CHD4 acts as a critical regulator in the survival of spermatogonial stem cells in mice†
CHD4 acts as a critical regulator in the survival of spermatogonial stem cells in mice†
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DOI：
10.1093/biolre/ioac162
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发表时间：
2022-09-16
影响因子：
3.6
通讯作者：
Song, Wei
中科院分区：
文献类型：
--
作者：
Li, Pengyu;Tang, Jielin;Song, Wei
染色体结构域解旋酶DNA结合蛋白4基因敲除后，凋亡基因的表达上调，伴随TNF信号通路的异常激活，导致生殖细胞过度凋亡和男性不育，精子发生是精原干细胞自我更新和分化之间的稳态平衡维持的，这依赖于转录因子和染色质调节基因表达的严格调控。染色体结构域解旋酶DNA结合蛋白4在精原干细胞中高度表达，但在小鼠精子发生中的作用尚不完全清楚。在这里，我们报告，生殖细胞特异性删除染色体结构域解旋酶DNA结合蛋白4导致雄性小鼠完全不育，精原干细胞和过度的生殖细胞凋亡的快速损失。在培养的精原干细胞中敲低染色体结构域解旋酶DNA结合蛋白4也促进了前列腺增生相关基因的表达，从而激活了肿瘤坏死因子信号通路。从机制上讲，染色体结构域解旋酶DNA结合蛋白4占据了关键的糖尿病相关基因的基因组调控区，包括Jun和Nfkb1。总之，我们的研究结果揭示了染色体结构域解旋酶DNA结合蛋白4在精原干细胞体内存活中的决定性作用，这将为深入了解男性不育的发病机制和潜在的新的治疗靶点提供帮助。
After chromodomain helicase DNA-binding protein 4 knockout, excessive apoptosis of germ cells and male infertility were caused by upregulated expression of apoptosis genes which were accompanied by abnormal activation of TNF signaling pathway.Spermatogenesis is sustained by homeostatic balance between the self-renewal and differentiation of spermatogonial stem cells, which is dependent on the strict regulation of transcription factor and chromatin modulator gene expression. Chromodomain helicase DNA-binding protein 4 is highly expressed in spermatogonial stem cells but roles in mouse spermatogenesis are not fully understood. Here, we report that the germ-cell-specific deletion of chromodomain helicase DNA-binding protein 4 resulted in complete infertility in male mice, with rapid loss of spermatogonial stem cells and excessive germ cell apoptosis. Chromodomain helicase DNA-binding protein 4-knockdown in cultured spermatogonial stem cells also promoted the expression of apoptosis-related genes and thereby activated the tumor necrosis factor signaling pathway. Mechanistically, chromodomain helicase DNA-binding protein 4 occupies the genomic regulatory region of key apoptosis-related genes, including Jun and Nfkb1. Together, our findings reveal the determinant role of chromodomain helicase DNA-binding protein 4 in spermatogonial stem cells survival in vivo, which will offer insight into the pathogenesis of male sterility and potential novel therapeutic targets.