Department of Biochemistry, University of Oxford, Oxford, OX1 3QU, UK.
Laboratory for Developmental Genetics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan.
Nucleic Acids Res. 2019 Sep 26;47(17):9005-9023. doi: 10.1093/nar/gkz607.
CpG islands (CGIs) are associated with the majority of mammalian gene promoters and function to recruit chromatin modifying enzymes. It has therefore been proposed that CGIs regulate gene expression through chromatin-based mechanisms, however in most cases this has not been directly tested. Here, we reveal that the histone H3 lysine 36 (H3K36) demethylase activity of the CGI-binding KDM2 proteins contributes only modestly to the H3K36me2-depleted state at CGI-associated gene promoters and is dispensable for normal gene expression. Instead, we discover that KDM2 proteins play a widespread and demethylase-independent role in constraining gene expression from CGI-associated gene promoters. We further show that KDM2 proteins shape RNA Polymerase II occupancy but not chromatin accessibility at CGI-associated promoters. Together this reveals a demethylase-independent role for KDM2 proteins in transcriptional repression and uncovers a new function for CGIs in constraining gene expression.
CpG 岛（CGIs）与大多数哺乳动物基因启动子相关联，其功能是募集染色质修饰酶。因此，人们提出 CGIs 通过基于染色质的机制来调节基因表达，但在大多数情况下，这尚未得到直接验证。在这里，我们揭示了 CGI 结合的 KDM2 蛋白的组蛋白 H3 赖氨酸 36（H3K36）去甲基酶活性对 CGI 相关基因启动子处的 H3K36me2 耗尽状态的贡献不大，并且对于正常的基因表达不是必需的。相反，我们发现 KDM2 蛋白在从 CGI 相关基因启动子约束基因表达方面发挥着广泛的、去甲基酶独立性的作用。我们进一步表明，KDM2 蛋白在 CGI 相关启动子处形成 RNA 聚合酶 II 占据但不改变染色质可及性。总之，这揭示了 KDM2 蛋白在转录抑制中的去甲基酶独立性作用，并揭示了 CGIs 在约束基因表达方面的新功能。
