In Utero Exposures, Infant Growth, and DNA Methylation of Repetitive Elements and Developmentally Related Genes in Human Placenta

Abstract

Background: Fetal programming describes the theory linking environmental conditions during embryonic and fetal development with risk of diseases later in life. Environmental insults in utero may lead to changes in epigenetic mechanisms potentially affecting fetal development.Objectives: We examined associations between in utero exposures, infant growth, and methylation of repetitive elements and gene-associated DNA in human term placenta tissue samples.Methods: Placental tissues and associated demographic and clinical data were obtained from subjects delivering at Women and Infants Hospital in Providence, Rhode Island (USA). Methylation levels of long interspersed nuclear element-1 (LINE-1) and the Alu element AluYb8 were determined in 380 placental samples from term deliveries using bisulfite pyrosequencing. Genomewide DNA methylation profiles were obtained in a subset of 184 samples using the Illumina Infinium HumanMethylation27 BeadArray. Multiple linear regression, model-based clustering methods, and gene set enrichment analysis examined the association between birth weight percentile, demographic variables, and repetitive element methylation and gene-associated CpG locus methylation.Results: LINE-1 and AluYb8 methylation levels were found to be significantly positively associated with birth weight percentile (p = 0.01 and p < 0.0001, respectively) and were found to differ significantly among infants exposed to tobacco smoke and alcohol. Increased placental AluYb8 methylation was positively associated with average methylation among CpG loci found in polycomb group target genes; developmentally related transcription factor binding sites were overrepresented for differentially methylated loci associated with both elements.Conclusions: Our results suggest that repetitive element methylation markers, most notably AluYb8 methylation, may be susceptible to epigenetic alterations resulting from the intrauterine environment and play a critical role in mediating placenta function, and may ultimately inform on the developmental basis of health and disease.

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

“…The AR 4 is expressed in most stem cells (13)(14)(15)(16)(17)(18). The AR in prostate stem/progenitor cells plays key roles in prostate development and differentiation processes (19,20) as well as in prostate cancer (PCa) initiation and progression (21,22).…”

DNA Methylation, Substance Use and Addiction: a Systematic Review of Recent Animal and Human Research from a Developmental Perspective

“…Wilhelm-Benartzi et al [36] found that maternal alcohol intake positively associated with global LINE-1 (but not with AluYb8) methylation in placental tissue. One candidate gene study found that cord blood methylation of the developmental gene ZAC1 positively correlated with prenatal maternal alcohol intake as well as associating with reduced fetal and postnatal weight [37].…”

Degree of methylation ofZAC1(PLAGL1) is associated with prenatal and post-natal growth in healthy infants of the EDEN mother child cohort

“…2,3 In addition, alcohol consumption is associated with alteration of DNA methylation. 4 Loss of imprinting (LOI) through loss (LOM) or gain (GOM) of methylation is involved in many human disorders and cancers. [5][6][7] Furthermore, it has been suggested that imprinted genes form a network of co-regulated genes (IGN) involved in the control of embryonic development.…”