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首页> 外文期刊>Epigenetics & Chromatin >Histone variant macroH2A1 deletion in mice causes female-specific steatosis
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Histone variant macroH2A1 deletion in mice causes female-specific steatosis

机译：小鼠中组蛋白变异体macroH2A1缺失导致女性特异性脂肪变性

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Background Vertebrate heterochromatin contains a non-allelic variant of the histone H2A called macroH2A1, which has the characteristic of being three times the size of the canonical H2A. The macroH2A1 C-terminal extension can recruit onto chromatin the poly-ADP-ribose polymerase (PARP)1, which is crucial for DNA repair. This led to the speculation that macroH2A1 could be essential for genome surveillance; however, no experimental evidence supported this hypothesis. Because macroH2A1 has been found to be enriched on the inactive X-chromosome in females, it is thought to play a role in sex chromosome dosage compensation through its ability to regulate gene expression. However, more genetic data are needed to further understand the function of macroH2A1 in mammals. Results Deletion of the murine gene H2afy, which encodes for macroH2A1, resulted in lipid accumulation in liver. Hepatic steatosis caused by H2afy disruption occurred specifically in homozygous mutant females. The metabolic disorder constantly affected half of the number of homozygote females. Given the mixed genetic background of the mutants, an unreported genetic modifier is likely to influence the penetrance of the phenotype. In addition, the X-linked thyroxine-binding globulin (Tbg) gene was specifically upregulated in steatotic livers. Chromatin immunoprecitation indicated that macroH2A1 is enriched at the Tbg promoter in wild-type female animals, indicating that increased Tbg expression in H2afy null mutants is likely to be a direct consequence of the absence of macroH2A1. Furthermore, male mice, which are not prone to the metabolic disorder, had a reduced level of macroH2A1 incorporated into the Tbg promoter. Conclusions Because TBG is the main carrier of the thyroid hormone T4, which regulates energy metabolism, we propose that overexpression of TBG is responsible for the fat accumulation observed in H2afy-deficient liver. Moreover, our results suggest that the sexual dimorphism of the steatotic phenotype is probably due to the different incorporation of macroH2A1 in males and females. In combination with previous studies, our data demonstrate a role for macroH2A1 in regulating homeostasis in a sex-dependent manner, subject to genetic background.
机译：背景脊椎动物异染色质包含组蛋白H2A的非等位基因变体，称为macroH2A1，其特征是标准H2A大小的三倍。 macroH2A1 C端延伸可将染色质上的ADP核糖聚合酶（PARP）1募集到染色质上，这对DNA修复至关重要。这导致人们猜测macroH2A1对于基因组监视可能是必不可少的。但是，没有实验证据支持这一假设。由于已发现macroH2A1在女性的非活性X染色体上富集，因此认为它通过调节基因表达的能力在性染色体剂量补偿中起作用。但是，需要更多的遗传数据来进一步了解macroH2A1在哺乳动物中的功能。结果删除了编码macroH2A1的鼠基因H2afy，导致脂质在肝脏中蓄积。由H2afy破坏引起的肝脂肪变性特别发生在纯合突变女性中。代谢紊乱持续影响纯合女性的一半。考虑到突变体的混合遗传背景，未报告的遗传修饰物可能会影响表型的渗透性。此外，X链甲状腺素结合球蛋白（Tbg）基因在脂肪变性肝脏中特异性上调。染色质免疫沉淀表明，在野生型雌性动物中，Tbg启动子处富含macroH2A1，这表明H2afy null突变体中Tbg表达的增加很可能是缺少macroH2A1的直接结果。此外，不易于发生代谢紊乱的雄性小鼠的MacroH2A1掺入Tbg启动子的水平降低。结论因为TBG是甲状腺激素T4的主要载体，它调节能量代谢，所以我们认为TBG的过表达是导致H2afy缺乏的肝脏中脂肪堆积的原因。此外，我们的结果表明，脂肪性表型的性二态性可能是由于macroH2A1在男性和女性中的掺入不同所致。与以前的研究相结合，我们的数据证明了macroH2A1在遗传背景下以性别依赖性方式调节稳态的作用。

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