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首页> 外文期刊>Epigenetics & Chromatin >Histone deacetylase inhibition leads to regulatory histone mark alterations and impairs meiosis in oocytes
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Histone deacetylase inhibition leads to regulatory histone mark alterations and impairs meiosis in oocytes

机译：组蛋白的脱乙酰酶抑制导致调节组蛋白标记改变，损害卵母细胞中的减数分裂

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Panobinostat (PB), a histone deacetylase (HDAC) inhibitor drug, is clinically used in the treatment of cancers. We investigated the effects of PB on murine ovarian functions in embryos and adult animals. C57BL/6J mice were treated with 5?mg/kg PB on alternate days from embryonic day (E) 6.5 to E15.5. We analysed the effects of PB on the ovaries by using immunofluorescence, gene expression analysis and DNA methylation analysis techniques. At E15.5, we observed increases in histone H3K9Ac, H4Ac and H3K4me3 marks, while the level of the silencing H3K9me3 mark decreased. Synaptonemal complex examination at E15.5, E17.5 and E18.5 showed a delay in meiotic progression characterized by the absence of synaptonemal complexes at E15.5 and the persistence of double-strand breaks (DSBs) at E17.5 and E18.5 in PB-exposed oocytes. We found that exposure to PB led to changes in the expression of 1169 transcripts at E15.5. Genes regulated by the male-specific factors SRY-Box Transcription Factor 9 (SOX9) and Doublesex and Mab-3-related Transcription factor 1 (DMRT1) were among the most upregulated genes in the ovaries of PB-exposed mice. In contrast, PB treatment led to decreases in the expression of genes regulated by the WNT4 pathway. Notably, we observed 119 deregulated genes encoding Zn-finger proteins. The observed alterations in epigenetic marks and gene expression correlated with decreases in the numbers of germ cells at E15.5. After birth, PB-exposed ovaries showed increased proliferation of primary and secondary follicles. We also observed decreases in the numbers of primordial, primary and secondary follicles in adult ovaries from mice that were exposed to PB in utero. Finally, epigenetic alterations such as decreased H3K4me3 and increased H4 acetylation levels were also detected in somatic cells surrounding fully grown oocytes. Our data suggest that inhibition of histone deacetylase by PB during a critical developmental window affects reprogramming and germ cell specification via alteration of epigenetic marks.
机译：Panobinostat（Pb）是一种组蛋白脱乙酰酶（HDAC）抑制剂药物，临床上用于治疗癌症。我们研究了PB对胚胎和成人动物鼠卵巢功能的影响。将C57BL / 6J小鼠用5μmg/ kg pb处理，在胚胎天（e）6.5至e15.5的交替日。通过使用免疫荧光，基因表达分析和DNA甲基化分析技术，分析了Pb对卵巢对卵巢的影响。在E15.5，我们观察到组蛋白H3K9AC，H4AC和H3K4ME3标记增加，而沉默H3K9ME3的水平降低。 E15.5，E17.5和E18.5在E15.5，E17.5和E18.5的Synaptonemal复合体检查表征的延迟，其特征在于E15.5在e15.5中没有Synapolemal络合物，并且在E17.5和E18处的双链断裂（DSB）的持续存在。 5在PB暴露的卵母细胞中。我们发现接触PB导致E15.5在1169转录物表达的变化。由男性特异性因子Sry-Box转录因子9（SOX9）和DoubleSex和MAB-3相关转录因子1（DMRT1）调节的基因是PB暴露小鼠卵巢中最上调的基因。相反，Pb处理导致由Wnt4途径调节的基因表达的表达降低。值得注意的是，我们观察了编码Zn-Finger蛋白的119个Deriocation基因。观察到的表观遗传标记和基因表达的改变与E15.5的生殖细胞数量的减少相关。出生后，PB暴露的卵巢表现出初级和二级卵泡的增殖增加。我们还观察到从小鼠暴露于子宫内Pb的成人卵巢中的原始卵巢，初级和二次卵泡的数量下降。最后，在周围完全生长的卵母细胞周围的体细胞中，还检测到诸如降低H3K4ME3和H4乙酰化水平的表观遗传改变。我们的数据表明，在关键发育窗口期间Pb对组蛋白脱乙酰酶的抑制影响通过改变表观遗传标记的重编程和生殖细胞规范。

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