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LINE-1 transposable elements regulate the exit of human pluripotency and early brain development [bulkRNA-seq]

ABSTRACT: LINE-1 transposable elements regulate the exit of human pluripotency and early brain development [bulkRNA-seq]

PROVIDER: PRJNA1194602 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR31621049_1.fastq.gz	Fastqsanger.gz
	SRR31621049_2.fastq.gz	Fastqsanger.gz
	SRR31621050_1.fastq.gz	Fastqsanger.gz
	SRR31621050_2.fastq.gz	Fastqsanger.gz
	SRR31621051_1.fastq.gz	Fastqsanger.gz

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METTL3-dependent m6A RNA Methylation Regulates Transposable Elements and Represses Human Naïve Pluripotency through Transposable Element-derived Enhancers

Project description:N6-methyladenosine (m6A) is the most prevalent mRNA modification with diverse regulatory roles in mammalian cells. While its functions are well-documented in mouse embryonic stem cells (mESCs), its role in human pluripotent stem cells (hPSCs) remains to be fully explored. METTL3 is the main enzyme responsible for m6A deposition. Here, using a METTL3 inducible knockout (iKO) system, we uncovered that, unlike in mESCs, METTL3 was indispensable for hPSC maintenance. Importantly, loss of METTL3 caused significant upregulation of pluripotency factors including naïve pluripotency genes and failure to exit pluripotency, thus impaired stem cell differentiation towards embryonic and extraembryonic cells including trophoblasts. Mechanistically, METTL3 iKO in hPSCs substantially increased expression and enhancer activities of two primate-specific transposable elements (TEs), SVA_D and HERVK/LTR5_Hs, which are normally modified by METTL3-dependent m6A. METTL3 loss activated SVA_D by lowering H3K9me3 deposition, and increased chromatin accessibility at LTR5_Hs through the naïve and other pluripotency factors. Conversely, we discovered that the activated SVA_D and LTR5_Hs loci positively regulated naïve gene expression by directly interacted with their promoters. These findings thus reveal that METTL3-dependent m6A RNA methylation has critical roles in suppressing TE expression and in the human pluripotency regulatory network.

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LINE-1 transposable elements regulate the exit of human pluripotency and early brain development

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LINE-1 transposable elements regulate the exit of human pluripotency and early brain development [bulkRNA-seq]

Project description: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.

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