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bioRxiv · 10.1101/2024.09.16.613328

Distinct H3K9me3 heterochromatin maintenance dynamics govern different gene programs and repeats in pluripotent cells

Zhang, J.·Donahue, G.·Gilbert, M. B.·Lapidot, T.·Nicetto, D.·Zaret, K. S.
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Abstract

H3K9me3-heterochromatin, established by lysine methyltransferases (KMTs) and compacted by HP1 isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3-heterochromatin stability is presently limited to individual domains and DNA repeats. We engineered Suv39h2 KO mouse embryonic stem cells to degrade remaining two H3K9me3- KMTs within one hour and found that both passive dilution and active removal contribute to H3K9me3 decay within 12-24 hours. We discovered four different H3K9me3 decay rates across the genome and chromatin features and transcription factor binding patterns that predict the stability classes. A "binary switch" governs heterochromatin compaction, with HP1 rapidly dissociating from heterochromatin upon KMTs depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening, and exit from pluripotency within 12 hr. Unexpectedly, receding H3K9me3 domains unearth residual HP1{beta} peaks enriched with heterochromatin-inducing proteins. Our findings reveal distinct H3K9me3-heterochromatin maintenance dynamics governing gene networks and repeats that together safeguard pluripotency.

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Zhang, J., Donahue, G., Gilbert, M. B., Lapidot, T., Nicetto, D., Zaret, K. S.. 2024-09-16. Distinct H3K9me3 heterochromatin maintenance dynamics govern different gene programs and repeats in pluripotent cells. https://doi.org/10.1101/2024.09.16.613328

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