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Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

ABSTRACT: Precise dynamic control of activating H3K4me3 and repressive H3K27me3 histone modifications at bivalent gene promoters is essential for normal development and frequently corrupted in cancer. Using whole genome CRISPR/Cas9 screens we identify specific roles for MTF2-PRC2.1 and PCGF1-PRC1.1 polycomb complexes, and MLL1/2-COMPASS-like complex components in maintaining bivalency. Contrary to expectations, loss of Menin or inhibition of the Menin-MLL1/2 interaction, induces activation of bivalent genes via loss of polycomb-mediated repression and defines distinct roles for MLL1/2 and Menin in gene regulation. Whilst Menin and MLL1/2 contribute to maintenance H3K4me3 at active genes, a separate Menin-independent function of MLL1/2 opposes polycomb mediated repression at bivalent genes. MLL1/2 are essential for basal transcription and, although dispensable for transcription factor driven activation, facilitate transcriptional consistency during dynamic changes in gene expression. This functional partitioning of COMPASS complex components reveals therapeutic opportunities to target oncogenic and immunosuppressive functions of PRC2 through pharmacological inhibition of Menin.

ORGANISM(S): Homo sapiens

PROVIDER: GSE181818 | GEO | 2023/01/13

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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Targeting Menin disrupts the KMT2A/B and polycomb balance to paradoxically activate bivalent genes [CRISPR]

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