Genome-wide alteration of 5-hydroxymenthylcytosine in a mouse model of Alzheimer's disease.
Genome-wide alteration of 5-hydroxymenthylcytosine in a mouse model of Alzheimer's disease.
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阿尔茨海默病小鼠模型中 5-羟薄荷基胞嘧啶的全基因组改变
DOI：
10.1186/s12864-016-2731-1
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发表时间：
2016-05-20
期刊：
影响因子：
4.4
通讯作者：
Li X
中科院分区：
文献类型：
--
作者：
Shu L;Sun W;Li L;Xu Z;Lin L;Xie P;Shen H;Huang L;Xu Q;Jin P;Li X
阿尔茨海默病(AD)是最常见的神经退行性疾病，会导致认知功能下降。在阿尔茨海默病中，淀粉样蛋白β多肽聚集先于神经原纤维缠结的积累，这两者都是疾病的标志。绝大多数AD病例(>；90%)不是源于遗传缺陷，因此支持在一生中逐渐获得的表观遗传修饰的核心作用。强有力的证据表明，表观遗传修饰，包括组蛋白修饰和DNA甲基化，在AD中具有重要意义。最近的研究表明，5-羟甲基胞嘧啶(5hmC)在神经发育和衰老过程中受到动态调节。我们发现，淀粉样多肽1-42(Aβ1-42)在体外可以显著降低5hmC的总体水平。我们发现，在APP-PSEN1双转基因(DTG)小鼠的不同脑区，包括大脑皮层、小脑和海马区，5hmC的水平对发病有不同的反应。我们观察到，随着DTG小鼠年龄的增长，海马区5hmC的总体水平显著下降，但皮质和小脑中的5hmC没有明显下降。全基因组图谱在DTG小鼠中发现了差异羟甲基化区域(DhMRs)，这些区域在内含子、外显子和基因间隔区高度丰富。基因本体论分析表明，DhMR相关基因在涉及神经元发育/分化和神经元功能/存活的多条信号通路中高度丰富。5hmC介导的表观遗传调控可能参与了AD的发病机制。本文的在线版本(doi：10.1186/s12864-0162731-1)包含补充材料，授权用户可以使用。
Alzheimer’s disease (AD) is the most common form of neurodegenerative disorder that leads to a decline in cognitive function. In AD, aggregates of amyloid β peptide precede the accumulation of neurofibrillary tangles, both of which are hallmarks of the disease. The great majority (>90 %) of the AD cases are not originated from genetic defects, therefore supporting the central roles of epigenetic modifications that are acquired progressively during the life span. Strong evidences have indicated the implication of epigenetic modifications, including histone modification and DNA methylation, in AD. Recent studies revealed that 5-hydroxymethylcytosine (5hmC) is dynamically regulated during neurodevelopment and aging. We show that amyloid peptide 1–42 (Aβ1-42) could significantly reduce the overall level of 5hmC in vitro. We found that the level of 5hmC displayed differential response to the pathogenesis in different brain regions, including the cortex, cerebellum, and hippocampus of APP-PSEN1 double transgenic (DTg) mice. We observed a significant decrease of overall 5hmC in hippocampus, but not in cortex and cerebellum, as the DTg mice aged. Genome-wide profiling identified differential hydroxymethylation regions (DhMRs) in DTg mice, which are highly enriched in introns, exons and intergenic regions. Gene ontology analyses indicated that DhMR-associated genes are highly enriched in multiple signaling pathways involving neuronal development/differentiation and neuronal function/survival. 5hmC-mediated epigenetic regulation could potentially be involved in the pathogenesis of AD. The online version of this article (doi:10.1186/s12864-016-2731-1) contains supplementary material, which is available to authorized users.