DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome单亲二体受试者的DNA甲基化图谱提供了人类基因组中父母表观遗传偏倚的图谱
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【摘要学习】
Genomic imprinting【基因印记】 is a mechanism in which gene expression varies depending on parental origin.Imprinting</u> occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions(DMRs).（印迹是通过两个亲本等位基因上的差异表观遗传标记而发生的，其中大多数印迹基因座以差异甲基化区域（DMR）的存在为特征） To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methyl-ation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpGanalyzed across ~1.9 Mb of the 15q11–q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNA-seq data, we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally,using a population sample of 4,004 blood methylomes, we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects.
【introduction学习】
Genomic imprinting is a mechanism in which the expression of genes** varies depending on the gender of the parent from which they are inherited. Imprinting is mediated via an epigenetic mechanism involving differential DNA methylation and histone modifications on the two parental alleles, with most imprinted genes marked by CpG-rich differentially **methylated regions (DMRs).1Although some reports suggest that >100 genes show evidence of imprinting in human,2recent genome-wide surveys of imprinted DNA methylation and gene expression have been able to confirm only about half this number.3,4.Uniparental disomy (UPD) （单亲二体）is a condition where both homologs of a chromosome pair are inherited from the same parent, either from the mother (maternal, or UPDmat) or from the father (paternal, or UPDpat). UPD can lead to functional nullisomy for imprinted genes（UPD可以导致印迹基因的功能无效，导致临床的综合征）, resulting in clinically recognizable syndromes such as Prader-Willi/Angel-man syndrome (PWS [MIM: 176270], AS [MIM: 105830],UPD(15)mat/pat), Beckwith-Wiedemann syndrome (BWS[MIM: 130650], UPD(11)pat), or transient neonatal dia-betes mellitus (TNDM [MIM: 601410], UPD(6)pat).5,6Incontrast, UPD for other chromosomes has not been associated with phenotypic （表型）consequences, leading to the presumption that these chromosomes do not harbor imprinted genes.
Several studies have utilized allele-specific gene expression as a method of detecting imprinted expression in humans,4,8–11although these approaches can be hindered by the requirement for informative polymorphisms（信息多态性）. However, in model organisms the use of reciprocal interstrain or inter-species hybrids can generate offspring with extremely high rates of heterozygosity, allowing the efficient detection of parentally biased expression.12,13 Alternative methods to detect imprinting have used the fact that the maternal and paternal genomes have differential epigenetic marks at most imprinted loci. This approach has an advantage over expression-based methods, in that these differential methylation marks are often preserved even in tissues that lack imprinted expression.14Because one of the key features of imprinted genes is the presence of parent-of-origin-specific methylation, the systematic comparison of DNA methylation patterns in maternal versus paternal chromosomes provides a powerful approach for the identification of imprinted loci that does not rely on the availability of polymorphisms. We previously applied this method to study parental epigenetic bias on chromosome 15,15and it has since been utilized in several other studies.3,16,17 We have assembled a collection of 53 individuals with maternal and paternal UPD and four Turner syndrome affected samples for 19 different chromosomes, allowing the efficient detection of DMRs associated with imprintedgenes for most of the human genome. This cohort is further supplemented by additional tissue samples with uniparental inheritance for every chromosome. Here we report the identification of 77 DMRs inthehuman genome that show consistent parental epigenetic bias. Using RNA- seq data from 33 tissues, we further show that many of these loci show evidence of imprinted expression. Finally, we perform a population-scale methylome analysis to define patterns of normal epigenetic variation at imprinted DMRs and identify rare individuals who exhibit global epigenetic shifts across multiple imprinted loci.
AIM:
To identify sites of parental epigenetic bias
RESLUT：
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1.identified 77 DMRs, including nearly all thosedescribed in previous studies, in addition to 34 DMRs not previously reported 总共鉴定了77个DMR，其中60个表现出母亲的甲基化偏向，17个表现为父亲的甲基化偏向。
2.
include a DMR at TUBGCP5 within the recurrent15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder.
detected signatures consistent with imprinted expression associated with nine novel DMRs.
METHODS
1.收集了53名患有母系和父系UPD的个体，以及19条不同染色体的4个特纳综合征患者样本------→从中鉴定出77个DMR，其中34 DMR是从未被报道过的
2.用33个组织的RNAseq数据进行分析———→这些位点中的许多都显示出印记表达
3.进行群体规模的甲基组分析，以定义印记DMR的正常表观遗传变异模式，并识别在多个印记位点上表现出表观遗传转移的罕见个体。
CONCLUSION:
1.父母偏倚的表观遗传标记并不总是局限于离散的调控元件，例如CpG岛或基因启动子，它可以扩展到整个染色体结构域
2.并非所有与印迹基因相关的差异甲基化位点都显示半甲基化模式，其中一个亲本等位基因被完全甲基化，另一个等位基因在很大程度上为未甲基化。
COMMENTS
太难了，我看不懂；超出了我的理解范畴
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