通过筛选人类印迹DMR甲基化鉴定基因组印迹的遗传和非遗传修饰因子。

IF 3.5 2区 生物学 Q1 GENETICS & HEREDITY
Francesco Cecere, Raissa Relator, Michael Levy, Ankit Verma, Haley McConkey, Bruno Hay Mele, Laura Pignata, Carlo Giaccari, Emilia D'Angelo, Subham Saha, Abu Saadat, Angela Sparago, Claudia Angelini, Flavia Cerrato, Bekim Sadikovic, Andrea Riccio
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引用次数: 0

摘要

背景:基因组印迹是正常发育所必需的,在影响生长、代谢、神经行为和癌症的先天性疾病中,已经发现了控制印迹基因起源依赖表达的母体差异甲基化区(iDMRs)的异常甲基化。在大多数情况下,印迹异常的原因是未知的。此外,这些研究通常是在有限数量的CpGs上进行的,并且缺乏对普通人群中iDMR甲基化的系统调查。结果:通过分析大量内部生成或在线可获得的未受影响个体和患有复杂和罕见疾病的患者的全基因组甲基化阵列数据集,我们确定了大量人群中最常见的iDMR甲基化谱,并确定了许多导致其血液DNA变异性的遗传和非遗传因素。我们发现甲基化变异性在iDMRs中并不均匀,靠近ZFP57结合位点的CpGs对甲基化变化的敏感性较低。我们证明了三种iDMR的甲基化多态性和其他几种非典型行为,并报道了25种疾病和47种非疾病复杂性状以及15种孟德尔和染色体疾病与iDMR甲基化变化的关联。最显著相关的复杂特征包括衰老、胞浆内单精子注射、非洲与欧洲血统、女性、产前和产后暴露于污染物和血细胞类型组成,而相关的遗传疾病包括唐氏综合症和发育障碍,其中DNA甲基转移酶DNMT1和DNMT3B、H3K36甲基转移酶SETD2、染色质重塑物SRCAP和SMARCA4以及转录因子ADNP存在分子缺陷。结论:这些发现确定了一些遗传和非遗传因素,包括与人类基因组印迹维持相关的新基因,这些因素可能在印迹异常疾病的病因学中起作用,并在分子诊断中具有明确的意义。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
Identification of genetic and non-genetic modifiers of genomic imprinting through screening of imprinted DMR methylation in humans.

Background: Genomic imprinting is required for normal development, and abnormal methylation of differentially methylated regions (iDMRs) controlling the parent of origin-dependent expression of the imprinted genes has been found in congenital disorders affecting growth, metabolism, neurobehavior, and in cancer. In most of these cases the cause of the imprinting abnormalities is unknown. Also, these studies have generally been performed on a limited number of CpGs, and a systematic investigation of iDMR methylation in the general population is lacking.

Results: By analysing a vast number of either in-house generated or online available whole-genome methylation array datasets of unaffected individuals, and patients with complex and rare disorders, we determined the most common iDMR methylation profiles in a large population and identified many genetic and non-genetic factors contributing to their variability in blood DNA. We found that methylation variability was not homogeneous within the iDMRs and that the CpGs closer to the ZFP57 binding sites are less susceptible to methylation changes. We demonstrated the methylation polymorphism of three iDMRs and the atypical behaviour of several others, and reported the association of 25 disease- and 47 non-disease-complex traits as well as 15 Mendelian and chromosomal disorders with iDMR methylation changes. The most significantly associated complex traits included ageing, intracytoplasmic sperm injection, African versus European ancestry, female sex, pre- and postnatal exposure to pollutants and blood cell type compositions, while the associated genetic diseases included Down syndrome and the developmental disorders with molecular defects in the DNA methyltransferases DNMT1 and DNMT3B, H3K36 methyltransferase SETD2, chromatin remodelers SRCAP and SMARCA4 and transcription factor ADNP.

Conclusions: These findings identify several genetic and non-genetic factors including new genes associated with genomic imprinting maintenance in humans, which may have a role in the aetiology of the diseases with imprinting abnormalities and have clear implications in molecular diagnostics.

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来源期刊
Epigenetics & Chromatin
Epigenetics & Chromatin GENETICS & HEREDITY-
CiteScore
7.00
自引率
0.00%
发文量
35
审稿时长
1 months
期刊介绍: Epigenetics & Chromatin is a peer-reviewed, open access, online journal that publishes research, and reviews, providing novel insights into epigenetic inheritance and chromatin-based interactions. The journal aims to understand how gene and chromosomal elements are regulated and their activities maintained during processes such as cell division, differentiation and environmental alteration.
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