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K Aagaard-Tillery, Obstetrics and Gynecology, Baylor College of Medicine, Houston, 77030, United States
K Grove, ONPRC, Beaverton, United States
J Bishop, OHSU, Beaverton, United States
X Ke, University of Utah, Salt Lake City, United States
Q Fu, University of Utah, Salt Lake City, United States
R McKnight, University of Utah, Salt Lake City, United States
R Lane, University of Utah, Salt Lake City, United States

Correspondence: Kjersti Aagaard-Tillery, Email: aagaardt{at}bcm.tmc.edu

Abstract

Objective. Chromatin structure is epigenetically altered via covalent modifications of histones to allow for heritable gene regulation without altering the nucleotide sequence. Based on our previous work in rodent models of nutritional constraint, we hypothesized that a maternal high fat diet would alter the epigenomic profile of the developing offspring.

Methods. Age and weight matched adult female Japanese macaques were placed on control (14% fat) or high-fat (32% fat) breeder diets and mated annually over 4 years. Successive fetuses were delivered near term and underwent necropsy with tissue harvest for molecular and epigenomic characterization.

Results. Chronic consumption of a maternal high-fat diet results in a 3-fold increase in fetal liver triglycerides and histologic correlates of non-alcoholic fatty liver disease. These gross changes in the fetal liver are accompanied by a statistically significant hyperacetylation of fetal hepatic tissue at H3K14 (P=0.038) with a trend towards increased acetylation at H3K9 (P=0.097) and at H3K18 (P=0.096). Subsequent characterization of key epigenetic determinants associated with H3 acetylation marks revealed similar significant alterations in association with a high fat maternal diet (e.g., relative fetal HDAC1 gene and protein expression with in vitro activity). We employ these observations in ChIP-differential display PCR to identify potential fetal genes whose expression is reprogrammed under conditions of a high fat maternal diet.

Conclusions. These results suggest that a caloric dense maternal diet leading to obesity epigenetically alters fetal chromatin structure in primates via covalent modifications of histones, and hence lends a molecular basis to the fetal origins of adult disease hypothesis.

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