College of Animal Science and Technology, Northwest A&F University, Shaanxi 712100, China.
College of Animal Science and Technology, Northwest A&F University, Shaanxi 712100, China.
Biochim Biophys Acta Gene Regul Mech. 2017 Oct;1860(10):1094-1102. doi: 10.1016/j.bbagrm.2017.08.009. Epub 2017 Sep 8.
Spermatogonial stem cells (SSCs) possess the capacity of self-renewal and differentiation, which are the basis of spermatogenesis. In maintenance of SSC homeostasis, intrinsic/extrinsic factors and various signaling pathways tightly control the fate of SSCs. Methyltransferase SETDB1 (Set domain, bifurcated 1) catalyzes histone H3 lysine 9 (H3K9) trimethylation and represses gene expression. SETDB1 is required for maintaining the survival of spermatogonial stem cells in mice. However, the underlying molecular mechanism remains unclear. In the present study, we found that Setdb1 regulates PTEN/AKT/FOXO1 pathway to inhibit SSC apoptosis. Co-immunoprecipitation and reporter gene assay revealed that SETDB1 interacted and coordinated with AKT to regulate FOXO1 activity and expression of the downstream target genes Bim and Puma. Among the SETDB1-bound genes, the H3K9me3 levels on the promoter regions of Bim and Pten decreased in Setdb1-KD group; in contrast, H3K9me3 status on promoters of Bax and Puma remained unchanged. Therefore, SETDB1 was responsible for regulating the transcription activity of genes in the apoptotic pathway at least in part through modulating H3K9me3. This study replenishes the research on the epigenetic regulation of SSC survival, and provides a new insight for the future study of epigenetic regulation of spermatogenesis.
精原干细胞（SSCs）具有自我更新和分化的能力，这是精子发生的基础。在 SSC 稳态的维持中，内在/外在因素和各种信号通路严格控制 SSC 的命运。甲基转移酶 SETDB1（SET 域，分叉 1）催化组蛋白 H3 赖氨酸 9（H3K9）三甲基化并抑制基因表达。SETDB1 对于维持小鼠精原干细胞的存活是必需的。然而，其潜在的分子机制尚不清楚。在本研究中，我们发现 Setdb1 调节 PTEN/AKT/FOXO1 通路抑制 SSC 凋亡。共免疫沉淀和报告基因分析显示，SETDB1 与 AKT 相互作用并协调，以调节 FOXO1 活性和下游靶基因 Bim 和 Puma 的表达。在 SETDB1 结合的基因中，Bim 和 Pten 启动子区域上的 H3K9me3 水平在 Setdb1-KD 组中降低；相比之下，Bax 和 Puma 启动子上的 H3K9me3 状态保持不变。因此，SETDB1 负责通过调节 H3K9me3 至少部分调节凋亡途径中基因的转录活性。本研究补充了 SSC 存活的表观遗传调控研究，为未来研究精子发生的表观遗传调控提供了新的视角。
