also provided a valuable framework for exploring gene regulation mechanisms in disease contexts.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE269652 | GEO | 2026/03/19

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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Histone modifications and SP1 balance Pol II recruitment at bivalent promoters during gastrulation

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