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
{"title":"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。","authors":"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","doi":"10.1016/j.xgen.2025.100979","DOIUrl":null,"url":null,"abstract":"<p><p>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.</p>","PeriodicalId":72539,"journal":{"name":"Cell genomics","volume":" ","pages":"100979"},"PeriodicalIF":11.1000,"publicationDate":"2025-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"LINE-1 retrotransposons mediate cis-acting transcriptional control in human pluripotent stem cells and regulate early brain development.\",\"authors\":\"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\",\"doi\":\"10.1016/j.xgen.2025.100979\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>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.</p>\",\"PeriodicalId\":72539,\"journal\":{\"name\":\"Cell genomics\",\"volume\":\" \",\"pages\":\"100979\"},\"PeriodicalIF\":11.1000,\"publicationDate\":\"2025-08-19\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Cell genomics\",\"FirstCategoryId\":\"1085\",\"ListUrlMain\":\"https://doi.org/10.1016/j.xgen.2025.100979\",\"RegionNum\":0,\"RegionCategory\":null,\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CELL BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Cell genomics","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1016/j.xgen.2025.100979","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CELL BIOLOGY","Score":null,"Total":0}
LINE-1 retrotransposons mediate cis-acting transcriptional control in human pluripotent stem cells and regulate early brain development.
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.