We report locus-specific disintegration of megabase-scale chromosomal conformations in brain after neuronal ablation of Setdb1 (also known as Kmt1e; encodes a histone H3 lysine 9 methyltransferase), including a large topologically associated 1.2-Mb domain conserved in humans and mice that encompasses >70 genes at the clustered protocadherin locus (hereafter referred to as cPcdh). The cPcdh topologically associated domain (TAD^cPcdh) in neurons from mutant mice showed abnormal accumulation of the transcriptional regulator and three-dimensional (3D) genome organizer CTCF at cryptic binding sites, in conjunction with DNA cytosine hypomethylation, histone hyperacetylation and upregulated expression. Genes encoding stochastically expressed protocadherins were transcribed by increased numbers of cortical neurons, indicating relaxation of single-cell constraint. SETDB1-dependent loop formations bypassed 0.2-1 Mb of linear genome and radiated from the TAD^cPcdh fringes toward cis-regulatory sequences within the cPcdh locus, counterbalanced shorter-range facilitative promoter-enhancer contacts and carried loop-bound polymorphisms that were associated with genetic risk for schizophrenia. We show that the SETDB1 repressor complex, which involves multiple KRAB zinc finger proteins, shields neuronal genomes from excess CTCF binding and is critically required for structural maintenance of TAD^cPcdh.

中文翻译：

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甲基转移酶SETDB1调节大的神经元特异性拓扑染色质结构域。

我们报告神经元消融Setdb1（也称为Kmt1e；编码组蛋白H3赖氨酸9甲基转移酶），包括一个大的拓扑相关的1.2 Mb域在人类和小鼠中守恒的神经元消融后脑中的兆碱基规模的染色体构象的基因座特异性瓦解。聚集的原钙粘蛋白基因座（以下称为cPcdh）中的> 70个基因。cPcdh拓扑相关域（TAD ^cPcdh）在突变小鼠的神经元中显示出转录调节因子和三维（3D）基因组组织者CTCF在隐蔽结合位点的异常积累，以及DNA胞嘧啶的低甲基化，组蛋白超乙酰化和表达上调。编码随机表达的原钙粘蛋白的基因被增加的皮层神经元转录，表明单细胞约束的松弛。SETDB1依赖性环形成绕过线性基因组的0.2-1 Mb，并从TAD ^cPcdh辐射出现在cPcdh位点内的顺式调控序列上，抵消了短程促进启动子-增强子的接触，并带有与精神分裂症的遗传风险相关的环状结合多态性。我们显示，SETDB1阻遏物复合物，涉及多个KRAB锌指蛋白，可屏蔽过量CTCF结合的神经元基因组，并且对TAD ^cPcdh的结构维持^至关重要。