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

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

doi:10.1038/s41467-022-28105-1

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.

Highlights

Germ cells are essential to pass DNA from one generation to the
In order to characterize dynamically expressed Transposable Elements (TEs) subfamilies during germ cell specification, we analyzed the RNA-seq data sets previously published from our lab[16], including day 4 (D4) human primordial germ cells (PGCs)-like cells differentiated from primed state human embryonic stem cells (hESCs) through incipient mesoderm like cells (Fig. 1A and Supplementary Data 1), an intermediate cell type between primed hESCs and hPGCLCs4
Using our in vitro model, we likewise show that LTR5Hs elements acquire an open chromatin state, are hypomethylated and bound by key PGC transcription factors (TFs) including NANOG, TFAP2C, SOX17, and SOX15 after hPGC-Like Cells (hPGCLCs) induction

Summary

Introduction

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. Our data reveals the essential role of Hominidae-specific LTR5Hs TEENhancers in human germ cell development. Given the central importance of PGCs to reproduction, the developmental cues and regulatory milieu governing specification of PGCs has been broadly studied in various animal models[1]. While these models have proven instructive in PGC biology, constraints imposed by ethical and technical limitations have rendered the precise mechanisms governing human (h) PGC (hPGC) specification in vivo unclear. Of particular interest when considering TE contribution to the regulatory landscape of the genome are Endogenous retroviruses (ERVs), a superfamily within the LTR retrotransposon class

Methods

Results

Conclusion