PRC1 suppresses a female gene regulatory network to ensure testicular differentiation

So Maezawa; Masashi Yukawa; Kazuteru Hasegawa; Ryo Sugiyama; Mizuho Iizuka; Mengwen Hu; Akihiko Sakashita; Miguel Vidal; Haruhiko Koseki; Artem Barski; Tony DeFalco; Satoshi H Namekawa

doi:10.1038/s41419-023-05996-6

PRC1 suppresses a female gene regulatory network to ensure testicular differentiation

Cell Death Dis. 2023 Aug 4;14(8):501. doi: 10.1038/s41419-023-05996-6.

Authors

So Maezawa^{1

2

3

4}, Masashi Yukawa^{5

6

7}, Kazuteru Hasegawa^{8

5}, Ryo Sugiyama⁹, Mizuho Iizuka⁹, Mengwen Hu^{8

5

10}, Akihiko Sakashita^{8

5

11}, Miguel Vidal¹², Haruhiko Koseki¹³, Artem Barski^{5

6}, Tony DeFalco^{8

5}, Satoshi H Namekawa^{14

15

16}

Affiliations

¹ Reproductive Sciences Center, Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA. s-maezawa@rs.tus.ac.jp.
² Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA. s-maezawa@rs.tus.ac.jp.
³ Department of Animal Science and Biotechnology, School of Veterinary Medicine, Azabu University, Sagamihara, Kanagawa, 252-5201, Japan. s-maezawa@rs.tus.ac.jp.
⁴ Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, 278-8510, Japan. s-maezawa@rs.tus.ac.jp.
⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA.
⁶ Division of Allergy and Immunology, Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, 45229, USA.
⁷ Department of Chemical Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, Sha Tin, New Territories, Hong Kong.
⁸ Reproductive Sciences Center, Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA.
⁹ Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Chiba, 278-8510, Japan.
¹⁰ Department of Microbiology and Molecular Genetics, University of California, Davis, CA, 95616, USA.
¹¹ Department of Molecular Biology, Keio University School of Medicine, Tokyo, 160-8582, Japan.
¹² Centro de Investigaciones Biológicas Margarita Salas, Department of Cellular and Molecular Biology, Madrid, 28040, Spain.
¹³ Developmental Genetics Laboratory, RIKEN Center for Allergy and Immunology, Yokohama, Kanagawa, Japan.
¹⁴ Reproductive Sciences Center, Division of Developmental Biology, Perinatal Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, 45229, USA. snamekawa@ucdavis.edu.
¹⁵ Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, 45229, USA. snamekawa@ucdavis.edu.
¹⁶ Department of Microbiology and Molecular Genetics, University of California, Davis, CA, 95616, USA. snamekawa@ucdavis.edu.

Abstract

Gonadal sex determination and differentiation are controlled by somatic support cells of testes (Sertoli cells) and ovaries (granulosa cells). In testes, the epigenetic mechanism that maintains chromatin states responsible for suppressing female sexual differentiation remains unclear. Here, we show that Polycomb repressive complex 1 (PRC1) suppresses a female gene regulatory network in postnatal Sertoli cells. We genetically disrupted PRC1 function in embryonic Sertoli cells after sex determination, and we found that PRC1-depleted postnatal Sertoli cells exhibited defective proliferation and cell death, leading to the degeneration of adult testes. In adult Sertoli cells, PRC1 suppressed specific genes required for granulosa cells, thereby inactivating the female gene regulatory network. Chromatin regions associated with female-specific genes were marked by Polycomb-mediated repressive modifications: PRC1-mediated H2AK119ub and PRC2-mediated H3K27me3. Taken together, this study identifies a critical Polycomb-based mechanism that suppresses ovarian differentiation and maintains Sertoli cell fate in adult testes.

Publication types

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

MeSH terms

Cell Differentiation / genetics
Chromatin
Female
Gene Regulatory Networks
Histones* / genetics
Histones* / metabolism
Humans
Male
Polycomb Repressive Complex 1* / genetics
Polycomb Repressive Complex 1* / metabolism
Polycomb Repressive Complex 2 / genetics
Polycomb Repressive Complex 2 / metabolism
Polycomb-Group Proteins / genetics
Polycomb-Group Proteins / metabolism
Testis / metabolism

Substances

Polycomb Repressive Complex 1
Histones
Polycomb Repressive Complex 2
Chromatin
Polycomb-Group Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding