Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk
Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk
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DOI：
10.1080/15592294.2019.1581591
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发表时间：
2019-02-01
期刊：
影响因子：
3.7
通讯作者：
Marini, Nicholas J.
中科院分区：
文献类型：
--
作者：
Gonseth, Semira;Shaw, Gary M.;Marini, Nicholas J.
唇裂伴或不伴腭裂（CL/P）是一种常见的人类出生缺陷，其病因尚不清楚。一些研究表明，围受孕期补充叶酸可以降低后代CL/P的风险。在这项研究中，我们通过确定DNA甲基化变化是否与CL/P相关来验证叶酸的预防作用是通过表观遗传修饰表现出来的这一假设。为了更容易观察母体叶酸对后代表观基因组的潜在影响，我们专注于美国强制性膳食叶酸强化之前的出生（即出生年份1997年或更早）。在一项182人病例对照研究中，使用Illumina（R）Human Beadchip 450 K阵列，从存档的新生儿血斑中评估基因组DNA甲基化水平。CL/P病例相对于对照组显示出显著的表观基因组低甲基化：63%的询问的CpG在新生儿病例中具有较低的甲基化水平，这一趋势在种族分层的亚组中保持不变。28个CpG位点达到表观基因组范围的显著性，并且全部为病例低甲基化。最显著的CL/P相关差异甲基化区域包括VTRNA 2 -1基因，其在病例中也是低甲基化的（FWER p = 0.014）。该区域先前已被表征为营养响应的亚稳态表观等位基因，并且CL/P相关的甲基化变化通常在推定的亚稳态表观等位基因区域处或附近更大。CL/P相关DMR的基因集富集分析显示参与腭发育的基因如WNT 9 B、MIR 140和LHX 8的过度表达。CL/P相关的DNA甲基化变化可能部分解释了口面裂对母体叶酸水平反应的机制。
Cleft lip with or without cleft palate (CL/P) is a common human birth defect whose etiologies remain largely unknown. Several studies have demonstrated that periconceptional supplementation of folic acid can reduce risk of CL/P in offspring. In this study, we tested the hypothesis that the preventive effect of folic acid is manifested through epigenetic modifications by determining whether DNA methylation changes are associated with CL/P. To more readily observe the potential effects of maternal folate on the offspring epigenome, we focused on births prior to mandatory dietary folate fortification in the United States (i.e. birth year 1997 or earlier). Genomic DNA methylation levels were assessed from archived newborn bloodspots in a 182-member case-control study using the Illumina (R) Human Beadchip 450K array. CL/P cases displayed striking epigenome-wide hypomethylation relative to controls: 63% of CpGs interrogated had lower methylation levels in case newborns, a trend which held up in racially stratified sub-groups. 28 CpG sites reached epigenome-wide significance and all were case-hypomethylated. The most significant CL/P-associated differentially methylated region encompassed the VTRNA2-1 gene, which was also hypomethylated in cases (FWER p = 0.014). This region has been previously characterized as a nutritionally-responsive, metastable epiallele and CL/P-associated methylation changes, in general, were greater at or near putative metastable epiallelic regions. Gene Set Enrichment Analysis of CL/P-associated DMRs showed an over-representation of genes involved in palate development such as WNT9B, MIR140 and LHX8. CL/P-associated DNA methylation changes may partly explain the mechanism by which orofacial clefts are responsive to maternal folate levels.