Otsuka Kai, Sakashita Akihiko, Maezawa So, Schultz Richard M, Namekawa Satoshi H
Department of Microbiology and Molecular Genetics, University of California, Davis, California 95616, USA.
Department of Applied Biological Science, Faculty of Science and Technology, Tokyo University of Science, Noda, Chiba 278-8510, Japan.
Genome Res. 2025 Mar 12;35(3):417-31. doi: 10.1101/gr.279924.124.
As transposable elements (TEs) coevolved with the host genome, the host genome exploited TEs as functional regulatory elements of gene expression. Here we show that a subset of KRAB domain-containing zinc-finger proteins (KZFPs), which are highly expressed in mitotically dividing spermatogonia, repress the enhancer function of endogenous retroviruses (ERVs) and that the release from KZFP-mediated repression allows activation of ERV enhancers upon entry into meiosis. This regulatory feature is observed for independently evolved KZFPs and ERVs in mice and humans, suggesting evolutionary conservation in mammals. Further, we show that KZFP-targeted ERVs are underrepresented on the sex chromosomes in meiosis, suggesting that meiotic sex chromosome inactivation (MSCI) may antagonize the coevolution of KZFPs and ERVs in mammals. Our study uncovers a mechanism by which a subset of KZFPs regulate ERVs to sculpt germline transcriptomes. We propose that epigenetic programming during the transition from mitotic spermatogonia to meiotic spermatocytes facilitates the coevolution of KZFPs and TEs on autosomes and is antagonized by MSCI.
随着转座元件（TEs）与宿主基因组共同进化，宿主基因组将TEs作为基因表达的功能调控元件加以利用。在此我们表明，一类在有丝分裂的精原细胞中高度表达的含KRAB结构域的锌指蛋白（KZFPs）抑制内源性逆转录病毒（ERVs）的增强子功能，而进入减数分裂时，从KZFP介导的抑制作用中释放出来会使ERV增强子激活。在小鼠和人类中，独立进化的KZFPs和ERVs都存在这种调控特征，这表明在哺乳动物中具有进化保守性。此外，我们表明在减数分裂过程中，KZFP靶向的ERVs在性染色体上的代表性不足，这表明减数分裂性染色体失活（MSCI）可能会对抗哺乳动物中KZFPs和ERVs的共同进化。我们的研究揭示了一种机制，即一部分KZFPs通过调控ERVs来塑造生殖系转录组。我们提出，从有丝分裂的精原细胞向减数分裂的精母细胞转变过程中的表观遗传编程促进了常染色体上KZFPs和TEs的共同进化，而MSCI则对其起到拮抗作用。
