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. 2024 Dec;26(12):2115-2128.
doi: 10.1038/s41556-024-01547-z. Epub 2024 Oct 31.

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

Jingchao Zhang  1   2   3 , Greg Donahue  1   2   3 , Michael B Gilbert  2   4 , Tomer Lapidot  5   6 , Dario Nicetto  1   2   3 , Kenneth S Zaret  7   8   9
Affiliations

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

Jingchao Zhang et al. Nat Cell Biol. 2024 Dec.

Abstract

H3K9me3 heterochromatin, established by lysine methyltransferases (KMTs) and compacted by heterochromatin protein 1 (HP1) isoforms, represses alternative lineage genes and DNA repeats. Our understanding of H3K9me3 heterochromatin stability is presently limited to individual domains and DNA repeats. Here we engineered Suv39h2-knockout mouse embryonic stem cells to degrade remaining two H3K9me3 KMTs within 1 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 KMT depletion and a particular threshold level of HP1 limiting pioneer factor binding, chromatin opening and exit from pluripotency within 12 h. Unexpectedly, receding H3K9me3 domains unearth residual HP1β 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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Conflict of interest statement

Competing interests: The authors declare no competing interests.

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