The essential function of CTCF is demonstrated by the early embryonic lethality of mice that are null for Ctcf 22. Numerous nuclear processes including transcription regulation, imprinting, chromatin insulation, X-chromosome inactivation, and repair of DNA double-strand breaks (DSBs) have been linked to the organizational function of CTCF 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21. CTCF thereby partitions the genome into autonomously functioning expression units 2, 9. CTCF functions by halting cohesin-mediated extrusion of chromatin fibers thus creating chromosome loops 6, 7, 8. CTCF is an exceptionally conserved 11-zinc finger (ZFs) DNA-binding protein that binds thousands of genomic sites in the fly, mouse, and human genomes 3, 4, 5. The CCCTC-binding factor (CTCF) is a chief organizer of chromosome looping in multicellular eukaryotes ranging from insects to humans 1, 2. How the three-dimensional (3D) genome is organized through diverse developmental stages is one of the key questions in the epigenetics field. 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. 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. Although CM germ cells exhibit only 25% of CTCF WT expression, chromatin binding of CTCF is preferentially lost from CTCF-BORIS heterodimeric sites. Testes with combined depletion of both CTCF and BORIS show reduced size, defective meiotic recombination, increased apoptosis, and malformed spermatozoa. Whereas Ctcf +/+ Boris +/+, Ctcf +/− Boris +/+, and Ctcf +/+ Boris −/− males are fertile, Ctcf +/− Boris −/− (Compound Mutant CM) males are sterile. To understand the CTCF-BORIS relationship, mouse models with varied CTCF and BORIS levels were generated. Unexpectedly, BORIS-null mice have only minimal germ cell defects. Its specialized paralog, BORIS, heterodimerizes with CTCF but is expressed only in male germ cells and in cancer states. CTCF is a key organizer of the 3D genome.
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