Distinct requirements for Sin3a in perinatal male gonocytes and differentiating spermatogonia.
Distinct requirements for Sin3a in perinatal male gonocytes and differentiating spermatogonia.
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DOI：
10.1016/j.ydbio.2012.10.009
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发表时间：
2013-01-01
影响因子：
2.7
通讯作者：
Payne CJ
中科院分区：
文献类型：
--
作者：
Gallagher SJ;Kofman AE;Huszar JM;Dannenberg JH;DePinho RA;Braun RE;Payne CJ
染色质修饰剂Swi-independent 3a（SIN 3A）与相关的组蛋白脱乙酰酶一起，以细胞特异性方式通过多种转录因子影响发育和分化期间的基因表达。Sin 3a对于维持小鼠胚泡、胚胎成纤维细胞和成肌细胞的内细胞团细胞是必需的，但对于滋养外胚层或支持细胞的存活不是必需的。为了更好地了解这种转录调节因子如何调节单个谱系内不同发育阶段的细胞，我们在小鼠中使用条件性基因靶向来消融来自围产期静止雄性生殖细胞和出生后分化精原细胞的Sin 3a。缺乏Sin 3a的维甲酸基因8（Stra 8）刺激的有丝分裂生殖细胞表达表现出增加的DNA损伤和凋亡，但通过减数分裂和精子发生共同进展，并以约50%的对照水平产生附睾精子，足以正常生育。相比之下，缺乏Sin 3a的围产期生殖细胞经历了快速消耗，这与细胞周期的重新进入相吻合，在循环时表现出2.5倍的组蛋白H3磷酸化增加，这表明了前期/中期阻滞;生殖细胞在出生后两周几乎完全不存在，导致不育。基因表达谱的新生儿睾丸含有Sin 3a缺失的生殖母细胞确定上调的转录高度相关的发育过程和模式的形成，和下调的转录参与核受体的活动，包括Nr 4a 1（Nur 77）。有趣的是，Nr 4a 1水平在含有Stra 8表达、Sin 3a缺失的精原细胞的睾丸中升高。SIN 3A直接与Nr 4a 1启动子结合，并且Nr 4a 1表达在体外精原细胞分化后减少。我们的结论是，在男性生殖细胞，Sin 3a是所需的生殖细胞的有丝分裂折返，但维持分化的精原细胞和随后的生精过程是必需的。
Chromatin modifier Swi-independent 3a (SIN3A), together with associated histone deacetylases, influences gene expression during development and differentiation through a variety of transcription factors in a cell-specific manner. Sin3a is essential for the maintenance of inner cell mass cells of mouse blastocysts, embryonic fibroblasts, and myoblasts, but is not required for the survival of trophectoderm or Sertoli cells. To better understand how this transcriptional regulator modulates cells at different developmental stages within a single lineage, we used conditional gene targeting in mice to ablate Sin3a from perinatal quiescent male gonocytes and from postnatal differentiating spermatogonia. Mitotic germ cells expressing stimulated by retinoic acid gene 8 (Stra8) that lacked Sin3a exhibited increased DNA damage and apoptosis, yet collectively progressed through meiosis and spermiogenesis and generated epididymal sperm at approximately 50% of control levels, sufficient for normal fertility. In contrast, perinatal gonocytes lacking Sin3a underwent rapid depletion that coincided with cell cycle reentry, exhibiting 2.5-fold increased histone H3 phosphorylation upon cycling that suggested a prophase/metaphase block; germ cells were almost entirely absent two weeks after birth, resulting in sterility. Gene expression profiling of neonatal testes containing Sin3a-deleted gonocytes identified upregulated transcripts highly associated with developmental processes and pattern formation, and downregulated transcripts involved in nuclear receptor activity, including Nr4a1 (Nur77). Interestingly, Nr4a1 levels were elevated in testes containing Stra8-expressing, Sin3a-deleted spermatogonia. SIN3A directly binds to the Nr4a1 promoter, and Nr4a1 expression is diminished upon spermatogonial differentiation in vitro. We conclude that within the male germline, Sin3a is required for the mitotic reentry of gonocytes, but is dispensable for the maintenance of differentiating spermatogonia and subsequent spermatogenic processes.
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影响因子：
14.8
作者：
Dahl, John Arne;Collas, Philippe
通讯作者：
Collas, Philippe
影响因子：
1.5
作者：
Gallardo, Teresa;Shirley, Lane;Castrillon, Diego H.
通讯作者：
Castrillon, Diego H.
影响因子：
16
作者：
Heinz S;Benner C;Spann N;Bertolino E;Lin YC;Laslo P;Cheng JX;Murre C;Singh H;Glass CK
通讯作者：
Glass CK
影响因子：
7.3
作者：
Gilbert, D. C.;Chandler, I.;Shipley, J.
通讯作者：
Shipley, J.
DOI：
10.1073/pnas.0730719100
发表时间：
2003-04-29
影响因子：
11.1
作者：
Ara, T;Nakamura, Y;Nagasawa, T
通讯作者：
Nagasawa, T