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首页> 外文期刊>Human Molecular Genetics >Genome-wide loss of 5-hmC is a novel epigenetic feature of huntington's disease
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Genome-wide loss of 5-hmC is a novel epigenetic feature of huntington's disease

机译：全基因组5-hmC的丧失是亨廷顿氏病的一种新的表观遗传学特征

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摘要

5-Hydroxymethylcytosine (5-hmC)mayrepresent anewepigeneticmodification of cytosine. While thedynamics of 5-hmC during neurodevelopment have recently been reported, little is known about its genomic distribution and function(s) in neurodegenerative diseases such as Huntington's disease (HD).We here observed a marked reduction of the 5-hmC signal in YAC128 (yeast artificial chromosome transgenewith 128 CAG repeats) HDmouse brain tissueswhencomparedwith age-matched wild-type (WT) mice, suggestingadeficiencyof 5-hmCreconstructionin HDbrains duringpostnatal development. Genome-wide distributionanalysisof5-hmCfurtherconfirmedthediminishment of the 5-hmC signal in striatum and cortex in YAC128 HD mice. General genomic features of 5-hmC are highlyconserved, notbeingaffectedbyeitherdiseaseor brain regions. Intriguingly, wehaveidentifieddisease-specific (YAC128 versus WT) differentially hydroxymethylated regions (DhMRs), and found that acquisition of DhmRs in gene body is a positive epigenetic regulator for gene expression. Ingenuity pathway analysis (IPA) of genotypespecificDhMR- annotatedgenesrevealedthatalternationofanumberofcanonicalpathwaysinvolvingneuronaldevelopment/differentiation (Wnt/b-catenin/Sox pathway, axonal guidance signaling pathway) and neuronal function/survival (glutamate receptor/calcium/CREB, GABA receptor signaling, dopamine-DARPP32 feedback pathway, etc.) could be important for the onset of HD. Our results indicate that loss of the 5-hmC marker is a novel epigenetic feature in HD, and that this aberrant epigenetic regulationmay impair the neurogenesis, neuronal function and survival in HD brain. Our study also opens a new avenue for HD treatment; re-establishing the native 5-hmC landscapemay have the potential to slow/halt the progression of HD.
机译：5-羟甲基胞嘧啶（5-hmC）可能代表胞嘧啶的新表观遗传修饰。虽然最近报道了神经发育过程中5-hmC的动力学，但对于它在诸如亨廷顿氏病（HD）等神经退行性疾病中的基因组分布和功能知之甚少。我们在这里观察到YAC128中5-hmC信号显着降低。 （具有128个CAG重复序列的酵母人工染色体转基因）与年龄匹配的野生型（WT）小鼠相比，HDmouse的脑组织较弱，提示在出生后发育过程中HDbrains的5hmC重建不足。 5-hmC的全基因组分布分析进一步证实了YAC128 HD小鼠纹状体和皮质中5-hmC信号的减弱。 5-hmC的一般基因组特征是高度保守的，不受疾病或大脑区域的影响。有趣的是，我们已经鉴定出疾病特异性（YAC128与WT）差异化的羟甲基化区域（DhMRs），并发现基因体中DhmRs的获得是基因表达的积极表观遗传调控因子。基因型特异性DhMR注释基因的独创性途径分析（IPA）揭示了涉及神经发育/分化的多种典型途径（Wnt / b-catenin / Sox途径，轴突指导信号途径）和神经元功能/存活途径（谷氨酸受体/钙受体，ABA-钙，CREB，等）对于HD的发作可能很重要。我们的结果表明，5-hmC标记的缺失是HD的一种新的表观遗传学特征，这种异常的表观遗传调控可能会损害HD大脑的神经发生，神经元功能和生存。我们的研究也为高清治疗开辟了一条新途径。重新建立本地的5hmC格局可能会减缓/阻止HD进程。

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