title: Epigenomic profiling in visceral white adipose tissue of offspring of mice exposed to late gestational sleep fragmentation.
abstract: BACKGROUND
  Sleep fragmentation during late gestation (LG-SF) is one of the major perturbations associated with sleep apnea and other sleep disorders during pregnancy. We have previously shown that LG-SF induces metabolic dysfunction in offspring mice during adulthood.
  
  
  OBJECTIVE
  To investigate the effects of late LG-SF on metabolic homeostasis in offspring and to determine the effects of LG-SF on the epigenome of visceral white adipose tissue (VWAT) in the offspring.
  
  
  METHODS
  Time-pregnant mice were exposed to LG-SF or sleep control during LG (LG-SC) conditions during the last 6 days of gestation. At 24 weeks of age, lipid profiles and metabolic parameters were assessed in the offspring. We performed large-scale DNA methylation analyses using methylated DNA immunoprecipitation (MeDIP) coupled with microarrays (MeDIP-chip) in VWAT of 24-week-old LG-SF and LG-SC offspring (n=8 mice per 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 significant increases in body weight (31.7 vs 28.8 g; P=0.001), visceral (642.1 vs 497.0 mg; P=0.002) and subcutaneous (293.1 vs 250.1 mg; P=0.001) fat mass, plasma cholesterol (110.6 vs 87.6 mg dl(-1); P=0.001), triglycerides (87.3 vs 84.1 mg dl(-1); P=0.003) and homeostatic model assessment-insulin resistance values (8.1 vs 6.1; P=0.007) in the LG-SF group. MeDIP analyses revealed that 2148 DMRs (LG-SF vs LG-SC; P<0.0001, model-based analysis of tilling-arrays algorithm). A large proportion of the DMR-associated genes have reported functions that are altered in obesity and metabolic syndrome, such as Cartpt, Akt2, Apoe, Insr1 and so on. 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 with the metabolic processes and inflammatory responses in VWAT. LG-SF-induced epigenetic alterations may underlie increases in the susceptibility to obesity and metabolic syndrome in the offspring.
authors: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors: R
authors: R
authors: Cortese
authors: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors: A
authors: A
authors: Khalyfa
authors: Bioinformatics Core Facility, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA.
authors: R
authors: 0000000261051704
authors: R
authors: Bao
authors: Bioinformatics Core Facility, Comprehensive Cancer Center, The University of Chicago, Chicago, IL, USA.
authors: J
authors: J
authors: Andrade
authors: Section of Pediatric Sleep Medicine, Department of Pediatrics, Pritzker School of Medicine, The University of Chicago, Chicago, IL, USA.
authors: D
authors: D
authors: Gozal
mesh_terms: D052436:Adipose Tissue, White / Q000378:metabolism*; D000818:Animals; D000831:Animals, Newborn; D004195:Disease Models, Animal; D057890:Epigenomics; D005260:Female; D050152:Intra-Abdominal Fat / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000378:metabolism*; D011247:Pregnancy; D011248:Pregnancy Complications / Q000378:metabolism*; D011297:Prenatal Exposure Delayed Effects / Q000378:metabolism*; D012892:Sleep Deprivation / Q000378:metabolism*