Epigenetics and Cell Fate Centre, UMR7216 CNRS, Université de Paris, Paris, France.
Cell and Tissue Imaging Facility, UMR3215 PICT-IBiSA, Institut Curie, Paris, France.
Nat Commun. 2021 Apr 23;12(1):2428. doi: 10.1038/s41467-021-22575-5.
Heterochromatin is a critical chromatin compartment, whose integrity governs genome stability and cell fate transitions. How heterochromatin features, including higher-order chromatin folding and histone modifications associated with transcriptional silencing, are maintained following a genotoxic stress challenge is unknown. Here, we establish a system for targeting UV damage to pericentric heterochromatin in mammalian cells and for tracking the heterochromatin response to UV in real time. We uncover profound heterochromatin compaction changes during repair, orchestrated by the UV damage sensor DDB2, which stimulates linker histone displacement from chromatin. Despite massive heterochromatin unfolding, heterochromatin-specific histone modifications and transcriptional silencing are maintained. We unveil a central role for the methyltransferase SETDB1 in the maintenance of heterochromatic histone marks after UV. SETDB1 coordinates histone methylation with new histone deposition in damaged heterochromatin, thus protecting cells from genome instability. Our data shed light on fundamental molecular mechanisms safeguarding higher-order chromatin integrity following DNA damage.
异染色质是一个关键的染色质区域，其完整性控制着基因组的稳定性和细胞命运的转变。在受到遗传毒性应激挑战后，异染色质的特征（包括与转录沉默相关的高级染色质折叠和组蛋白修饰）是如何维持的，目前尚不清楚。在这里，我们建立了一种在哺乳动物细胞中靶向定位于着丝粒异染色质的 UV 损伤的系统，并实时跟踪异染色质对 UV 的反应。我们发现，在修复过程中，异染色质发生了深刻的压缩变化，这是由 UV 损伤传感器 DDB2 协调的，它刺激连接组蛋白从染色质上的位移。尽管异染色质大规模展开，但异染色质特异性组蛋白修饰和转录沉默仍得以维持。我们揭示了甲基转移酶 SETDB1 在 UV 后维持异染色质组蛋白标记中的核心作用。SETDB1 协调组蛋白甲基化与受损异染色质中新的组蛋白沉积，从而保护细胞免受基因组不稳定性的影响。我们的数据揭示了在 DNA 损伤后保护高级染色质完整性的基本分子机制。
