Cytosine methylation dysregulation in neonates following intrauterine growth restriction.
BACKGROUND
Perturbations of the intrauterine environment can affect fetal development during critical periods of plasticity, and can increase susceptibility to a number of age-related diseases (e.g., type 2 diabetes mellitus; T2DM), manifesting as late as decades later. We hypothesized that this biological memory is mediated by permanent alterations of the epigenome in stem cell populations, and focused our studies specifically on DNA methylation in CD34+ hematopoietic stem and progenitor cells from cord blood from neonates with intrauterine growth restriction (IUGR) and control subjects.


RESULTS
Our epigenomic assays utilized a two-stage design involving genome-wide discovery followed by quantitative, single-locus validation. We found that changes in cytosine methylation occur in response to IUGR of moderate degree and involving a restricted number of loci. We also identify specific loci that are targeted for dysregulation of DNA methylation, in particular the hepatocyte nuclear factor 4alpha (HNF4A) gene, a well-known diabetes candidate gene not previously associated with growth restriction in utero, and other loci encoding HNF4A-interacting proteins.


CONCLUSIONS
Our results give insights into the potential contribution of epigenomic dysregulation in mediating the long-term consequences of IUGR, and demonstrate the value of this approach to studies of the fetal origin of adult disease.
Einstein
Francine
F
Department of Obstetrics, Gynecology and Women's Health, Albert Einstein College of Medicine, Bronx, New York, United States of America.
Thompson
Reid F
RF
Bhagat
Tushar D
TD
Fazzari
Melissa J
MJ
Verma
Amit
A
Barzilai
Nir
N
Greally
John M
JM
D003596:Cytosine / Q000378:metabolism*; D019175:DNA Methylation; D005317:Fetal Growth Retardation / Q000235:genetics*; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007231:Infant, Newborn; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic
C496592:HNF4A protein, human; D051557:Hepatocyte Nuclear Factor 4; D003596:Cytosine