According to the Developmental Origins of Adult Disease Hypothesis, perturbations in the gestational orearly postnatal environment influence the development of adult diseases. Data from our laboratory and others collectively suggest that this occurs with reprogramming of gene expression via epigenetic changes to the 'histone code'. What constitutes the 'histone code'? While almost all cells of an individual bear near identical genomic constitutions, phenotype is ultimately determined by the gene expression profile. Gene expression is maintained by two major mechanisms: (1) transcription factors and post-transcriptional modifiers, and (2) epigenetic modifications, in particular DNA methylation and core-histone modifications. Research is rapidly demonstrating the importance of the epigenetic code to normal human development as well as the burden of disease that occurs when the epigenetic code or machinery malfunctions. However, it remains a fundamental question in the field of epigenomics research if and how the fetal epigenome varies in response to maternal phenotype and diet modifications, and if it is truly predictive of later in life disease states (suh as obesity and diabetes). Our lab is dedicated to studying the effects of the in utero milieu on epigenetic changes in the fetus. We have developed a non-human primate model of obesity, now in its ninth year, to study the fetal histone code. We have shown that it is maternal high fat diet consumption (rather than maternal obesity per se) which results in abnormal development of both the hypothalamic neurocircuitry and peripheral entrainment integral to regulation of fetal glucose and lipid homeostasis;these alterations are accompanied by epigenetic changes in chromatin structure resulting in reprogramming of fetal gene expression. As a result of this work, we are now uniquely poised to apply concomitantly developed high throughput sequencing technologies with advanced analytical approaches to decipher the molecular means by which the primate epigenome is modified. In this proposal we present our application of these technologies (ChIP-Seq, RNA-Seq, and custom CpG arrays) in our genome wide characterization of the fetal primate hepatic epigenome. Our studies are relevant to public health since they will clarify how the maternal diet influences the developing primate infant, and whether these changes increase the risk of later in life obesity.

Public Health Relevance

Given the growing body of evidence that many (if not the vast majority) of chronic, non-communicable disease have their origins in fetal life, understanding the in utero factors that impact fetal metabolism and development are among the most important public health issues of our time. Our lab is dedicated to studying the effects of the in utero miliu on epigenetic changes in the fetus. We have developed a non-human primate model of obesity, now in its ninth year, to study the fetal histone code. We have shown that it is maternal high fat diet consumption (rather than maternal obesity per se) which results in abnormal development of both the hypothalamic neurocircuitry and peripheral entrainment which regulate fetal glucose and lipid homeostasis;these alterations are accompanied by epigenetic changes in chromatin structure resulting in reprogramming of fetal gene expression. As a result of this work, we are now uniquely poised to apply concomitantly developed high throughput sequencing technologies with advanced analytical approaches to decipher the molecular means by which the primate epigenome is modified.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK089201-03
Application #
8710202
Study Section
Pregnancy and Neonatology Study Section (PN)
Program Officer
Silva, Corinne M
Project Start
2012-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Baylor College of Medicine
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
City
Houston
State
TX
Country
United States
Zip Code
77030
Kahr, Maike K; Suter, Melissa A; Ballas, Jerasimos et al. (2016) Geospatial analysis of food environment demonstrates associations with gestational diabetes. Am J Obstet Gynecol 214:110.e1-9
Pew, Braden K; Harris, R Alan; Sbrana, Elena et al. (2016) Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress. Am J Obstet Gynecol 215:384.e1-384.e89
Chu, Derrick M; Antony, Kathleen M; Ma, Jun et al. (2016) The early infant gut microbiome varies in association with a maternal high-fat diet. Genome Med 8:77
Harris, R Alan; Alcott, Callison E; Sullivan, Elinor L et al. (2016) Genomic Variants Associated with Resistance to High Fat Diet Induced Obesity in a Primate Model. Sci Rep 6:36123
Gonzalez-Rodriguez, Pablo; Cantu, Jessica; O'Neil, Derek et al. (2016) Alterations in expression of imprinted genes from the H19/IGF2 loci in a multigenerational model of intrauterine growth restriction (IUGR). Am J Obstet Gynecol 214:625.e1-625.e11
Chu, Derrick M; Aagaard, Kjersti M (2016) Microbiome: Eating for trillions. Nature 532:316-7
Prince, Amanda L; Ma, Jun; Kannan, Paranthaman S et al. (2016) The placental membrane microbiome is altered among subjects with spontaneous preterm birth with and without chorioamnionitis. Am J Obstet Gynecol 214:627.e1-627.e16
Suter, Melissa A; Abramovici, Adi R; Griffin, Emily et al. (2015) In utero nicotine exposure epigenetically alters fetal chromatin structure and differentially regulates transcription of the glucocorticoid receptor in a rat model. Birth Defects Res A Clin Mol Teratol 103:583-8
Prince, Amanda L; Chu, Derrick M; Seferovic, Maxim D et al. (2015) The perinatal microbiome and pregnancy: moving beyond the vaginal microbiome. Cold Spring Harb Perspect Med 5:
Seferovic, Maxim D; Goodspeed, Danielle M; Chu, Derrick M et al. (2015) Heritable IUGR and adult metabolic syndrome are reversible and associated with alterations in the metabolome following dietary supplementation of 1-carbon intermediates. FASEB J 29:2640-52

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