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 and Victor V. Lobanenkov ()
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Samuel Rivero-Hinojosa: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Elena M. Pugacheva: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Sungyun Kang: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Claudia Fabiola Méndez-Catalá: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Alexander L. Kovalchuk: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Alexander V. Strunnikov: Guangzhou Institutes of Biomedicine and Health, Molecular Epigenetics Laboratory
Dmitri Loukinov: National Institute of Allergy and Infectious Diseases, National Institutes of Health
Jeannie T. Lee: Massachusetts General Hospital
Victor V. Lobanenkov: National Institute of Allergy and Infectious Diseases, National Institutes of Health

Nature Communications, 2021, vol. 12, issue 1, 1-17

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-24140-6

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