Early Life Environmental Exposure Creates “Super-Promoters” By Developmentally Reprogramming the Epigenome of Genes Associated with NAFLD

Presentation Number: OR15-1
Date of Presentation: April 1st, 2017

Lindsey Starr Trevino*, Cristian Coarfa, Jianrong Dong, Charles E Foulds, Morgan Gallo and Cheryl Lyn Walker
Baylor College of Medicine, Houston, TX


Early life exposure to endocrine-disrupting chemicals (EDCs) can lead to obesity and metabolic syndrome in adulthood. Although this is thought to occur via developmental reprogramming of the epigenome, the molecular mechanisms underlying this developmental reprogramming are not well defined. The liver plays a central role in whole body fat metabolism and obesity, and is a target for environmental exposures that contribute to development of non-alcoholic fatty liver disease (NAFLD). We observed that rats exposed postnatally to the EDC bisphenol A (BPA), when fed a high fat diet (HFD) as adults, had increased liver weight, increased serum triglycerides, increased serum LDL/VLDL, and increased serum free cholesterol. These data are consistent with the hypothesis that BPA had developmentally reprogramed the liver, making exposed rats prone to a NAFLD phenotype.

To test this hypothesis, we combined RNA-seq and ChIP-seq analyses in liver tissue from vehicle- and BPA-exposed animals. RNA-seq identified a unique cassette of genes that were induced in response to HFD only in the livers of BPA-reprogrammed rats. Of these reprogrammed genes, the top pathways identified by gene set enrichment analysis (GSEA) were involved in fatty acid and/or lipid metabolism and are known to play a role in NAFLD. We have previously shown that acute, neonatal exposure to EDCs can reprogram the epigenome of developing tissues by increasing the activity of mixed lineage leukemia (MLL), the histone methyltransferase in the COMPASS complex responsible for methylation of histone H3 at lysine 4 (H3K4), an active chromatin mark. To determine the underlying mechanism responsible for the observed change in response to HFD, we performed ChIP-seq for histone modifications associated with active (H3K4me3, H3K4me1, H3K27ac) and repressive (H3K27me3) histone marks. The epigenome of 178 reprogrammed genes exhibited new H3K4me1, H3K4me3 and/or H3K27ac marks at their promoters. Importantly, these novel, active chromatin marks 1) appeared in the neonatal liver in response to BPA; 2) persisted into adulthood; and 3) were not associated with any change in gene expression in the absence to HFD (i.e. their persistence was not a consequenceof altered gene expression). Therefore, the neonatal BPA exposure resulted in an altered epigenetic landscape that persisted into adulthood and preceded the increase in gene expression seen in the reprogrammed rats in response to HFD.

H3K4me1 and H3K27ac marks are generally associated with active enhancer regions, and their presence at promoters is indicative of so-called “super promoters”. Together, these data suggest that early life EDC exposure modulates the activity of the COMPASS complex to reprogram the developing epigenome and generate new “super promoters” that are responsive to later life stimuli, such as HFD, resulting in a liver phenotype that is prone to NAFLD and metabolic disease.


Nothing to Disclose: LST, CC, JD, CEF, MG, CLW