Young LINE-1 transposon 5' UTRs marked by elongation factor ELL3 function as enhancers to regulate naïve pluripotency in embryonic stem cells

Siyan Meng; Xiaoxu Liu; Shiqi Zhu; Peng Xie; Haitong Fang; Qingyun Pan; Ke Fang; Fanfan Li; Jin Zhang; Zhuanzhuan Che; Quanyong Zhang; Guangyao Mao; Yan Wang; Ping Hu; Kai Chen; Fei Sun; Wei Xie; Zhuojuan Luo; Chengqi Lin

doi:10.1038/s41556-023-01211-y

Young LINE-1 transposon 5' UTRs marked by elongation factor ELL3 function as enhancers to regulate naïve pluripotency in embryonic stem cells

Nat Cell Biol. 2023 Sep;25(9):1319-1331. doi: 10.1038/s41556-023-01211-y. Epub 2023 Aug 17.

Authors

Siyan Meng^#^{1

2}, Xiaoxu Liu^#¹, Shiqi Zhu^#¹, Peng Xie^#³, Haitong Fang¹, Qingyun Pan¹, Ke Fang¹, Fanfan Li¹, Jin Zhang¹, Zhuanzhuan Che¹, Quanyong Zhang^{4

5}, Guangyao Mao¹, Yan Wang⁶, Ping Hu⁶, Kai Chen^{4

5}, Fei Sun¹, Wei Xie¹, Zhuojuan Luo^{7

8

9

10}, Chengqi Lin^{11

12

13

14}

Affiliations

¹ Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, China.
² Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China.
³ School of Biological Science and Medical Engineering, Southeast University, Nanjing, China.
⁴ State Key Laboratory of Primate Biomedical Research, Institute of Primate Translational Medicine, Kunming University of Science and Technology, Kunming, China.
⁵ Yunnan Key Laboratory of Primate Biomedical Research, Kunming, China.
⁶ Department of Prenatal Diagnosis, Women's Hospital of Nanjing Medical University, Nanjing Maternity and Child Health Care Hospital, Nanjing, China.
⁷ Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, China. zjluo@seu.edu.cn.
⁸ Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. zjluo@seu.edu.cn.
⁹ Jiangsu Provincial Key Laboratory of Critical Care Medicine, Southeast University, Nanjing, China. zjluo@seu.edu.cn.
¹⁰ Shenzhen Research Institute, Southeast University, Shenzhen, China. zjluo@seu.edu.cn.
¹¹ Key Laboratory of Developmental Genes and Human Disease, School of Life Science and Technology, Southeast University, Nanjing, China. cqlin@seu.edu.cn.
¹² Co-innovation Center of Neuroregeneration, Nantong University, Nantong, China. cqlin@seu.edu.cn.
¹³ Shenzhen Research Institute, Southeast University, Shenzhen, China. cqlin@seu.edu.cn.
¹⁴ Jiangsu Province Hi-Tech Key Laboratory for Biomedical Research, Southeast University, Nanjing, China. cqlin@seu.edu.cn.

^# Contributed equally.

PMID: 37591949
DOI: 10.1038/s41556-023-01211-y

Abstract

LINE-1s are the major clade of retrotransposons with autonomous retrotransposition activity. Despite the potential genotoxicity, LINE-1s are highly activated in early embryos. Here we show that a subset of young LINE-1s, L1Md_Ts, are marked by the RNA polymerase II elongation factor ELL3, and function as enhancers in mouse embryonic stem cells. ELL3 depletion dislodges the DNA hydroxymethylase TET1 and the co-repressor SIN3A from L1Md_Ts, but increases the enrichment of the Bromodomain protein BRD4, leading to loss of 5hmC, gain of H3K27ac, and upregulation of the L1Md_T nearby genes. Specifically, ELL3 occupies and represses the L1Md_T-based enhancer located within Akt3, which encodes a key regulator of AKT pathway. ELL3 is required for proper ERK activation and efficient shutdown of naïve pluripotency through inhibiting Akt3 during naïve-primed transition. Our study reveals that the enhancer function of a subset of young LINE-1s controlled by ELL3 in transcription regulation and mouse early embryo development.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

5' Untranslated Regions
Animals
Embryonic Stem Cells
Mice
Nuclear Proteins* / genetics
Peptide Elongation Factors
Transcription Factors* / genetics

Substances

5' Untranslated Regions
Nuclear Proteins
Transcription Factors
Peptide Elongation Factors