Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA.
Center for Cancer and Immunology Research, Children's National Research Institute, Washington, DC, USA.
Nat Commun. 2021 Jun 22;12(1):3846. doi: 10.1038/s41467-021-24140-6.
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 CtcfBoris, CtcfBoris, and CtcfBoris males are fertile, CtcfBoris (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.
CTCF 是 3D 基因组的关键组织者。其专门的 paralog ， BORIS ，与 CTCF 异二聚化，但仅在雄性生殖细胞和癌症状态下表达。出人意料的是， BORIS 缺失的小鼠只有最小的生殖细胞缺陷。为了了解 CTCF-BORIS 关系，生成了具有不同 CTCF 和 BORIS 水平的小鼠模型。尽管 CtcfBoris ， CtcfBoris 和 CtcfBoris 雄性可育，但 CtcfBoris （复合突变体； CM ）雄性不育。同时耗尽 CTCF 和 BORIS 的睾丸显示出体积减小、减数分裂重组缺陷、凋亡增加和畸形精子。尽管 CM 生殖细胞仅表达 CTCF WT 的 25%，但 CTCF 的染色质结合优先从 CTCF-BORIS 异二聚体位点丢失。此外，CM 睾丸失去了大量精子发生基因的表达，并获得了“对生育有不良影响”的发育不当基因的表达。因此，CTCF 和 BORIS 的联合作用既需要抑制减数分裂前基因，又需要激活减数分裂后基因，以完成完整的精子发生程序。
