Developmental origins of disease and determinants of chromatin structure: maternal diet modifies the primate fetal epigenome

Abstract

Chromatin structure is epigenetically altered via covalent modifications of histones to allow for heritable gene regulation without altering the nucleotide sequence. Multiple lines of evidence from rodents have established a role for epigenetic remodeling in regulating gene transcription in response to an altered gestational milieu. However, to date, it is unknown whether variations in the intrauterine environment in primates similarly induce changes in key determinants of hepatic chromatin structure. We hypothesized that a maternal high-fat diet would alter the epigenomic profile of the developing offspring, which would result in alterations in fetal gene expression. Age-and weight-matched adult female Japanese macaques were placed on control (13% fat) or high-fat (35% fat) breeder diets and mated annually over a 4-year interval. Fetuses in successive years were delivered near term (e130 of 167 days) and underwent necropsy with tissue harvest. Fetal histones were acid extracted for characterization of H3 modification and chromatin immunoprecipitation (ChIP) with differential display PCR; fetal RNA, DNA, and cytoplasmic and nuclear protein extracts were similarly extracted for comparison. Chronic consumption of a maternal high-fat diet results in a threefold 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 (199 . 85G9 . 64 . 096). However, epigenetic modifications on fetal hepatic H3 associated with gene repression were absent or subtle (PO0 . 05). 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 histone deacetylase 1 (HDAC1) gene expression 0 . 61G0 . 25; PZ0 . 011). Consistent with our mRNA expression profile, fetal nuclear extracts from offspring of highfat diet animals were observed to be significantly relatively deplete of HDAC1 protein (36 . 07G6 . 73 vs 83 . 18G7 . 51; PZ0 . 006) and in vitro HDAC functional activity (0 . 252G0 . 03 vs 0 . 698G0 . 02; P!0 . 001). We employ these observations in ChIP differential display PCR to attempt to identify potential fetal genes whose expression is reprogramed under conditions of a high-fat maternal diet. We quantitatively confirm a minimum of a 40% alteration in the expression of several genes of interest: glutamic pyruvate transaminase (alanine aminotransferase) 2 (GPT2) (1 . 59G0 . 23-fold; PZ0 . 08), DNAJA2 (1 . 36G0 . 21; PZ0 . 09), and Rdh12 (1 . 88G0 . 15; PZ0 . 01) are appreciably increased in fetal hepatic tissue from maternal caloric-dense diet animals when compared with control while Npas2, a peripheral circadian regulator, was significantly downmodulated in the offspring of high-fat diet animals (0 . 66G0 . 08; PZ0 . 03). In this study, we show that a current significant in utero exposure (caloric-dense hi...

Exposure of neonatal rats to maternal cafeteria feeding during suckling alters hepatic gene expression and DNA methylation in the insulin signalling pathway

“…We have also confirmed that the epigenome may be sensitive to this form of dietary challenge during the suckling phase in rodents. This corresponds with work demonstrating that high-fat diets can impact upon histone acetylation and DNA methylation in rodents and macaques (Aagaard-Tillery et al 2008, Vucetic et al 2010.…”

Early nutrition programming of long-term health

“…Epigenetics comprises, among other more technically challenging methods, the investigation of DNA methylation profiles as the primary mark of environmentally mediated changes to gene expression. While the exact role of epigenetic mechanisms in fetal programming of metabolic diseases and body weight regulation remains to be further investigated, a number of animal models have demonstrated a causal relationship between early nutrition and later metabolic phenotype with gene dysregulation mediating such adverse metabolic outcomes (58)(59)(60)(61)(62) . A recently published article reviews the scientific evidence base of the association between the role of epigenetics in the fetal programming of adverse metabolic outcomes concluding that despite a vast amount of epigenomic data generated, the challenge still is to decipher the biological and clinical relevance of these epigenetic changes (63) .…”

Epigenetics: from the past to the present

“…A similar study was performed by Aagaard-Tillery et al (2008) in primate fetuses whose mothers were exposed during pregnancy to a control diet or a diet rich in fat. High fat intake led to an increase in triglycerides and the development of a fatty liver in the fetuses.…”