Large-scale integration of DNA methylation and gene expression array platforms identifies both cis and trans relationships.
Large-scale integration of DNA methylation and gene expression array platforms identifies both cis and trans relationships.
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DOI：
10.1080/15592294.2022.2079293
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发表时间：
2022-12
期刊：
影响因子：
3.7
通讯作者：
York, Timothy P.
中科院分区：
文献类型：
--
作者：
Lancaster, Eva E.;Vladimirov, Vladimir, I;Riley, Brien P.;Landry, Joseph W.;Roberson-Nay, Roxann;York, Timothy P.
尽管表观基因组关联研究已经成功地确定了与疾病状态相关的DNA甲基化(DNaM)模式，但对疾病背后的病因机制的任何进一步表征仍然难以捉摸。这一知识差距并不是由于缺乏dNaM-特征关联，而是因为研究设计问题影响了Ewas结果的可解释性。尽管在预测特定CpG位点的功能方面存在已知的局限性，但大多数Ewas都坚持这样一个广泛的假设，即改变dNaM会导致最近端基因转录的伴随变化。这项研究结合了两个队列中的dNaM和基因表达(GE)测量，即青春期和青年双胞胎研究(AYATS)和怀孕、种族、环境、基因(PREG)研究，以提高对表观基因组调控机制的理解。顺式基因中与GE相关的CpG位点在转录因子结合区和中低CpG密度区富含CpG。与反式GE相关的CpG位点也在已知调控意义的区域中得到丰富，包括增强子区域。这些结果突出了将dNaM-转录注释限制在小基因组区间的问题，并质疑假设顺式dNaM-GE途径的有效性。基于这些发现，对Ewas结果的解释仅限于没有多组支持的研究，进一步的研究应该确定与GE相关的dNaM过度表达的基因组区域。对与GE相关的CpG位点的深入表征可以改善对改变的dNaM下游功能影响的预测，并为解释由Ewas产生的dNaM-性状关联的最佳做法提供信息。
Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm–trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with trans GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a cis DNAm–GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm–trait associations generated by EWAS.
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影响因子：
4.4
作者：
Bibikova, Marina;Barnes, Bret;Shen, Richard
通讯作者：
Shen, Richard
DOI：
10.1038/nrm4043
发表时间：
2015-09
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
Du J;Johnson LM;Jacobsen SE;Patel DJ
通讯作者：
Patel DJ
影响因子：
3.9
作者：
Anastasiadi D;Esteve-Codina A;Piferrer F
通讯作者：
Piferrer F
DOI：
10.1111/j.2517-6161.1995.tb02031.x
发表时间：
1995-01-01
影响因子：
5.8
作者：
BENJAMINI, Y;HOCHBERG, Y
通讯作者：
HOCHBERG, Y
影响因子：
4.5
作者：
Feldmann A;Ivanek R;Murr R;Gaidatzis D;Burger L;Schübeler D
通讯作者：
Schübeler D