Department of Biochemistry and Molecular Biology, Faculty of Science and Informatics, University of Szeged, Közép fasor 52, H-6726 Szeged, Hungary.
Doctoral School in Biology, Faculty of Science and Informatics, University of Szeged, H-6726 Szeged, Hungary.
Int J Mol Sci. 2022 Dec 2;23(23):15173. doi: 10.3390/ijms232315173.
Huntington's Disease (HD) is a fatal neurodegenerative disorder caused by the expansion of a polyglutamine-coding CAG repeat in the gene. One of the main causes of neurodegeneration in HD is transcriptional dysregulation that, in part, is caused by the inhibition of histone acetyltransferase (HAT) enzymes. HD pathology can be alleviated by increasing the activity of specific HATs or by inhibiting histone deacetylase (HDAC) enzymes. To determine which histone's post-translational modifications (PTMs) might play crucial roles in HD pathology, we investigated the phenotype-modifying effects of PTM mimetic mutations of variant histone H3.3 in a model of HD. Specifically, we studied the mutations (K→Q: acetylated; K→R: non-modified; and K→M: methylated) of lysine residues K9, K14, and K27 of transgenic H3.3. In the case of H3.3K14Q modification, we observed the amelioration of all tested phenotypes (viability, longevity, neurodegeneration, motor activity, and circadian rhythm defects), while H3.3K14R had the opposite effect. H3.3K14Q expression prevented the negative effects of reduced (a HAT acting on H3K14) on HD pathology, while it only partially hindered the positive effects of heterozygous (an HDAC acting on H3K14). Thus, we conclude that the Gcn5-dependent acetylation of H3.3K14 might be an important epigenetic contributor to HD pathology.
亨廷顿病（HD）是一种致命的神经退行性疾病，由 基因中编码多聚谷氨酰胺的 CAG 重复扩展引起。HD 中神经退行性变的主要原因之一是转录失调，部分原因是组蛋白乙酰转移酶（HAT）酶的抑制。通过增加特定 HAT 的活性或抑制组蛋白去乙酰化酶（HDAC），可以缓解 HD 病理学。为了确定哪种组蛋白的翻译后修饰（PTMs）可能在 HD 病理学中起关键作用，我们研究了变体组蛋白 H3.3 的 PTM 模拟突变在 HD 模型中的表型修饰作用。具体来说，我们研究了赖氨酸残基 K9、K14 和 K27 的突变（K→Q：乙酰化；K→R：未修饰；和 K→M：甲基化）的转基因 H3.3。在 H3.3K14Q 修饰的情况下，我们观察到所有测试表型（活力、寿命、神经退行性变、运动活性和昼夜节律缺陷）的改善，而 H3.3K14R 则有相反的效果。H3.3K14Q 表达可防止减少（一种作用于 H3K14 的 HAT）对 HD 病理学的负面影响，而仅部分阻碍杂合 （一种作用于 H3K14 的 HDAC）的积极影响。因此，我们得出结论，Gcn5 依赖性 H3.3K14 乙酰化可能是 HD 病理学的一个重要表观遗传贡献者。
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