在这项研究中，我们研究了 19p12 ​​基因座中的复发性拷贝数变异 (CNV)，这些变异与神经发育障碍相关。该位点中的两个基因 ZNF675 和 ZNF681 是通过灵长类动物中的基因复制产生的，它们在人类的几个病理性 CNV 中的存在表明，这两个基因中的一个或两个是正常人类大脑发育所必需的。 ZNF675 和 ZNF681 是 Krüppel 相关盒锌指 (KZNF) 蛋白家族的成员，该家族是一类对于特定基因组区域的表观遗传沉默非常重要的转录抑制因子。人类基因组中存在大约 170 种灵长类特异性 KZNF。尽管 KZNF 主要与抑制逆转录转座子衍生的 DNA 相关，但越来越多的证据表明它们可以被用于其他基因调控过程。我们发现 ZNF675 的基因缺失会导致皮质类器官的发育缺陷，并且我们的数据表明，观察到的部分神经发育表型是由 ZNF675 对神经发育基因 Hes 家族 BHLH 转录因子 1 (HES1) 启动子的基因调控作用介导的。我们还发现了与神经系统疾病相关的基因（小头磷脂 1 和 sestrin 3）最近进化的调节证据。我们表明 ZNF675 干扰 HES1 自身抑制，这是维持神经祖细胞所必需的过程。作为一些 KZNF 如何整合到预先存在的基因表达网络中的一个引人注目的例子，这些发现表明 ZNF675 的出现导致了 HES1 自身调节平衡的变化。 ZNF675 CNV 与人类发育障碍以及 ZNF675 介导的神经发育基因调节的关联表明，它演变成人类大脑发育的重要因素。© 2024 作者。 《比较神经病学杂志》由 Wiley periodicals LLC 出版。

In this study, we investigated recurrent copy number variations (CNVs) in the 19p12 locus, which are associated with neurodevelopmental disorders. The two genes in this locus, ZNF675 and ZNF681, arose via gene duplication in primates, and their presence in several pathological CNVs in the human population suggests that either or both of these genes are required for normal human brain development. ZNF675 and ZNF681 are members of the Krüppel-associated box zinc finger (KZNF) protein family, a class of transcriptional repressors important for epigenetic silencing of specific genomic regions. About 170 primate-specific KZNFs are present in the human genome. Although KZNFs are primarily associated with repressing retrotransposon-derived DNA, evidence is emerging that they can be co-opted for other gene regulatory processes. We show that genetic deletion of ZNF675 causes developmental defects in cortical organoids, and our data suggest that part of the observed neurodevelopmental phenotype is mediated by a gene regulatory role of ZNF675 on the promoter of the neurodevelopmental gene Hes family BHLH transcription factor 1 (HES1). We also find evidence for the recently evolved regulation of genes involved in neurological disorders, microcephalin 1 and sestrin 3. We show that ZNF675 interferes with HES1 auto-inhibition, a process essential for the maintenance of neural progenitors. As a striking example of how some KZNFs have integrated into preexisting gene expression networks, these findings suggest the emergence of ZNF675 has caused a change in the balance of HES1 autoregulation. The association of ZNF675 CNV with human developmental disorders and ZNF675-mediated regulation of neurodevelopmental genes suggests that it evolved into an important factor for human brain development.© 2024 The Author(s). The Journal of Comparative Neurology published by Wiley Periodicals LLC.