SETDB1 dependent H3K9me3/H3K36me3 dual chromatin regulate cell differentiation by restricting enhancers

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Cellular identity is conferred by specific gene expression profiles that are regulated by transcription factors and chromatin. Combination of specific histone modifications characterize gene activity. Active genes typically display an enrichment in histone H3 lysine 4 trimethylation (H3K4me3) at their promoters, whereas SET Domain 2 (SETD2) trimethylates histone H3 lysine 36 (H3K36me3) in their gene bodies. Chromatin signatures of gene silencing are more complex. A large subset of developmentally silenced genes is targeted by proteins of the Polycomb group and usually harbor histone H3 lysine 27 trimethylation (H3K27me3). Other silent genes harbor no typical histone modification, or an enrichment in histone H3 lysine 9 trimethylation (H3K9me3). SET Domain Bifurcated 1 (SETDB1) is responsible for H3K9 trimethylation on genes and endogenous retroviruses. Knocking-out Setdb1 results in early embryonic lethality. Moreover, SETDB1 loss in differentiated cells leads to aberrant lineage specific gene reactivation, showing that SETDB1 is important for development through the maintenance of appropriate cellular identity. Recently, an atypical SETDB1 chromatin has been identified at mouse ES telomeres or on the 3’end of a subset of zinc finger genes in human cancer cells. Enriched in apparently opposing histone marks (H3K9me3 and H3K36me3) the function of this dual chromatin, if any, has not yet been elucidated.

We identified almost 5000 loci harboring H3K9me3 and H3K36me3 on the same nucleosome in mouse ESCs. These dual domains are SETDB1-dependent and NSD dependent, but only partially SETD2 dependent, for H3K9me3 and H3K36me3 respectively. H3K9me3/H3K36me3 dual domains are located on future enhancers to restrict their gene activating functions. Distinct subsets of H3K9me3/H3K36me3 dual domains in ESC become enhancers in distinct tissues. Based on our data, we propose that dual H3K9me3/H3K36me3 helps to maintain stemness.

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