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Dynamic association of H3K36me3 with pericentromeric heterochromatin regulates its replication time

S. K. Pradhan,Hui Zhang,Ksenia G Kolobynina,Alexander Rapp,Maria Arroyo,Cristina Cardoso

Published 2025 in EMBO Reports

ABSTRACT

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 are 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 that H3K36me3 dynamically enriches at pericentromeric heterochromatin, composed of major satellite DNA repeats, prior to replication during mid S phase in mouse embryonic stem cells. By knocking down lysine 36-specific methyltransferases or by targeting the H3K36M oncohistone to pericentromeric heterochromatin, we reduce global or local H3K36me3 levels, respectively, revealing its essential role in preserving the replication timing of constitutive heterochromatin. Loss of H3K36me3 accompanies increased RNA polymerase II serine-5 phosphorylation and lowered major satellite RNA levels, indicating transcriptional dysregulation. Notably, we identify a strand-specific contribution of major satellite forward transcripts in regulating the replication timing of constitutive heterochromatin and maintaining chromatin stability, highlighting the importance of non-coding RNAs as critical regulators of replication timing. A dynamic enrichment of H3K36me3 at pericentromeric heterochromatin (PCH) safeguards replication timing in mouse embryonic stem cells. Major satellite RNAs have a strand-specific role in maintaining the replication timing of PCH. H3K36me3 dynamically accumulates at pericentromeric heterochromatin before its replication. Loss of H3K36me3 disrupts replication timing and leads to chromatin instability. H3K36me3 loss leads to transcriptional dysregulation of major satellite RNA. Forward major satellite RNA supports earlier replication of pericentromeric heterochromatin. H3K36me3 dynamically accumulates at pericentromeric heterochromatin before its replication. Loss of H3K36me3 disrupts replication timing and leads to chromatin instability. H3K36me3 loss leads to transcriptional dysregulation of major satellite RNA. Forward major satellite RNA supports earlier replication of pericentromeric heterochromatin. A dynamic enrichment of H3K36me3 at pericentromeric heterochromatin (PCH) safeguards replication timing in mouse embryonic stem cells. Major satellite RNAs have a strand-specific role in maintaining the replication timing of PCH.

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