Goldberg David C, Cloud Cameron, Lee Sol Moe, Barnes Bret, Gruber Steven, Kim Elliot, Pottekat Anita, Westphal Maximillian S, McAuliffe Luana, Majounie Elisa, Kalayil Manian Manesh, Zhu Qingdi, Tran Christine, Hansen Mark, Stojakovic Jelena, Parker Jared B, Kohli Rahul M, Porecha Rishi, Renke Nicole, Zhou Wanding
Center for Computational and Genomic Medicine, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Illumina, Inc., San Diego, CA 92122, USA.
Cell Genom. 2025 Jul 2:100929. doi: 10.1016/j.xgen.2025.100929.
Epigenome-wide association studies (EWASs) are transforming our understanding of the interplay between epigenetics and complex human traits. We introduce the methylation screening array (MSA) to enable scalable and quantitative screening of trait-associated DNA cytosine modifications in large human populations. The MSA integrates EWASs and cell-type-linked methylation signatures, covering diverse traits and diseases. Using the MSA to profile the ternary-code DNA methylations-dissecting 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and unmodified cytosine-revealed a previously unappreciated role of 5hmC in mediating human trait associations and epigenetic clocks. We demonstrated that 5hmCs complement 5mCs in defining epigenetic cell identities. In-depth analyses highlighted the cell-type context of EWAS and genome-wide association study (GWAS) hits. Targeting aging, we uncovered shared and tissue-specific 5hmC aging dynamics and tissue-specific rates of mitotic hyper- and hypomethylation. These findings chart a landscape of the complex interplay of the two forms of cytosine modifications in diverse human tissues and their roles in health and disease.
全表观基因组关联研究（EWAS）正在改变我们对表观遗传学与复杂人类性状之间相互作用的理解。我们引入甲基化筛选阵列（MSA），以实现对大量人群中与性状相关的DNA胞嘧啶修饰进行可扩展的定量筛选。MSA整合了EWAS和细胞类型相关的甲基化特征，涵盖了各种性状和疾病。使用MSA对三元编码DNA甲基化进行分析——剖析5-甲基胞嘧啶（5mC）、5-羟甲基胞嘧啶（5hmC）和未修饰的胞嘧啶——揭示了5hmC在介导人类性状关联和表观遗传时钟方面以前未被认识到的作用。我们证明5hmC在定义表观遗传细胞身份方面补充了5mC。深入分析突出了EWAS和全基因组关联研究（GWAS）结果的细胞类型背景。针对衰老，我们发现了共享的和组织特异性的5hmC衰老动态以及有丝分裂高甲基化和低甲基化的组织特异性速率。这些发现描绘了两种形式的胞嘧啶修饰在不同人类组织中的复杂相互作用及其在健康和疾病中的作用的图景。
