Department of Human Genetics, David Geffen School of Medicine, UCLA, 615 Charles E. Young Drive South, Los Angeles, CA, 90095, USA.
Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, CA, 90095, USA.
BMC Bioinformatics. 2022 Sep 5;23(1):364. doi: 10.1186/s12859-022-04899-1.
Pathogenic mutations in genes that control chromatin function have been implicated in rare genetic syndromes. These chromatin modifiers exhibit extraordinary diversity in the scale of the epigenetic changes they affect, from single basepair modifications by DNMT1 to whole genome structural changes by PRM1/2. Patterns of DNA methylation are related to a diverse set of epigenetic features across this full range of epigenetic scale, making DNA methylation valuable for mapping regions of general epigenetic dysregulation. However, existing methods are unable to accurately identify regions of differential methylation across this full range of epigenetic scale directly from DNA methylation data.
To address this, we developed DMRscaler, a novel method that uses an iterative windowing procedure to capture regions of differential DNA methylation (DMRs) ranging in size from single basepairs to whole chromosomes. We benchmarked DMRscaler against several DMR callers in simulated and natural data comparing XX and XY peripheral blood samples. DMRscaler was the only method that accurately called DMRs ranging in size from 100 bp to 1 Mb (pearson's r = 0.94) and up to 152 Mb on the X-chromosome. We then analyzed methylation data from rare-disease cohorts that harbor chromatin modifier gene mutations in NSD1, EZH2, and KAT6A where DMRscaler identified novel DMRs spanning gene clusters involved in development.
Taken together, our results show DMRscaler is uniquely able to capture the size of DMR features across the full range of epigenetic scale and identify novel, co-regulated regions that drive epigenetic dysregulation in human disease.
控制染色质功能的基因中的致病性突变与罕见的遗传综合征有关。这些染色质修饰物在其影响的表观遗传变化的规模上表现出非凡的多样性，从 DNMT1 引起的单个碱基对修饰到 PRM1/2 引起的全基因组结构变化。DNA 甲基化模式与整个表观遗传尺度上的一系列不同的表观遗传特征相关，使得 DNA 甲基化对于绘制普遍的表观遗传失调区域非常有价值。然而，现有的方法无法直接从 DNA 甲基化数据中准确识别整个表观遗传尺度上的差异甲基化区域。
为了解决这个问题，我们开发了 DMRscaler，这是一种新颖的方法，它使用迭代窗口处理程序来捕获大小从单个碱基对到整个染色体的差异 DNA 甲基化（DMR）区域。我们在模拟和自然数据中比较 XX 和 XY 外周血样本，将 DMRscaler 与几个 DMR 调用器进行了基准测试。DMRscaler 是唯一一种能够准确调用大小从 100bp 到 1Mb（皮尔逊 r=0.94）和长达 152Mb 的 X 染色体上的 DMR 的方法。然后，我们分析了携带 NSD1、EZH2 和 KAT6A 等染色质修饰基因突变的罕见疾病队列中的甲基化数据，DMRscaler 在此分析中确定了跨越涉及发育的基因簇的新型 DMR。
总之，我们的研究结果表明，DMRscaler 能够独特地捕获整个表观遗传尺度上 DMR 特征的大小，并识别出新型的、共同调节的区域，这些区域在人类疾病中导致了表观遗传失调。
