研究人员发现了一个KRAB-ZFP转录因子ZNF558，它在人类而非黑猩猩的前脑神经祖细胞中表达。ZNF558是作为LINE-1转座子的抑制者而进化的，但已被用来调节一个单一的靶标，即有丝分裂基因SPATA18。ZNF558在线粒体稳态中起作用，在大脑器官中的功能缺失实验表明，ZNF558在人类早期大脑发育中影响发育时间。
ZNF558的表达受一个可变数目串联重复的大小控制，与人类相比，黑猩猩的可变数目串联重复更长，在人类群体中也是可变的。因此，这项工作提供了关于顺式结构变异如何建立一个影响人类大脑进化的调控网络的机制性见解。
据悉，尽管蛋白质编码基因的变化有限，但与黑猩猩相比，人类前脑的大小和复杂性都有所扩大，这表明基因表达调节是大脑进化的一个重要驱动力。
附：英文原文
Title: A cis-acting structural variation at the ZNF558 locus controls a gene regulatory network in human brain development
Author: Pia A. Johansson, Per Ludvik Bratts, Christopher H. Douse, PingHsun Hsieh, Anita Adami, Julien Pontis, Daniela Grassi, Raquel Garza, Edoardo Sozzi, Rodrigo Cataldo, Marie E. Jnsson, Diahann A.M. Atacho, Karolina Pircs, Feride Eren, Yogita Sharma, Jenny Johansson, Alessandro Fiorenzano, Malin Parmar, Malin Fex, Didier Trono, Evan E. Eichler, Johan Jakobsson
Issue&Volume: 2021-10-07
Abstract: The human forebrain has expanded in size and complexity compared to chimpanzees despite limited changes in protein-coding genes, suggesting that gene expression regulation is an important driver of brain evolution. Here, we identify a KRAB-ZFP transcription factor, ZNF558, that is expressed in human but not chimpanzee forebrain neural progenitor cells. ZNF558 evolved as a suppressor of LINE-1 transposons but has been co-opted to regulate a single target, the mitophagy gene SPATA18. ZNF558 plays a role in mitochondrial homeostasis, and loss-of-function experiments in cerebral organoids suggests that ZNF558 influences developmental timing during early human brain development. Expression of ZNF558 is controlled by the size of a variable number tandem repeat that is longer in chimpanzees compared to humans, and variable in the human population. Thus, this work provides mechanistic insight into how a cis-acting structural variation establishes a regulatory network that affects human brain evolution.
DOI: 10.1016/j.stem.2021.09.008
Source: https://www.cell.com/cell-stem-cell/fulltext/S1934-5909(21)00384-2
Cell Stem Cell：《细胞—干细胞》，创刊于2007年。隶属于细胞出版社，最新IF：25.269
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本期文章：《细胞—干细胞》：Online/在线发表
