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Dynamic association of H3K36me3 with pericentromeric heterochromatin promotes its transcription to regulate replication timing
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2025-06-13
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The flexibility of the spatio-temporal genome replication program during development and disease highlights the regulatory role of plastic epigenetic mechanisms over genetic determinants. Histone post-translational modifications have been broadly implicated in replication timing control, yet the specific mechanisms through which individual histone marks influence replication dynamics, particularly in heterochromatin, remain unclear. Here, we demonstrate the dynamic enrichment of H3K36me3 at pericentromeric heterochromatin (PCHs) consisting of major satellite (MajSat) repeats preceding replication during the S II sub-phase in mouse embryonic stem cells. Through the knock down of lysine 36 specific methyltransferases or targeted introduction of oncohistone to PCHs, we reduced both global or local H3K36me3 levels, respectively, revealing its essential role in preserving the replication timing of constitutive heterochromatin. Loss of H3K36me3 was accompanied by increased RNA polymerase II serine-5 phosphorylation but reduced MajSat RNA levels, indicating transcriptional dysregulation. Notably, we identify a strand-specific contribution of MajSat forward transcripts in regulating the replication timing of PCHs and maintaining chromatin stability, highlighting the importance of non-coding RNAs as critical regulators of replication timing.
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Except where otherwise noted, this license is described as CC-BY-NC 4.0 - Attribution-NonCommercial 4.0 International
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| Version | Date | Summary |
|---|---|---|
| 2025-06-13 11:18:01 | Dynamic association of H3K36me3 with pericentromeric heterochromatin promotes its transcription to regulate replication timing through major satellite RNA | |
2* | 2025-06-12 15:52:15 | Dynamic association of H3K36me3 with pericentromeric heterochromatin promotes its transcription to regulate replication timing through major satellite RNA |
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