Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections

Xinyu Xiang; Yu Tao; Jonathan DiRusso; Fei-Man Hsu; Jinchun Zhang; Ziwei Xue; Julien Pontis; Didier Trono; Wanlu Liu; Amander T Clark

doi:10.1038/s41467-022-28105-1

Human reproduction is regulated by retrotransposons derived from ancient Hominidae-specific viral infections

Nat Commun. 2022 Jan 24;13(1):463. doi: 10.1038/s41467-022-28105-1.

Authors

Xinyu Xiang^#¹, Yu Tao^#², Jonathan DiRusso^{2

3}, Fei-Man Hsu², Jinchun Zhang¹, Ziwei Xue¹, Julien Pontis⁴, Didier Trono⁴, Wanlu Liu^{5

6

7

8}, Amander T Clark^{9

10

11

12}

Affiliations

¹ Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, 718 East Haizhou Rd., Haining, 314400, China.
² Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
³ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA.
⁴ School of Life Sciences, Ecole Polytechnique Fe ́de ́rale de Lausanne (EPFL), 1015, Lausanne, Switzerland.
⁵ Zhejiang University-University of Edinburgh Institute (ZJU-UoE Institute), Zhejiang University School of Medicine, International Campus, Zhejiang University, 718 East Haizhou Rd., Haining, 314400, China. wanluliu@intl.zju.edu.cn.
⁶ Department of Orthopedic Surgery of the Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, 310029, China. wanluliu@intl.zju.edu.cn.
⁷ Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cell and Regenerative Medicine, Zhejiang University, Hangzhou, Zhejiang, 310058, China. wanluliu@intl.zju.edu.cn.
⁸ Alibaba-Zhejiang University Joint Research Center of Future DigitalHealthcare, Zhejiang University, Hangzhou, Zhejiang, 310058, China. wanluliu@intl.zju.edu.cn.
⁹ Department of Molecular Cell and Developmental Biology, University of California, Los Angeles, Los Angeles, CA, 90095, USA. clarka@ucla.edu.
¹⁰ Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA, 90095, USA. clarka@ucla.edu.
¹¹ Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA, 90095, USA. clarka@ucla.edu.
¹² Jonsson Comprehensive Cancer Center, University of California, Los Angeles, Los Angeles, CA, 90095, USA. clarka@ucla.edu.

^# Contributed equally.

Abstract

Germ cells are essential to pass DNA from one generation to the next. In human reproduction, germ cell development begins with the specification of primordial germ cells (PGCs) and a failure to specify PGCs leads to human infertility. Recent studies have revealed that the transcription factor network required for PGC specification has diverged in mammals, and this has a significant impact on our understanding of human reproduction. Here, we reveal that the Hominidae-specific Transposable Elements (TEs) LTR5Hs, may serve as TEENhancers (TE Embedded eNhancers) to facilitate PGC specification. LTR5Hs TEENhancers become transcriptionally active during PGC specification both in vivo and in vitro with epigenetic reprogramming leading to increased chromatin accessibility, localized DNA demethylation, enrichment of H3K27ac, and occupation of key hPGC transcription factors. Inactivation of LTR5Hs TEENhancers with KRAB mediated CRISPRi has a significant impact on germ cell specification. In summary, our data reveals the essential role of Hominidae-specific LTR5Hs TEENhancers in human germ cell development.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Endogenous Retroviruses / genetics
Endogenous Retroviruses / physiology*
Enhancer Elements, Genetic
Gene Expression Regulation, Developmental
Germ Cells / physiology
Germ Cells / virology
Hominidae / genetics
Hominidae / physiology
Hominidae / virology*
Humans
Reproduction*
Retroelements*
Retroviridae Infections / physiopathology
Retroviridae Infections / virology*
Transcription Factors / genetics
Transcription Factors / metabolism

Substances

Retroelements
Transcription Factors

Grants and funding

R01 HD079546/HD/NICHD NIH HHS/United States