Abstract：
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.
摘要：
在这项研究中,我们调查了19p12基因座中的反复拷贝数变异（CNVs），与神经发育障碍有关。这个基因座中的两个基因，ZNF675和ZNF681，在灵长类动物中通过基因复制产生，并且它们在人群中的几种病理性CNV中的存在表明，这些基因中的任何一个或两个都是正常人脑发育所必需的。ZNF675和ZNF681是Krüppel相关盒锌指（KZNF）蛋白家族的成员，一类对特定基因组区域的表观遗传沉默很重要的转录抑制子。人类基因组中存在约170种灵长类动物特异性KZNFs。尽管KZNFs主要与抑制逆转录转座子衍生的DNA有关，有证据表明，它们可以用于其他基因调控过程。我们表明ZNF675的遗传缺失会导致皮质类器官的发育缺陷，我们的数据表明，观察到的神经发育表型的一部分是由ZNF675对神经发育基因Hes家族BHLH转录因子1（HES1）启动子的基因调节作用介导的。我们还发现了最近进化的与神经系统疾病有关的基因调控的证据，小脑素1和sestrin3.我们显示ZNF675干扰HES1自抑制，维持神经祖细胞所必需的过程。作为一些KZNFs如何整合到先前存在的基因表达网络中的一个突出例子，这些发现提示ZNF675的出现引起了HES1自动调节平衡的改变.ZNF675CNV与人类发育障碍和ZNF675介导的神经发育基因调节的关联表明，它已发展成为人脑发育的重要因素。
