The combined action of CTCF and its testis-specific paralog BORIS is essential for spermatogenesis

Samuel Rivero-Hinojosa; Elena M Pugacheva; Sungyun Kang; Claudia Fabiola Méndez-Catalá; Alexander L Kovalchuk; Alexander V Strunnikov; Dmitri Loukinov; Jeannie T Lee; Victor V Lobanenkov

doi:10.1038/s41467-021-24140-6

The combined action of CTCF and its testis-specific paralog BORIS is essential for spermatogenesis

Nat Commun. 2021 Jun 22;12(1):3846. doi: 10.1038/s41467-021-24140-6.

Authors

Affiliations

¹ Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. sriverohin@childrensnational.org.
² Center for Cancer and Immunology Research, Children's National Research Institute, Washington, DC, USA. sriverohin@childrensnational.org.
³ Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. epugacheva@niaid.nih.gov.
⁴ Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
⁵ Department of Biology, Indiana University, Bloomington, IN, USA.
⁶ Laboratory of Genetics and Molecular Oncology, Building A4, Faculty of Higher Studies (FES) Iztacala, National Autonomous University of Mexico (UNAM), Tlalnepantla, State of Mexico, Mexico.
⁷ Guangzhou Institutes of Biomedicine and Health, Molecular Epigenetics Laboratory, Guangzhou, China.
⁸ Department of Molecular Biology, Massachusetts General Hospital, Boston, MA, USA.
⁹ Department of Genetics, Harvard Medical School, Boston, MA, USA.
¹⁰ Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA. vlobanenkov@niaid.nih.gov.

Abstract

CTCF is a key organizer of the 3D genome. Its specialized paralog, BORIS, heterodimerizes with CTCF but is expressed only in male germ cells and in cancer states. Unexpectedly, BORIS-null mice have only minimal germ cell defects. To understand the CTCF-BORIS relationship, mouse models with varied CTCF and BORIS levels were generated. Whereas Ctcf^+/+Boris^+/+, Ctcf^+/-Boris^+/+, and Ctcf^+/+Boris^-/- males are fertile, Ctcf^+/-Boris^-/- (Compound Mutant; CM) males are sterile. Testes with combined depletion of both CTCF and BORIS show reduced size, defective meiotic recombination, increased apoptosis, and malformed spermatozoa. Although CM germ cells exhibit only 25% of CTCF WT expression, chromatin binding of CTCF is preferentially lost from CTCF-BORIS heterodimeric sites. Furthermore, CM testes lose the expression of a large number of spermatogenesis genes and gain the expression of developmentally inappropriate genes that are "toxic" to fertility. Thus, a combined action of CTCF and BORIS is required to both repress pre-meiotic genes and activate post-meiotic genes for a complete spermatogenesis program.

Publication types

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

MeSH terms

Animals
CCCTC-Binding Factor / genetics*
CCCTC-Binding Factor / metabolism
DNA-Binding Proteins / genetics*
DNA-Binding Proteins / metabolism
Gene Expression Regulation, Neoplastic*
Humans
Infertility, Male / genetics
Male
Meiosis / genetics
Mice
Mice, Knockout
Promoter Regions, Genetic / genetics
Protein Binding
RNA-Seq / methods
Recombination, Genetic
Spermatogenesis / genetics*
Spermatozoa / metabolism
Testis / metabolism*

Substances

CCCTC-Binding Factor
Ctcf protein, mouse
Ctcfl protein, mouse
DNA-Binding Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding