Abstract：
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.
摘要：
外周异染色质是组蛋白H3K9（H3K9）甲基化1-3标记的染色体的关键成分。然而,什么将H3K9特异性组蛋白甲基转移酶招募到脊椎动物的外周区域仍不清楚4，为什么不同物种的外周区域尽管缺乏高度保守的DNA序列，但共享相同的H3K9甲基化标记2，5。在这里，我们显示锌指蛋白ZNF512和ZNF512B通过直接DNA结合特异性定位于外周区域。值得注意的是,ZNF512和ZNF512B都足以在异位靶向的重复区和外周区开始从头形成异染色质，因为他们直接招募SUV39H1和SUV39H2（SUV39H）来催化H3K9甲基化。SUV39H2对H3K9三甲基化做出了更大的贡献，而SUV39H1似乎更有助于沉默，可能是由于其与HP1蛋白的优先关联。来自不同物种的ZNF512和ZNF512B可以特异性地靶向其他脊椎动物的周心区域，因为ZNF512和ZNF512B的锌指之间的非典型长接头残基为识别每个锌指靶向的非连续组织的三核苷酸三联体提供了灵活性。这项研究解决了两个长期存在的问题：组成型异染色质是如何启动的，以及脊椎动物中同一组保守机制如何靶向看似可变的外周序列。
