Epigenetic regulation of the nuclear genome associated with mitochondrial dysfunction in Leber's hereditary optic neuropathy (LHON).

IF 1 Q4 GENETICS & HEREDITY
Aswathy P Nair, Ambika Selvakumar, Janani Gopalarethinam, B Abishek Kumar, Balachandar Vellingiri, Mohana Devi Subramaniam
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Abstract

Leber's hereditary optic neuropathy (LHON) is a mitochondrial hereditary disease in which visual loss affects complex 1 activity of the electron transport chain of mitochondria. It first manifests as painless dulling or blurry in one or even both eyes, and as it develops, sharpness and color perception are lost. In addition to primary mitochondrial DNA (mtDNA) mutations, there are also other environmental and epigenetic factors involved in the pathogenesis of LHON. One of the most common locations for deadly pathogenic mutations in humans is the human complex I accessory NDUFS4 subunit gene. The iron-sulfur clusters of the electron input domain were distorted in the absence of NDUFS4, which reduced complex I function and elevated the production of reactive oxygen species. Therefore, here, we studied the epigenetic alterations of NDUFS4 by focusing on histone activation and repressive markers. We isolated peripheral blood mononuclear cells (PBMCs) from LHON patients and healthy individuals and examined epigenetic modifications in ND4 mutant cells and control cells. Chromatin immunoprecipitation-qRT PCR (ChIP-qRT PCR) assays were performed to investigate the modifications of histones. In comparison to their controls, both LHON patients and ND4 mutant cells exhibited a significant enrichment in activation and repressive markers. This finding indicates that these modifications might mitigate the impact of LHON mutations on complex 1 and aid in elucidating the mechanism underlying the progression of LHON disease.

Abstract Image

勒伯遗传性视神经病变(LHON)中与线粒体功能障碍相关的核基因组表观遗传调控。
勒伯遗传性视神经病变(LHON)是一种线粒体遗传病,视力丧失会影响线粒体电子传递链的复合物 1 的活动。该病最初表现为单眼甚至双眼无痛性视力迟钝或模糊,随着病情的发展,锐利度和色觉也会丧失。除了原发性线粒体 DNA(mtDNA)突变外,LHON 的发病机制还涉及其他环境和表观遗传因素。人类致命致病突变最常见的位置之一是人类复合体 I 附件 NDUFS4 亚基基因。在 NDUFS4 缺失的情况下,电子输入域的铁硫簇会发生扭曲,从而降低复合体 I 的功能并增加活性氧的产生。因此,我们在此通过关注组蛋白活化和抑制标记来研究 NDUFS4 的表观遗传学改变。我们分离了 LHON 患者和健康人的外周血单核细胞(PBMC),并检测了 ND4 突变细胞和对照细胞的表观遗传学改变。通过染色质免疫共沉淀-qRT PCR(ChIP-qRT PCR)检测来研究组蛋白的修饰。与对照组相比,LHON患者和ND4突变体细胞的激活和抑制标记物都有显著的富集。这一发现表明,这些修饰可能会减轻LHON突变对复合体1的影响,并有助于阐明LHON疾病的进展机制。
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来源期刊
Human Genome Variation
Human Genome Variation Biochemistry, Genetics and Molecular Biology-Genetics
CiteScore
2.30
自引率
0.00%
发文量
39
审稿时长
13 weeks
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