Targeting pericentric non-consecutive motifs for heterochromatin initiation

• 成果类型: Article
• 署名作者: Ma, Runze; Zhang, Yan; Zhang, Jing; Zhang, Pinqi; Liu, Zeqi; Fan, Yiming; Wang, Hao-Tian; Zhang, Zhuqiang; Zhu, Bing
• 署名单位: Chinese Academy of Sciences; Institute of Biophysics, CAS; Chinese Academy of Sciences; Chinese Academy of Sciences; University of Chinese Academy of Sciences, CAS; Chinese Academy of Sciences; Kunming Institute of Zoology, CAS; Chinese Academy of Sciences; Institute of Biophysics, CAS
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4499
• DOI: 10.1038/s41586-024-07640-5
• 发表日期: 2024-07-18
• 关键词: histone-h3 lysine-9 methylation; chromatin; h3; binding; maintenance; RECOGNITION; nucleation; alignment; proteins; ELEMENTS

摘要

Pericentric heterochromatin is a critical component of chromosomes marked by histone H3 K9 (H3K9) methylation1-3. However, what recruits H3K9-specific histone methyltransferases to pericentric regions in vertebrates remains unclear4, as does why pericentric regions in different species share the same H3K9 methylation mark despite lacking highly conserved DNA sequences2,5. Here we show that zinc-finger proteins ZNF512 and ZNF512B specifically localize at pericentric regions through direct DNA binding. Notably, both ZNF512 and ZNF512B are sufficient to initiate de novo heterochromatin formation at ectopically targeted repetitive regions and pericentric regions, as they directly recruit SUV39H1 and SUV39H2 (SUV39H) to catalyse H3K9 methylation. SUV39H2 makes a greater contribution to H3K9 trimethylation, whereas SUV39H1 seems to contribute more to silencing, probably owing to its preferential association with HP1 proteins. ZNF512 and ZNF512B from different species can specifically target pericentric regions of other vertebrates, because the atypical long linker residues between the zinc-fingers of ZNF512 and ZNF512B offer flexibility in recognition of non-consecutively organized three-nucleotide triplets targeted by each zinc-finger. This study addresses two long-standing questions: how constitutive heterochromatin is initiated and how seemingly variable pericentric sequences are targeted by the same set of conserved machinery in vertebrates. Zinc-finger proteins ZNF512 and ZNF512B are shown to target pericentric DNA through a conserved mechanism that depends on their atypical long linkers, providing insight into how constitutive heterochromatin formation is initiated across various species.