Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P16104 (H2AX)
 3,930 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

During spermiogenesis, histones are replaced first by transition proteins and then by protamines, resulting in a very condensed sperm DNA structure that is absolutely critical for normal sperm function. We have demonstrated previously that, despite a 9-wk recovery period, mature sperm from rats treated for 9 wk with bleomycin, etoposide, and cis-platinum (BEP), the drugs used to treat testicular cancer, have reduced levels of protamine 1 and a concomitant upregulation of specific histones, highlighting a problem in histone eviction. Here, we demonstrate that regulators of histone removal are increased in elongating spermatids following recovery; however, Ac-H4 and gamma H2AX histones remain elevated in elongating spermatids or caudal epididymal spermatozoa 9 wk post-BEP treatment. This indicates that chromatin remodelers and effector proteins that respond to histone removal cues may be a target of BEP treatment. A decrease in the expression of SMARCE1 in elongating spermatids may explain the persistent retention of histones in cauda epididymal sperm 9 wk after the cessation of BEP treatment. Remarkably, proteins implicated in the translational control and posttranslational processing of protamine 1 are also significantly elevated 9 wk post-BEP treatment, suggesting that histone eviction may dictate the DNA availability for protamine binding. Males mated to control females 9 wk after BEP treatment have reduced litter sizes; moreover, the profile of gene expression in the developing testes of their pups is altered. Altering the proportion of histones to protamine in mature spermatozoa has an adverse impact on male fecundity, with modifications to epigenetic marks potentially threatening normal progeny development.
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PMID:The effects of chemotherapy with bleomycin, etoposide, and cis-platinum (BEP) on rat sperm chromatin remodeling, fecundity and testicular gene expression in the progeny. 2398 70

Chromatin remodeling during spermatogenesis culminates in the exchange of nucleosomes for transition proteins and protamines as an important part of spermatid development to give rise to healthy sperm. Comparative immunofluorescence analyses of equine and murine testis histological sections were used to characterize nucleoprotein exchange in the stallion. Histone H4 hyperacetylation is considered a key event of histone removal during the nucleoprotein transition to a protamine-based sperm chromatin structure. In the stallion, but not the mouse, H4 was already highly acetylated in lysine residues K5, K8, and K12 in round spermatids almost immediately after meiotic division. Time courses of transition protein 1 (TP1), protamine 1, H2A histone family member Z (H2AFZ), and testis-specific histone H2B variant (TH2B) expression in stallion spermatogenesis were similar to the mouse where protamine 1 and TP1 were only expressed in elongating spermatids much later in spermatid development. The additional acetylation of H4 in K16 position (H4K16ac) was detected during a brief phase of spermatid elongation in both species, concomitant with the phosphorylation of the noncanonical histone variant H2AFX resulting from DNA strand break-mediated DNA relaxation. The results suggest that H4K16 acetylation, which is dependent on DNA damage signaling, may be more important for nucleosome replacement in spermiogenesis than indicated by data obtained in rodents and highlight the value of the stallion as an alternative animal model for investigating human spermatogenesis. A revised classification system of the equine spermatogenic cycle for simplified comparison with the mouse is proposed to this end.
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PMID:Early histone H4 acetylation during chromatin remodeling in equine spermatogenesis. 2918 93