Epigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk.

TitreEpigenomic profiling of newborns with isolated orofacial clefts reveals widespread DNA methylation changes and implicates metastable epiallele regions in disease risk.
Publication TypeJournal Article
Year of Publication2019
AuthorsGonseth-Nusslé, S, Shaw, GM, Roy, R, Segal, MR, Asrani, K, Rine, J, Wiemels, J, Marini, NJ
JournalEpigenetics
Pagination1-16
Date Published03/2019
DOI10.1080/15592294.2019.1581591
ISSN1559-2308
Mots-clésbirth defect, DNA Methylation, epigenetics, Folic Acid, metastable epiallele, Orofacial cleft
Abstract

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® 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.

Alternate URL

https://www.ncbi.nlm.nih.gov/pubmed/30870065?dopt=Abstract

Alternate JournalEpigenetics
Citation Key / SERVAL ID9462
Peer reviewRefereed
PubMed ID30870065
Grant ListR01 HD074695 / HD / NICHD NIH HHS / United States
                         

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