Genetic variants influence on the placenta regulatory landscape

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

DNA methylation loci in placenta associated with birthweight and expression of genes relevant for early development and adult diseases

Background Birthweight marks an important milestone of health across the lifespan, including cardiometabolic disease risk in later life. The placenta, a transient organ at the maternal-fetal interface, regulates fetal growth. Identifying genetic loci where DNA methylation in placenta is associated with birthweight can unravel genomic pathways that are dysregulated in aberrant fetal growth and cardiometabolic diseases in later life. Results We performed placental epigenome-wide association study (EWAS) of birthweight in an ethnic diverse cohort of pregnant women (n = 301). Methylation at 15 cytosine-(phosphate)-guanine sites (CpGs) was associated with birthweight (false discovery rate (FDR) < 0.05). Methylation at four (26.7%) CpG sites was associated with placental transcript levels of 15 genes (FDR < 0.05), including genes known to be associated with adult lipid traits, inflammation and oxidative stress. Increased methylation at cg06155341 was associated with higher birthweight and lower FOSL1 expression, and lower FOSL1 expression was correlated with higher birthweight. Given the role of the FOSL1 transcription factor in regulating developmental processes at the maternal-fetal interface, epigenetic mechanisms at this locus may regulate fetal development. We demonstrated trans-tissue portability of methylation at four genes (MLLT1, PDE9A, ASAP2, and SLC20A2) implicated in birthweight by a previous study in cord blood. We also found that methylation changes known to be related to maternal underweight, preeclampsia and adult type 2 diabetes were associated with lower birthweight in placenta. Conclusion We identified novel placental DNA methylation changes associated with birthweight. Placental epigenetic mechanisms may underlie dysregulated fetal development and early origins of adult cardiometabolic diseases. Clinical trial registration ClinicalTrials.gov, NCT0091213

Multi-ancestry genome-wide association study of gestational diabetes mellitus highlights genetic links with type 2 diabetes

Gestational diabetes mellitus (GDM) is associated with increased risk of pregnancy complications and adverse perinatal outcomes. GDM often reoccurs and is associated with increased risk of subsequent diagnosis of type 2 diabetes (T2D). To improve our understanding of the aetiological factors and molecular processes driving the occurrence of GDM, including the extent to which these overlap with T2D pathophysiology, the GENetics of Diabetes In Pregnancy Consortium assembled genome-wide association studies of diverse ancestry in a total of 5485 women with GDM and 347 856 without GDM. Through multi-ancestry meta-analysis, we identified five loci with genome-wide significant association (P < 5 x 10(-8)) with GDM, mapping to/near MTNR1B (P = 4.3 x 10(-54)), TCF7L2 (P = 4.0 x 10(-16)), CDKAL1 (P = 1.6 x 10(-4)), CDKN2A-CDKN2B (P = 4.1 x 10(-9)) and HKDC1 (P = 2.9 x 10(-8)). Multiple lines of evidence pointed to the shared pathophysiology of GDM and T2D: (i) four of the five GDM loci (not HKDC1) have been previously reported at genome-wide significance for T2D; (ii) significant enrichment for associations with GDM at previously reported T2D loci; (iii) strong genetic correlation between GDM and T2D and (iv) enrichment of GDM associations mapping to genomic annotations in diabetes-relevant tissues and transcription factor binding sites. Mendelian randomization analyses demonstrated significant causal association (5% false discovery rate) of higher body mass index on increased GDM risk. Our results provide support for the hypothesis that GDM and T2D are part of the same underlying pathology but that, as exemplified by the HKDC1 locus, there are genetic determinants of GDM that are specific to glucose regulation in pregnancy.Peer reviewe

French Roadmap for complex Systems 2008-2009

This second issue of the French Complex Systems Roadmap is the outcome of the Entretiens de Cargese 2008, an interdisciplinary brainstorming session organized over one week in 2008, jointly by RNSC, ISC-PIF and IXXI. It capitalizes on the first roadmap and gathers contributions of more than 70 scientists from major French institutions. The aim of this roadmap is to foster the coordination of the complex systems community on focused topics and questions, as well as to present contributions and challenges in the complex systems sciences and complexity science to the public, political and industrial spheres

Consequences of a maternal perinatal undernutrition on the development of Brain-Adipose Axis in male rat : focus on leptin

Une malnutrition périnatale sensibilise au développement, à l’âge adulte, du syndrome métabolique. Ce syndrome est associé à une altération de l’équilibre entre prise alimentaire et dépense énergétique. L’axe hypothalamo-adipocytaire, constitué du système nerveux central et du tissu adipeux, joue un rôle majeur dans le contrôle du métabolisme. En effet, ces deux tissus vont, via la leptine, être capables de réguler la prise alimentaire et la dépense énergétique. Peu de travaux ont porté sur les conséquences de stress périnataux sur la mise en place de l’axe hypothalamo-adipocytaire chez le nouveau-né.Nous avons entrepris, en ciblant nos travaux sur la leptine, d’analyser les conséquences d’une dénutrition maternelle périnatale (DMP) de 50% (modèle FR50) sur la mise en place de cet axe chez le raton de la naissance au sevrage.Les animaux témoins présentent un pic de leptine autour de la deuxième semaine de vie qui est fortement réduit chez les ratons FR50. Cette diminution est associée à une altération des connexions hypothalamiques des neurones à POMC. La réduction des taux de leptine chez le nouveau-né est conjointe à une diminution des concentrations de leptine dans le plasma des mères et dans le lait, ce qui montre que la période de lactation et le statut nutritionnel maternel jouent un rôle capital dans les mécanismes de programmation. En périphérie, les animaux FR50 présentent un changement transitoire de phénotype du tissu adipeux périgonadique, avec l’apparition d’un phénotype de type brun. L’ensemble de nos travaux indique que la DMP modifie la mise en place de l’axe hypothalamo-adipocytaire et que la période de lactation constitue une période clé pour la programmation de mécanismes impliqués dans le contrôle du métabolisme énergétique.Perinatal malnutrition sensitizes to the development of chronic adult diseases such as the metabolic syndrome. These metabolic disorders frequently result from an imbalance between food intake and energy expenditure.The brain-adipose axis (BAA) that is constituted from central nervous system and adipose tissues plays a crucial role in the regulation of metabolism. These two tissues indeed control both food intake and energy expenditure, via different factors such as leptin. Little is known concerning the consequences of perinatal stress on the development of BAA in newborns,.The major goal of my Ph D was to analyze the consequences of a 50% maternal perinatal undernutrition (FR50 model) on the development of BAA in male rat from birth to weaningControl animals exhibited a plasma surge of leptin around the second week of life while this peak was drasticallyreduced in FR50 pups. This reduction is associated with an alteration of the hypothalamic projections of POMC nerve fibers. The decreased leptin plasma levels in FR50 pups is accompanied by a reduction of leptin concentration both in plasma from mothers as in the milk from undernourished mothers, reinforcing the idea that lactation and nutritional status of the mother during this period are key “programming” factors. Interestingly, in postnatal day (PND) 21 FR50 animals, perigonadal adipose tissue exhibited a transient modification with the acquisition of a brown-like Altogether, our results indicate that maternal perinatal undernutrition modifies the development of the BAA and that lactation is a critical timewindow for the programming of mechanisms involved in the regulation of energy metabolism

Conséquences d'une dénutrition maternelle périnatale sur la mise en place de l'axe hypothalamo-adipocytaire chez le rat mâle (focus sur la leptine)

Une malnutrition périnatale sensibilise au développement, à l âge adulte, du syndrome métabolique. Ce syndrome est associé à une altération de l équilibre entre prise alimentaire et dépense énergétique. L axe hypothalamo-adipocytaire, constitué du système nerveux central et du tissu adipeux, joue un rôle majeur dans le contrôle du métabolisme. En effet, ces deux tissus vont, via la leptine, être capables de réguler la prise alimentaire et la dépense énergétique. Peu de travaux ont porté sur les conséquences de stress périnataux sur la mise en place de l axe hypothalamo-adipocytaire chez le nouveau-né.Nous avons entrepris, en ciblant nos travaux sur la leptine, d analyser les conséquences d une dénutrition maternelle périnatale (DMP) de 50% (modèle FR50) sur la mise en place de cet axe chez le raton de la naissance au sevrage.Les animaux témoins présentent un pic de leptine autour de la deuxième semaine de vie qui est fortement réduit chez les ratons FR50. Cette diminution est associée à une altération des connexions hypothalamiques des neurones à POMC. La réduction des taux de leptine chez le nouveau-né est conjointe à une diminution des concentrations de leptine dans le plasma des mères et dans le lait, ce qui montre que la période de lactation et le statut nutritionnel maternel jouent un rôle capital dans les mécanismes de programmation. En périphérie, les animaux FR50 présentent un changement transitoire de phénotype du tissu adipeux périgonadique, avec l apparition d un phénotype de type brun. L ensemble de nos travaux indique que la DMP modifie la mise en place de l axe hypothalamo-adipocytaire et que la période de lactation constitue une période clé pour la programmation de mécanismes impliqués dans le contrôle du métabolisme énergétique.Perinatal malnutrition sensitizes to the development of chronic adult diseases such as the metabolic syndrome. These metabolic disorders frequently result from an imbalance between food intake and energy expenditure.The brain-adipose axis (BAA) that is constituted from central nervous system and adipose tissues plays a crucial role in the regulation of metabolism. These two tissues indeed control both food intake and energy expenditure, via different factors such as leptin. Little is known concerning the consequences of perinatal stress on the development of BAA in newborns,.The major goal of my Ph D was to analyze the consequences of a 50% maternal perinatal undernutrition (FR50 model) on the development of BAA in male rat from birth to weaningControl animals exhibited a plasma surge of leptin around the second week of life while this peak was drasticallyreduced in FR50 pups. This reduction is associated with an alteration of the hypothalamic projections of POMC nerve fibers. The decreased leptin plasma levels in FR50 pups is accompanied by a reduction of leptin concentration both in plasma from mothers as in the milk from undernourished mothers, reinforcing the idea that lactation and nutritional status of the mother during this period are key programming factors. Interestingly, in postnatal day (PND) 21 FR50 animals, perigonadal adipose tissue exhibited a transient modification with the acquisition of a brown-like Altogether, our results indicate that maternal perinatal undernutrition modifies the development of the BAA and that lactation is a critical timewindow for the programming of mechanisms involved in the regulation of energy metabolism.LILLE1-Bib. Electronique (590099901) / SudocSudocFranceF

Probabilistic modeling to estimate jellyfish ecophysiological properties and size distributions

International audienceWhile Ocean modeling has made significant advances over the last decade, its complex biological component is still oversimplified. In particular, modeling organisms in the ocean system must integrate parameters to fit both physiological and ecological behaviors that are together very difficult to determine. Such difficulty occurs for modeling Pelagia noctiluca. This jellyfish has a high abundance in the Mediterranean Sea and could contribute to several biogeochemical processes. However, gelatinous zooplanktons remain poorly represented in biogeochemical models because uncertainties about their ecophysiology limit our understanding of their potential role and impact. To overcome this issue, we propose, for the first time, the use of the Statistical Model Checking Engine (SMCE), a probabilitybased computational framework that considers a set of parameters as a whole. Contrary to standard parameter inference techniques, SMCE identifies sets of parameters that fit both laboratory-culturing observations and in situ patterns while considering uncertainties. Doing so, we estimated the best parameter sets of the ecophysiological model that represents the jellyfish growth and degrowth in laboratory conditions as well as its size. Behind this application, SMCE remains a computational framework that supports the projection of a model with uncertainties in broader contexts such as biogeochemical processes to drive future studies

CFD water spray model development and physical parameter study on the evaporative cooling

International audiencePolydisperse evaporating spray study is complex due to the influence of a large number of physical parameters. Several studies have performed CFD simulations to investigate the cooling performance of water spray systems, but a few have investigated their impact upon heat exchangers. For industrial applications, developing a new and simple approach to simulate polydisperse evaporating sprays upon complex 3D geometries is of great interest. Thus this paper is the first contribution to a CFI) numerical tool development to study water spray impact on heat exchangers and presents a CFD water spray model. The spray model is divided into two steps: the spray formation and its dispersion in air flow. The spray development step describes the moment from droplet injection to the position where droplet velocity equals air velocity. This position and the spray dimension are accessed through the droplet trajectory analysis, while the amount of liquid water evaporated is obtained by integrating the droplet size decrease equation. This first part provides boundary conditions for the second step used in a 3D CFD software: CodeSaturne. This CFD code solves the Navier-Stokes equations for the spray with the k-epsilon turbulence model. Three transport variables are introduced: the liquid potential temperature, theta(L), the total water specific humidity, q(w) which are conservative variables for the evaporation processes; and the total number, of droplets, N-c. The droplet evaporation is added to the N-c equation through a source term approach. A lognormal law is also used to represent and follow the evolution of the droplet spectra. The model results are compared with experimental results from droplets injected in counter-flow configurations in a wind tunnel. Temperature fields show good agreements with the experimental data. Finally, this paper provides a parametric analysis of water evaporation and air cooling upon a specified surface. The impacts of the relative humidity, spray angle, water mass flow rate and droplet size distribution are investigated. Our approach is an alternative to classical Lagrangian approaches used in spray applications. It provides accurate and consistent results with low computational time in comparison with the literature

A mixed passengers-goods transportation network for territories with a low population density

International audienc

CH4 IPDA Lidar mission data simulator and processor for MERLIN: prototype development at LMD/CNRS/Ecole Polytechnique

The MEthane Remote sensing Lidar missioN (MERLIN), currently in phase C, is a joint cooperation between France and Germany on the development of a spatial Integrated Path Differential Absorption (IPDA) LIDAR (LIght Detecting And Ranging) to conduct global observations of atmospheric methane. This presentation will focus on the status of a LIDAR mission data simulator and processor developed at LMD (Laboratoire de Météorologie Dynamique), Ecole Polytechnique, France, for MERLIN to assess the performances in realistic observational situations