Zaidan Nur Zafirah, Sridharan Rupa
Wisconsin Institute for Discovery, University of Wisconsin-Madison, Madison, WI 53715, USA.
Genetics Training Program, University of Wisconsin-Madison, Madison, WI 53715, USA.
Nucleic Acids Res. 2020 Dec 16;48(22):12660-12674. doi: 10.1093/nar/gkaa1091.
The heterochromatin protein 1 (HP1) family members are canonical effectors and propagators of gene repression mediated by histone H3 lysine 9 (H3K9) methylation. HP1γ exhibits an increased interaction with active transcription elongation-associated factors in embryonic stem cells (ESCs) compared to somatic cells. However, whether this association has a functional consequence remains elusive. Here we find that genic HP1γ colocalizes and enhances enrichment of transcription elongation-associated H3K36me3 rather than H3K9me3. Unexpectedly, sustained H3K36me3 deposition is dependent on HP1γ. HP1γ-deleted ESCs display reduced H3K36me3 enrichment, concomitant with decreased expression at shared genes which function to maintain cellular homeostasis. Both the H3K9me3-binding chromodomain and histone binding ability of HP1γ are dispensable for maintaining H3K36me3 levels. Instead, the chromoshadow together with the hinge domain of HP1γ that confer protein and nucleic acid-binding ability are sufficient because they retain the ability to interact with NSD1, an H3K36 methyltransferase. HP1γ-deleted ESCs have a slower self-renewal rate and an impaired ability to differentiate towards cardiac mesoderm. Our findings reveal a requirement for HP1γ in faithful establishment of transcription elongation in ESCs, which regulates pluripotency.
异染色质蛋白1（HP1）家族成员是由组蛋白H3赖氨酸9（H3K9）甲基化介导的基因抑制的典型效应器和传播者。与体细胞相比，HP1γ在胚胎干细胞（ESC）中与活性转录延伸相关因子的相互作用增强。然而，这种关联是否具有功能后果仍不清楚。在这里，我们发现基因HP1γ共定位并增强转录延伸相关的H3K36me3而不是H3K9me3的富集。出乎意料的是，持续的H3K36me3沉积依赖于HP1γ。缺失HP1γ的ESC显示H3K36me3富集减少，同时在维持细胞稳态的共享基因处表达降低。HP1γ的H3K9me3结合染色质结构域和组蛋白结合能力对于维持H3K36me3水平都是可有可无的。相反，赋予蛋白质和核酸结合能力的HP1γ的染色体阴影与铰链结构域就足够了，因为它们保留了与H3K36甲基转移酶NSD1相互作用的能力。缺失HP1γ的ESC自我更新率较慢，向心脏中胚层分化的能力受损。我们的研究结果揭示了ESC中忠实建立转录延伸需要HP1γ，其调节多能性。
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