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 #
1R01DK089201-01A1
Application #
8372225
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
2012-08-01
Budget End
2013-07-31
Support Year
1
Fiscal Year
2012
Total Cost
$413,167
Indirect Cost
$133,634
Name
Baylor College of Medicine
Department
Obstetrics & Gynecology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030
Ma, Jun; Prince, Amanda L; Bader, David et al. (2014) High-fat maternal diet during pregnancy persistently alters the offspring microbiome in a primate model. Nat Commun 5:3889
Suter, Melissa A; Ma, Jun; Vuguin, Patricia M et al. (2014) In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model. Am J Obstet Gynecol 210:463.e1-463.e11
Cuevas Guaman, Milenka; Sbrana, Elena; Shope, Cynthia et al. (2014) Administration of antenatal glucocorticoids and postnatal surfactant ameliorates respiratory distress syndrome-associated neonatal lethality in Erk3(-/-) mouse pups. Pediatr Res 76:24-32
O'Neil, Derek; Mendez-Figueroa, Hector; Mistretta, Toni-Ann et al. (2013) Dysregulation of Npas2 leads to altered metabolic pathways in a murine knockout model. Mol Genet Metab 110:378-87
Suter, Melissa A; Takahashi, Diana; Grove, Kevin L et al. (2013) Postweaning exposure to a high-fat diet is associated with alterations to the hepatic histone code in Japanese macaques. Pediatr Res 74:252-8