Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis
Chromodomain Protein CDYL Acts as a Crotonyl-CoA Hydratase to Regulate Histone Crotonylation and Spermatogenesis
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染色质结构域蛋白 CDYL 作为巴豆酰辅酶 A 水合酶调节组蛋白巴豆酰化和精子发生
DOI：
10.1016/j.molcel.2017.07.011
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发表时间：
2017-09-07
期刊：
影响因子：
16
通讯作者：
Shang, Yongfeng
中科院分区：
文献类型：
--
作者：
Liu, Shumeng;Yu, Huajing;Shang, Yongfeng
赖氨酸巴豆酰化 (Kcr) 是一种新发现的组蛋白修饰，与哺乳动物细胞中的活性转录相关。在这里，我们报道了染色质结构域 Y 样转录辅阻遏物 CDYL 通过充当巴豆酰辅酶 A 水合酶将巴豆酰辅酶 A 转化为 β-羟基丁酰辅酶 A 来负向调节组蛋白 Kcr。我们发现 CDYL 对组蛋白 Kcr 的负调控与其转录抑制活性有内在联系，并在圆形精子细胞中性染色体相关基因的重新激活和伸长精子细胞中的全基因组组蛋白替换中发挥功能。值得注意的是，Cdyl 转基因小鼠表现出组蛋白 Kcr 失调和男性生育力降低，附睾精子数量和精子细胞活力下降。我们的研究揭示了组蛋白 Kcr 调节的生化途径，并暗示 CDYL 调节的组蛋白 Kcr 在精子发生中的作用，增加了对男性生殖生理学和 AZFc（无精症因子 c）缺失的不育男性生精失败机制的理解。
Lysine crotonylation (Kcr) is a newly identified histone modification that is associated with active transcription in mammalian cells. Here we report that the chromodomain Y-like transcription corepressor CDYL negatively regulates histone Kcr by acting as a crotonyl-CoA hydratase to convert crotonyl-CoA to beta-hydroxybutyryl-CoA. We showed that the negative regulation of histone Kcr by CDYL is intrinsically linked to its transcription repression activity and functionally implemented in the reactivation of sex chromosome-linked genes in round spermatids and genome-wide histone replacement in elongating spermatids. Significantly, Cdyl transgenic mice manifest dysregulation of histone Kcr and reduction of male fertility with a decreased epididymal sperm count and sperm cell motility. Our study uncovers a biochemical pathway in the regulation of histone Kcr and implicates CDYL-regulated histone Kcr in spermatogenesis, adding to the understanding of the physiology of male reproduction and the mechanism of the spermatogenic failure in AZFc (Azoospermia Factor c)-deleted infertile men.