唐氏综合征新生儿中主要先天性心脏缺陷的表观基因组特征。
Epigenomic signature of major congenital heart defects in newborns with Down syndrome.
机构信息
Department of Medical Microbiology and Immunology, School of Medicine, University of California, Davis, CA, USA.
Perinatal Origins of Disparities Center, University of California, Davis, CA, USA.
出版信息
Hum Genomics. 2023 Oct 6;17(1):92. doi: 10.1186/s40246-023-00540-1.
BACKGROUND
Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.
METHODS
We used the Illumina EPIC array and whole-genome bisulfite sequencing (WGBS) to quantitate DNA methylation for 86 NDBS samples from the California Biobank Program: (1) 45 DS-CHD (27 female, 18 male) and (2) 41 DS non-CHD (27 female, 14 male). We analyzed global CpG methylation and identified differentially methylated regions (DMRs) in DS-CHD versus DS non-CHD comparisons (both sex-combined and sex-stratified) corrected for sex, age of blood collection, and cell-type proportions. CHD DMRs were analyzed for enrichment in CpG and genic contexts, chromatin states, and histone modifications by genomic coordinates and for gene ontology enrichment by gene mapping. DMRs were also tested in a replication dataset and compared to methylation levels in DS versus typical development (TD) WGBS NDBS samples.
RESULTS
We found global CpG hypomethylation in DS-CHD males compared to DS non-CHD males, which was attributable to elevated levels of nucleated red blood cells and not seen in females. At a regional level, we identified 58, 341, and 3938 CHD-associated DMRs in the Sex Combined, Females Only, and Males Only groups, respectively, and used machine learning algorithms to select 19 Males Only loci that could distinguish CHD from non-CHD. DMRs in all comparisons were enriched for gene exons, CpG islands, and bivalent chromatin and mapped to genes enriched for terms related to cardiac and immune functions. Lastly, a greater percentage of CHD-associated DMRs than background regions were differentially methylated in DS versus TD samples.
CONCLUSIONS
A sex-specific signature of DNA methylation was detected in NDBS of DS-CHD compared to DS non-CHD individuals. This supports the hypothesis that epigenetics can reflect the variability of phenotypes in DS, particularly CHDs.
背景
先天性心脏缺陷（CHD）影响大约一半的唐氏综合征（DS）患者，但不完全外显的分子原因尚不清楚。以前的研究主要集中在确定与 DS 患者 CHD 相关的遗传风险因素，但缺乏对表观遗传标记贡献的综合研究。我们的目的是从患有主要 CHD 的 DS 个体的新生儿干血斑（NDBS）与无 CHD 的 DS 个体中鉴定和描述 DNA 甲基化差异。
方法
我们使用 Illumina EPIC 阵列和全基因组亚硫酸氢盐测序（WGBS）对来自加利福尼亚生物库计划的 86 个 NDBS 样本进行 DNA 甲基化定量：（1）45 个 DS-CHD（27 名女性，18 名男性）和（2）41 个 DS 非-CHD（27 名女性，14 名男性）。我们分析了全球 CpG 甲基化，并在性别、采血年龄和细胞比例校正的情况下，在 DS-CHD 与 DS 非-CHD 比较中鉴定了差异甲基化区域（DMR）（性别合并和性别分层）。通过基因组坐标分析 CHD-DMR 在 CpG 和基因背景、染色质状态和组蛋白修饰中的富集情况，并通过基因映射进行基因本体富集分析。还在复制数据集和 DS 与典型发育（TD）WGBS NDBS 样本的甲基化水平中对 DMR 进行了测试。
结果
我们发现 DS-CHD 男性与 DS 非-CHD 男性相比，全球 CpG 低甲基化，这归因于有核红细胞水平升高，而女性中未见这种情况。在区域水平上，我们分别在性别合并、女性仅和男性仅组中鉴定了 58、341 和 3938 个 CHD 相关 DMR，并且使用机器学习算法选择了 19 个可区分 CHD 与非-CHD 的男性仅 DMR。所有比较中的 DMR 均富集了基因外显子、CpG 岛和双价染色质，并映射到与心脏和免疫功能相关术语富集的基因上。最后，与背景区域相比，DS 与 TD 样本中 CHD 相关 DMR 的差异甲基化百分比更大。
结论
与 DS 非-CHD 个体相比，DS-CHD 的 NDBS 中检测到 DNA 甲基化的性别特异性特征。这支持了这样一种假设，即表观遗传学可以反映 DS 中表型的可变性，特别是 CHD。
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