DNA methylation analysis of Homeobox genes implicates HOXB7 hypomethylation as risk factor for neural tube defects
| Autor: | Elise Vangeel, Diether Lambrechts, Carla Verpoorten, Christine Wittevrongel, Raf Winand, Benedetta Izzi, Sophie Louwette, Chris Van Geet, Yves Moreau, Katrien Jansen, Kathleen Freson, Anne Rochtus |
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| Rok vydání: | 2015 |
| Předmět: |
Adult
Male congenital hereditary and neonatal diseases and abnormalities Cancer Research Meningomyelocele Population Biology Polymorphism Single Nucleotide Epigenesis Genetic medicine Animals Humans Epigenetics education Hox gene Molecular Biology Methylenetetrahydrofolate Reductase (NADPH2) Zebrafish Genetics Homeodomain Proteins education.field_of_study Genome SISTA Neural tube Infant Newborn Gene Expression Regulation Developmental Methylation DNA Methylation medicine.anatomical_structure Neurulation DNA methylation Homeobox CpG Islands Female Research Paper |
| DOI: | 10.6084/m9.figshare.1285536 |
| Popis: | Neural tube defects (NTDs) are common birth defects of complex etiology. Though family- and population-based studies have confirmed a genetic component, the responsible genes for NTDs are still largely unknown. Based on the hypothesis that folic acid prevents NTDs by stimulating methylation reactions, epigenetic factors, such as DNA methylation, are predicted to be involved in NTDs. Homeobox (HOX) genes play a role in spinal cord development and are tightly regulated in a spatiotemporal and collinear manner, partly by epigenetic modifications. We have quantified DNA methylation for the different HOX genes by subtracting values from a genome-wide methylation analysis using leukocyte DNA from 10 myelomeningocele (MMC) patients and 6 healthy controls. From the 1575 CpGs profiled for the 4 HOX clusters, 26 CpGs were differentially methylated (P-value < 0.05; β-difference > 0.05) between MMC patients and controls. Seventy-seven percent of these CpGs were located in the HOXA and HOXB clusters, with the most profound difference for 3 CpGs within the HOXB7 gene body. A validation case-control study including 83 MMC patients and 30 unrelated healthy controls confirmed a significant association between MMC and HOXB7 hypomethylation (-14.4%; 95% CI: 11.9-16.9%; P-value < 0.0001) independent of the MTFHR 667C>T genotype. Significant HOXB7 hypomethylation was also present in 12 unaffected siblings, each related to a MMC patient, suggestive of an epigenetic change induced by the mother. The inclusion of a neural tube formation model using zebrafish showed that Hoxb7a overexpression but not depletion resulted in deformed body axes with dysmorphic neural tube formation. Our results implicate HOXB7 hypomethylation as risk factor for NTDs and highlight the importance for future genome-wide DNA methylation analyses without preselecting candidate pathways. peerreview_statement: The publishing and review policy for this title is described in its Aims & Scope. aims_and_scope_url: http://www.tandfonline.com/action/journalInformation?show=aimsScope&journalCode=kepi20 ispartof: Epigenetics vol:10 issue:1 pages:92-101 ispartof: location:United States status: published |
| Databáze: | OpenAIRE |
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