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Accumulation of epigenetic alterations at the promoters of transcriptional regulator genes in the placentas of pregnancy cases with inadequate maternal gestational weight gain

ABSTRACT: The concept that fetal environment correlates with health later on has been defined as developmental origins of health and disease (DOHaD), in which epigenetic modifications are considered to serve as a memory of exposure to in utero environments. Although many animal studies have demonstrated direct associations of maternal nutritional conditions during pregnancy with epigenetic alterations in the offspring, such evidence from human studies has been very limited. To gain more insight into the effects of in utero environments on the human placental epigenome, we obtained genome-wide methylation profiles for 34 postpartum placentas from pregnancies of normal and fetal growth restriction cases with various extents of maternal gestational weight gain (GWG). Whereas we initially failed to identify specific loci whose methylation is commonly altered across all subjects in each of subgroups categorized by the extent of GWG and baby’s birth weight, the application of Smirnov-Grubbs' outlier test to the same dataset revealed the accumulation of epigenetic alterations in the placentas under the adverse in utero environments. This methodology is potentially applicable to various epigenome studies for human populations. Further annotations of the genomic and functional features of loci with altered DNA methylation demonstrated that environmentally induced hyper-methylation is significantly frequently occurred at the promoter region of transcriptional regulator genes including polycomb-targets and zinc-finger genes. Aberrant epigenetic modifications at such developmental regulator loci, if occurred in fetuses in a similar manner as observed in the placentas examined in this study, would elevate the risk of developing various diseases including metabolic and mental disorders in the later life.

ORGANISM(S): Homo sapiens

PROVIDER: GSE62733 | GEO | 2015/09/30

SECONDARY ACCESSION(S): PRJNA265046

REPOSITORIES: GEO

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Project description:Background: Maternal smoking during pregnancy is a major risk factor for adverse health outcomes. The main objective of the study was to assess the impact of in utero tobacco exposure on DNA methylation in children born at term with appropriate weight at birth. Methods: Twenty mother-newborn dyads, after uncomplicated pregnancies, in the absence of perinatal illness were included. All mothers were healthy with no cardiovascular risk factors, except for the associated risks among those mothers who smoked. Umbilical cord blood (for methylation arrays) and maternal peripheral venous blood (for cotine level measurement) were collected and an epigenome-wide association study was performed using a 450K epigenome-wide scan (Illumina Infinium HumanMethylation 450BeadChip) with adjustment to normalize the DNA methylation for data cell variability in whole blood. Results: The maternal plasmatic cotinine levels ranged from 10.70-115.40 ng/ml in the exposed group to 0-0.59 ng/ml in the non-exposed group. After adjusting for multiple comparisons in 427102 probes, statistically significant differences for 31 CpG sites, associated to 25 genes were observed. There was a greater than expected proportion of statistically-significant loci located in CpG islands (FisherM-bM-^@M-^Ys exact test, p=0.029) and of those CpG islands, 90.3% exhibit higher methylation levels in the exposed group. The most striking and significant CpG site, cg05727225, is located in the chromosome 11p15.4, within the adrenomedullin gene. Conclusions: In utero tobacco exposure, even in the absence of fetal growth restriction, may alter the epigenome, contributing to global DNA hypomethylation. Therefore, DNA status can be used as a biomarker of prenatal insults. Considering the possibility to reverse epigenetic modifications, a window of opportunity exists to change the programmed chronic disease. Twenty mother-newborn dyads, after uncomplicated pregnancies, in the absence of perinatal illness were included. All mothers were healthy with no cardiovascular risk factors, except for the associated risks among those mothers who smoked. Umbilical cord blood were collected and an epigenome-wide association study was performed using a 450K epigenome-wide scan (Illumina Infinium HumanMethylation 450BeadChip) with adjustment to normalize the DNA methylation for data cell variability in whole blood.

Project description:Dysregulation of the epigenome is a common event in malignancy. However, deciphering the earliest cancer associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. H3K27me3 ChIP-chip was performed on HMEC and vHMEC from 4 donors, H3K9ac was performed on cells from 2 donors. Both H3K27me3 and H3K9ac ChIP was performed on two time points for vHMEC and used the same input materia.

Project description:Dysregulation of the epigenome is a common event in malignancy. However, deciphering the earliest cancer associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. We sought to compare the differences in gene expression in vHMEC when compared to isogenic HMEC cells. Two time points in the vHMEC growth phase were used to assess if continual passage of vHMEC contributed to expression differences. RNA was extracted from a total of 4 HMEC (and matched vHMEC) lines.

Project description:Dysregulation of the epigenome is a common event in malignancy. However, deciphering the earliest cancer associated epigenetic events remains a challenge. Cancer epigenome studies to date have primarily utilised cancer cell lines or clinical samples, where it is difficult to identify the initial epigenetic lesions from those that occur over time. Here, we analysed the epigenome of normal Human Mammary Epithelial Cells (HMEC) and a matched variant cell population (vHMEC) that has escaped senescence and undergone partial carcinogenic transformation. Using this model system we sought to identify the earliest epigenetic changes that potentially occur during carcinogenesis. First we show that the transcriptome of vHMEC resembles that of basal-like breast cancer. Moreover, in vHMEC there is significant deregulation of MYC, p53, EZH2/polycomb, the Aryl Hydrocarbon Receptor (AHR) and miRNAs-143, 145, 199a and 519a at the transcriptional level. Second, we find that vHMEC exhibit genome-wide changes in DNA methylation affecting key cancer-associated pathways. Hypermethylation predominately impacted gene promoters (particularly those targeted by AHR and TP53) and polycomb associated loci, whereas hypomethylation frequently affected enhancers. Next we show that long range epigenetic deregulation occurred in vHMEC involving concordant change in chromatin modification and gene expression across ~0.5-1Mb regions. Finally, we demonstrate that the DNA methylation changes we observe in vHMECs, occur in basal-like breast cancer (notably FOXA1 hypermethylation).. Overall our results suggest that the first steps of carcinogenesis are associated with a co-ordinated deregulation of DNA methylation and chromatin modification spanning a range of genomic loci potentially targeted by key transcription factors and a corresponding deregulation of transcriptional networks. We sought to study the chromatin modification profile of human mammary epithelial cells (HMEC) and a matched isogenic variant population (vHMEC) utilising ChIP-seq. ChIP was performed against H3K27ac, H3K36me3 and H3K27me3 for a HMEC and vHMEC timpoint in one donor. H3K4me3 CHIP was performed in two donors, which were treated as biological replicates.

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Accumulation of epigenetic alterations at the promoters of transcriptional regulator genes in the placentas of pregnancy cases with inadequate maternal gestational weight gain

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