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During spermatogenesis, intricate gene expression is coordinately regulated by epigenetic modifiers, which are required for differentiation of spermatogonial stem cells (SSCs) contained among undifferentiated spermatogonia. We have previously found that KMT2B conveys H3K4me3 at bivalent and monovalent promoters in undifferentiated spermatogonia. Because these genes are expressed late in spermatogenesis or during embryogenesis, we expect that many of them are potentially programmed by KMT2B for future expression. Here, we show that one of the genes targeted by KMT2B, Tsga8, plays an essential role in spermatid morphogenesis. Loss of Tsga8 in mice leads to male infertility associated with abnormal chromosomal distribution in round spermatids, malformation of elongating spermatid heads and spermiation failure. Tsga8 depletion leads to dysregulation of thousands of genes, including the X-chromosome genes that are reactivated in spermatids, and insufficient nuclear condensation accompanied by reductions of TNP1 and PRM1, key factors for histone-to-protamine transition. Intracytoplasmic sperm injection (ICSI) of spermatids rescued the infertility phenotype, suggesting competency of the spermatid genome for fertilization. Thus, Tsga8 is a KMT2B target that is vitally necessary for spermiogenesis and fertility. © 2021. Published by The Company of Biologists Ltd.


Yuki Kobayashi, Shin-Ichi Tomizawa, Michio Ono, Kazushige Kuroha, Keisuke Minamizawa, Koji Natsume, Selma Dizdarević, Ivana Dočkal, Hiromitsu Tanaka, Tatsukata Kawagoe, Masahide Seki, Yutaka Suzuki, Narumi Ogonuki, Kimiko Inoue, Shogo Matoba, Konstantinos Anastassiadis, Nobuhisa Mizuki, Atsuo Ogura, Kazuyuki Ohbo. Tsga8 is required for spermatid morphogenesis and male fertility in mice. Development (Cambridge, England). 2021 Apr 15;148(8)

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PMID: 33766931

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