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Histone variant macroH2A1 regulates synchronous firing of replication origins in the inactive X chromosome
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2024-01Beschreibung
MacroH2A, the largest histone H2A variant, has been extensively linked to transcriptional silencing, cell identity maintenance, and is a hallmark of the inactive X chromosome (Xi). This histone variant forms more stable nucleosomes and, thereby, creates a transcriptionally robust chromatin state. However, it remains unclear whether macroH2A plays a role in DNA replication. Using knockdown and knockout cells for each macroH2A isoform, we show that macroH2A-containing nucleosomes slow down DNA replication fork progression in the Xi due to the higher stability of the macroH2A nucleosomes. Moreover, macroH2A1, but not macroH2A2, promotes synchrony of origin firing in the Xi, and genome-wide analysis showed that macroH2A1 is enriched at Xi origins. Furthermore, we found that macroH2A1 downregulation increases the size of DNA loops that correspond to replicon units. Proximity ligation assays and immunoprecipitation showed that both macroH2A1.1 and macroH2A1.2 interact with the DNA helicase subunit Mcm2. In addition, macroH2A1 depletion increases transcription of the Xi, affecting the DNA helicase loading during G1 and Xi replication timing. We propose that macroH2A1 association with origins enhances the licensing of pre-replication complexes via DNA helicase loading onto the Xi. On the other hand, macroH2A1 counteracts the unloading of the DNA helicase by maintaining the transcriptionally silenced state of the Xi. This study reveals a new dimension to macroH2A context- and isoform-specific roles, where macroH2A1 emerges as a new player preserving Xi replication dynamics.
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