Epigenetic profiling of somatic tissues from human autopsy specimens identifies tissue- and individual-specific DNA methylation patterns.
ABSTRACT DNA methylation is known to be associated with cell differentiation, aging, disease and cancer. There exists an expanding base of knowledge regarding tissue-specific DNA methylation, but we have little information about person-specific DNA methylation. Here, we analyze the DNA methylation patterns of multiple tissues from multiple individuals using a high-throughput quantitative assay of genome-wide DNA methylation, namely the Illumina GoldenGate BeadArray. DNA methylation patterns were largely conserved across 11 different tissues (r = 0.852) and across six individuals (r = 0.829), and we found that DNA was highly methylated in non-CpG islands and/or CpG sites that are not occupied by either H3K4me3 or H3K27me3 (P < 0.05). Finally, we found that the Illumina GoldenGate assay features a large number of probes (265/1505 probes, 17.6%) that contain single-nucleotide polymorphisms, which may interfere with DNA methylation analyses in genome-wide studies.
Article: Transcriptome changes affecting Hedgehog and cytokine signalling in the umbilical cord: implications for disease risk.[show abstract] [hide abstract]
ABSTRACT: Babies born at lower gestational ages or smaller birthweights have a greater risk of poorer health in later life. Both the causes of these sub-optimal birth outcomes and the mechanism by which the effects are transmitted over decades are the subject of extensive study. We investigated whether a transcriptomic signature of either birthweight or gestational age could be detected in umbilical cord RNA. The gene expression patterns of 32 umbilical cords from Singaporean babies of Chinese ethnicity across a range of birthweights (1698-4151 g) and gestational ages (35-41 weeks) were determined. We confirmed the differential expression pattern by gestational age for 12 genes in a series of 127 umbilical cords of Chinese, Malay and Indian ethnicity. We found that the transcriptome is substantially influenced by gestational age; but less so by birthweight. We show that some of the expression changes dependent on gestational age are enriched in signal transduction pathways, such as Hedgehog and in genes with roles in cytokine signalling and angiogenesis. We show that some of the gene expression changes we report are reflected in the epigenome. We studied the umbilical cord which is peripheral to disease susceptible tissues. The results suggest that soma-wide transcriptome changes, preserved at the epigenetic level, may be a mechanism whereby birth outcomes are linked to the risk of adult metabolic and arthritic disease and suggest that greater attention be given to the association between premature birth and later disease risk.PLoS ONE 01/2012; 7(7):e39744. · 4.09 Impact Factor
Article: Mono-allelic retrotransposon insertion addresses epigenetic transcriptional repression in human genome.[show abstract] [hide abstract]
ABSTRACT: Retrotransposons have been extensively studied in plants and animals and have been shown to have an impact on human genome dynamics and evolution. Their ability to move within genomes gives retrotransposons to affect genome instability. we examined the polymorphic inserted AluYa5, evolutionary young Alu, in the progesterone receptor gene to determine the effects of Alu insertion on molecular environment. We used mono-allelic inserted cell lines which carry both Alu-present and Alu-absent alleles. To determine the epigenetic change and gene expression, we performed restriction enzyme digestion, Pyrosequencing, and Chromatin Immunoprecipitation. We observed that the polymorphic insertion of evolutionally young Alu causes increasing levels of DNA methylation in the surrounding genomic area and generates inactive histone tail modifications. Consequently the Alu insertion deleteriously inactivates the neighboring gene expression. The mono-allelic Alu insertion cell line clearly showed that polymorphic inserted repetitive elements cause the inactivation of neighboring gene expression, bringing aberrant epigenetic changes.Journal of Biomedical Science 02/2012; 19:13. · 2.01 Impact Factor
Article: Genetic and non-genetic influences during pregnancy on infant global and site specific DNA methylation: role for folate gene variants and vitamin B12.[show abstract] [hide abstract]
ABSTRACT: Inter-individual variation in patterns of DNA methylation at birth can be explained by the influence of environmental, genetic and stochastic factors. This study investigates the genetic and non-genetic determinants of variation in DNA methylation in human infants. Given its central role in provision of methyl groups for DNA methylation, this study focuses on aspects of folate metabolism. Global (LUMA) and gene specific (IGF2, ZNT5, IGFBP3) DNA methylation were quantified in 430 infants by Pyrosequencing®. Seven polymorphisms in 6 genes (MTHFR, MTRR, FOLH1, CβS, RFC1, SHMT) involved in folate absorption and metabolism were analysed in DNA from both infants and mothers. Red blood cell folate and serum vitamin B(12) concentrations were measured as indices of vitamin status. Relationships between DNA methylation patterns and several covariates viz. sex, gestation length, maternal and infant red cell folate, maternal and infant serum vitamin B(12), maternal age, smoking and genotype were tested. Length of gestation correlated positively with IGF2 methylation (rho = 0.11, p = 0.032) and inversely with ZNT5 methylation (rho = -0.13, p = 0.017). Methylation of the IGFBP3 locus correlated inversely with infant vitamin B(12) concentration (rho = -0.16, p = 0.007), whilst global DNA methylation correlated inversely with maternal vitamin B(12) concentrations (rho = 0.18, p = 0.044). Analysis of common genetic variants in folate pathway genes highlighted several associations including infant MTRR 66G>A genotype with DNA methylation (χ(2) = 8.82, p = 0.003) and maternal MTHFR 677C>T genotype with IGF2 methylation (χ(2) = 2.77, p = 0.006). These data support the hypothesis that both environmental and genetic factors involved in one-carbon metabolism influence DNA methylation in infants. Specifically, the findings highlight the importance of vitamin B(12) status, infant MTRR genotype and maternal MTHFR genotype, all of which may influence the supply of methyl groups for DNA methylation. In addition, gestational length appears to be an important determinant of infant DNA methylation patterns.PLoS ONE 01/2012; 7(3):e33290. · 4.09 Impact Factor