From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define genetic-epigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and whole-genome coverage will have multiple mechanistic and practical implications. By producing and analyzing DNA sequence variation (n = 303), DNA methylation (n = 303) and mRNA expression data (n = 80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations. These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions.

Background: From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define geneticepigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variation on gene expression and DNA methylation in human placentas at high resolution and wholegenome coverage will have multiple mechanistic and practical implications.Results: By producing and analyzing DNA sequence variation (n=303), DNA methylation (n=303) and mRNA expression data (n=80) from placentas from healthy women, we investigate the regulatory landscape of the human placenta and offer analytical approaches to integrate different types of genomic data and address some potential limitations of current platforms. We distinguish two profiles of interaction between expression and DNA methylation, revealing linear or bimodal effects, reflecting differences in genomic context, transcription factor recruitment, and possibly cell subpopulations.Conclusions: These findings help to clarify the interactions of genetic, epigenetic, and transcriptional regulatory mechanisms in normal human placentas. They also provide strong evidence for genotype-driven modifications of transcription and DNA methylation in normal placentas. In addition to these mechanistic implications, the data and analytical methods presented here will improve the interpretability of genome-wide and epigenome-wide association studies for human traits and diseases that involve placental functions. Author summaryThe placenta is a critical organ playing multiple roles including oxygen and metabolite transfer from mother to fetus, hormone production, and vascular perfusion. With this study, we aimed to deliver a placenta-specific regulatory map based on a combination of publicly available and newly generated data. To complete this reference, we obtained genotype information (n=303), DNA methylation (n=303) and expression data (n=80) for placentas from healthy women. Our analysis of methylation and expression quantitative trait loci (QTLs) and correlations between methylation and expression data were designed to identify fundamental associations between genome, transcriptome, and epigenome in this key fetal organ. The results provide high-resolution genetic and epigenetic maps specific to the placenta based on a representative ethnically diverse cohort. As interest and efforts are growing to better understand the etiology of placental disease and the impact of the environment on placental function these data will provide a reference and enhance future investigations.

the behaviour of human gastric mucosa has been described more recently by Walder (1953). These investigations have provided much interesting information, but they throw no light on the possible normal functional relation between motor activity in the muscularis mucosae and that in the underlying main muscle coats. In the oesophagus, however, the chief muscle layers may be striated throughout, as in the rabbit and rat, or a mixture of striated and smooth muscle, as in the cat and human. Since the muscularis mucosae of this region has not so far been investigated it seemed of interest to study the behaviour of isolated oesophageal muscularis mucosae from certain of these species (cat, rabbit and rat) with a view to (a) comparing its responses to drugs with those already described for other regions, and (b) ascertaining whether the presence of striated muscle in the adjacent layers of the gut wall influenced in any demonstrable way the behaviour of the muscularis mucosae. METHODSThe method of separating the muscularis mucosae from the outer muscle coats was similar to that described by Gunn & Underhill (1914). The cats were killed in a variety of ways, the rabbits and rats by a blow on the head. The oesophagus was removed immediately, together with a small portion of the stomach and placed in cold Krebs' solution (Krebs & Henseleit, 1932). The stomach tissue was then removed by cutting along the white line on the mucosal surface which denotes the cardio-oesophageal junction. The oesophagus was divided into three equal portions and the mucosal layer, including the muscularis, obtained as a tube by making a longitudinal incision through the outer muscle layer and dissecting it off.The mucosal tube was then suspended in a bath (capacity 100 ml.) containing oxygenated Krebs' solution ( + 5% CO.) at 370C and attached to a light lever writing on smoked paper. All

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Hyperglycemia and other adverse exposures early in life that reprogram stem cells may lead to long-lasting phenotypic influences over the lifetime of an individual. Hyperglycemia and oxidative stress cause DNA damage when they exceed the protective capabilities of the cell, in turn affecting cellular function. DNA damage in response to hyperglycemia and oxidative stress was studied in human umbilical cord mesenchymal stem cells (hUC-MSCs) from large-for-gestational-age (LGA) infants of mothers with gestational diabetes mellitus (LGA-GDM) and control subjects. We tested the response of these cells to hyperglycemia and oxidative stress, measuring reactive oxygen species (ROS) levels and antioxidant enzyme activities. We find that hUC-MSCs from LGA-GDM infants have increased DNA damage when exposed to oxidative stress. With the addition of hyperglycemic conditions, these cells have an increase in ROS and a decrease in antioxidant glutathione peroxidase (GPx) activity, indicating a mechanism for the increased ROS and DNA damage. This study demonstrates that a memory of in utero hyperglycemia, mediated through downregulation of GPx activity, leads to an increased susceptibility to oxidative stress. The alteration of GPx function in self-renewing stem cells, can mediate the effect of intrauterine hyperglycemia to be propagated into adulthood and contribute to disease susceptibility.