LINE-1 transposable elements regulate the exit of human pluripotency and early brain development [CUT&Run]

The mechanisms underlying primate-specific genetic programs during early human development remain poorly understood. Long interspersed nuclear element 1 (L1) is the most abundant transposable element in the human genome and represents a vast source of divergent genetic information in hominoid genomes, yet its contribution to human development is largely unknown. Using multiomics profiling, we show here that thousands of hominoid-specific L1 loci are expressed in human induced pluripotent stem cells and cerebral organoids. The transcription of unique L1 elements correlates with the absence of DNA methylation and the presence of an active epigenetic state. CRISPRi silencing of L1s revealed the presence of nearly a hundred co-opted L1-derived chimeric transcripts, and silencing of these transcripts results in altered transcription of many genes involved in neural differentiation, leading to a reduction in cerebral organoid size, implicating L1s in hominoid-specific developmental processes. In conclusion, our results show that L1-derived transcripts provide a layer of primate- and human-specific transcriptome complexity that contributes to early human developmental processes.