Distinct requirements for Sin3a in perinatal male gonocytes and differentiating spermatogonia

Abstract

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.

The Modification of Tet1 in Male Germline Stem Cells and Interact with PCNA, HDAC1 to promote their Self-renewal and Proliferation

“…As a key part of epigenetic modification, histone modification plays important roles in spermatogenesis. As a histone deacetylase, Sin3A, a member of the Sin3 family, which is linked to tumorigenesis and regulate gene expression through their role as histone deacetylases (HDACs)32, it was also distinctly required in differentiating spermatogonia and cell cycle progression3334. Another histone deacetylase we noted is Hdac1, which could cooperate with Sin3A as SIN3A-HDAC1 complex, Hdac1 could also protect the testicular damage3536.…”

Sin3a-associated Hdac1 and Hdac2 are essential for hematopoietic stem cell homeostasis and contribute differentially to hematopoiesis

“…This is in agreement with previous findings that deletion of Hdac1/2 or Sin3a results in cell cycle arrest and apoptosis. 11,[21][22][23][24][25][26][27] Deregulated expression of genes linked to cell survival and stem cell maintenance, such as Dmkn, Nurcks1 and Tpt1, warrants further investigation to determine whether these genes are direct Hdac1/2 targets.…”

CYP26 Enzymes Are Necessary Within the Postnatal Seminiferous Epithelium for Normal Murine Spermatogenesis1

“…Floxed reporter mice have provided information regarding when Cre recombinase is first expressed and in what cell type for both Cre lines used in this study. For the Stra8-iCre line, Cre recombinase is first expressed at 3 days postpartum (dpp) in a subset of the Aal undifferentiated spermatogonia and all A1 differentiating spermatogonia [22,23]. For the Amh-Cre line, Cre recombinase is first expressed at Embryonic Day 15 and specifically in Sertoli cells [20].…”