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Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation

ABSTRACT: Background: Late gestational sleep fragmentation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. Objectives: To investigate the effects of late LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring. Methods: Time-pregnant mice were exposed to LG-SF or control sleep (LG-SC) conditions during the last 6 days of gestation. We performed large-scale DNA methylation analyses using MeDIP coupled to microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice/group). Univariate multiple-testing adjusted statistical analyses were applied to identify differentially methylated regions (DMRs) between the groups. DMRs were mapped to their corresponding genes, and tested for potential overlaps with biological pathways and gene networks. Results: We detected 2148 DMRs between LG-SF and LG-SC groups (p< 0.0001, MAT algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome. Overrepresented pathways and gene networks were related to metabolic regulation and inflammatory response. Conclusions: Our findings show a major role for epigenomic regulation of pathways associated to metabolic processes and inflammatory response in VWAT. Furthermore, LG-SF-induced epigenetic alterations appear to increase the susceptibility to obesity and metabolic syndrome in the offspring.

ORGANISM(S): Mus musculus

PROVIDER: GSE63208 | GEO | 2015/04/02

SECONDARY ACCESSION(S): PRJNA266992

REPOSITORIES: GEO

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Project description:BACKGROUND: Epigenetic processes enable the environment to modulate gene transcription during fetal development, ultimately leading to stable phenotypic changes throughout the lifespan. There is a relatively high prevalence of altered sleep patterns during late gestation, especially obstructive sleep apnea (OSA). Intermittent hypoxia (IH) is a hallmark of OSA caused by periodic obstructions of the upper airway, which occurs along with sleep fragmentation (SF). We have previously shown that adult offspring of late gestational SF (LG-SF) mothers exhibited metabolic alterations via epigenomic alterations. The aims of this study were to investigate the effects of LG-IH on metabolic features in offspring and to determine the effects of LG-IH on the epigenome of visceral white adipose tissue (VWAT) in the offspring. METHODS: Time-pregnant mice were exposed to LG-IH or room air (RA) paradigms conditions during the last 6 days of gestation (LG-IH and LG-RA groups, respectively). Offspring were weaned at 21 days and fed with normal chow diet. At 24 weeks, lipid profiles and metabolic parameters were assessed. We performed large scale DNA methylation analysis using MeDIP coupled to microarrays (MeDIP-chip) in offspring VWAT (n=8 mice per group). Regions exhibiting differential DNA methylation (DMRs) between the groups were mapped to their corresponding genes and tested for potential overlaps with biological processes and pathways using Ingenuity Pathway Analysis. RESULTS: We detected 1520 DMRs between the LG-IH and LG-RA groups (p< 0.0001, two-way ANOVA), associated with 693 genes. A significant portion of these genes (n=162) were also associated with previously identified DMRs in LG-SF offspring (p=1.35 x 10-97, hypergeometric test). Pathway analyses showed that genes affected by LG-IH and LG-SF, were mainly associated with molecular processes related to metabolic regulation and inflammatory response. In particular for LG-IH, biochemical pathways related to energy production through amino acid and fatty acid metabolism (i.e. methionine, choline and 2-oxobutanoate degradation pathways, methylmalonyl pathway, cysteine biosynthesis, etc.). CONCLUSIONS: Our findings suggest a major role for epigenomic alterations in the metabolic dysfunction of adult offspring born to LG-IH and LH-SF mothers. Furthermore, whereas LG-IH may concomitantly act upon metabolic pathways also affected by LG-SF, LG-IH also affects biochemical processes underlying energy production in VWAT of the offspring.

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Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation

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