LINE-1 retrotransposons mediate cis-acting transcriptional control in human pluripotent stem cells and regulate early brain development.

IF 11.1 Q1 CELL BIOLOGY
Anita Adami, Raquel Garza, Patricia Gerdes, Pia A Johansson, Fereshteh Dorazehi, Symela Koutounidou, Laura Castilla-Vallmanya, Diahann A M Atacho, Yogita Sharma, Jenny G Johansson, Oliver Tam, Agnete Kirkeby, Roger A Barker, Molly Gale Hammell, Christopher H Douse, Johan Jakobsson
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引用次数: 0

Abstract

Long interspersed nuclear element 1 (L1) retrotransposons represent a vast source of genetic variability. However, mechanistic analysis of whether and how L1s contribute to human developmental programs is lacking, in part due to the challenges associated with specific profiling and manipulation of human L1 expression. Here, we show that thousands of hominoid-specific L1 integrants are expressed in human induced pluripotent stem cells and cerebral organoids. The activity levels of individual L1 promoters vary widely and correlate with an active epigenetic state. Efficient on-target CRISPR interference (CRISPRi) silencing of L1s revealed nearly a hundred co-opted L1-derived chimeric transcripts, and L1 silencing resulted in changes in neural differentiation programs and reduced cerebral organoid size. Together, these data implicate L1s and L1-derived transcripts in hominoid-specific CNS developmental processes.

LINE-1逆转录转座子介导人类多能干细胞的顺式转录控制并调节早期大脑发育。
长散布的核元件1 (L1)反转录转座子代表了遗传变异的巨大来源。然而,缺乏关于L1是否以及如何促进人类发育程序的机制分析,部分原因是与人类L1表达的特定分析和操纵相关的挑战。在这里,我们发现数千种类人猿特异性L1整合物在人类诱导多能干细胞和脑类器官中表达。单个L1启动子的活性水平变化很大,并与活跃的表观遗传状态相关。有效的靶向CRISPR干扰(CRISPRi)沉默L1s揭示了近100个增选L1衍生的嵌合转录物,L1沉默导致神经分化程序的改变和脑类器官大小的减小。总之,这些数据暗示了l1和l1衍生转录物在类人猿特异性中枢神经系统发育过程中的作用。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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CiteScore
7.10
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