Nucleome programming is required for the foundation of totipotency in mammalian germline development

Masahiro Nagano, Bo Hu, Shihori Yokobayashi, Akitoshi Yamamura, Fumiya Umemura, Mariel Coradin, Hiroshi Ohta, Yukihiro Yabuta, Yukiko Ishikura, Ikuhiro Okamoto, Hiroki Ikeda, Naofumi Kawahira, Yoshiaki Nosaka, Sakura Shimizu, Yoji Kojima, Ken Mizuta, Tomoko Kasahara, Yusuke Imoto, Killian Meehan, Roman StocsitsGordana Wutz, Yasuaki Hiraoka, Yasuhiro Murakawa, Takuya Yamamoto, Kikue Tachibana, Jan Michel Peters, Leonid A. Mirny, Benjamin A. Garcia, Jacek Majewski, Mitinori Saitou

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

Germ cells are unique in engendering totipotency, yet the mechanisms underlying this capacity remain elusive. Here, we perform comprehensive and in-depth nucleome analysis of mouse germ-cell development in vitro, encompassing pluripotent precursors, primordial germ cells (PGCs) before and after epigenetic reprogramming, and spermatogonia/spermatogonial stem cells (SSCs). Although epigenetic reprogramming, including genome-wide DNA de-methylation, creates broadly open chromatin with abundant enhancer-like signatures, the augmented chromatin insulation safeguards transcriptional fidelity. These insulatory constraints are then erased en masse for spermatogonial development. Notably, despite distinguishing epigenetic programming, including global DNA re-methylation, the PGCs-to-spermatogonia/SSCs development entails further euchromatization. This accompanies substantial erasure of lamina-associated domains, generating spermatogonia/SSCs with a minimal peripheral attachment of chromatin except for pericentromeres—an architecture conserved in primates. Accordingly, faulty nucleome maturation, including persistent insulation and improper euchromatization, leads to impaired spermatogenic potential. Given that PGCs after epigenetic reprogramming serve as oogenic progenitors as well, our findings elucidate a principle for the nucleome programming that creates gametogenic progenitors in both sexes, defining a basis for nuclear totipotency.

Original languageEnglish
Article numbere110600
JournalEMBO Journal
Volume41
Issue number13
DOIs
StatePublished - Jul 4 2022

Keywords

  • 3D genome organization
  • epigenetic reprogramming
  • germ cells
  • lamina-associated domains
  • nucleome

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