Endocrine Abstracts

While organisms have evolved to maintain the fidelity of their genome, the epigenome, in contrast, is inherently plastic, with extensive remodeling required during normal development. This epigenomic plasticity plays a role in preparing the developing organism for its adult environment. The epigenome is able to sense environmental cues, providing an opportunity for adaptive changes during development that can provide a later-life survival advantage. However, epigenomic plasticity also carries a liability. Adverse environmental exposures can disrupt the developing epigenome, and this developmental reprogramming can have life-long consequences, increasing risk for many diseases. Our work has revealed vulnerabilities in the epigenetic machinery targeted by environmental exposures, specifically endocrine disrupting chemicals (EDCs) that activate nuclear hormone receptors (NHRs). EDCs initiate non-genomic NHR signaling, activating kinases that disrupt the epigenetic machinery of developing cells by phosphorylating and altering the activity of the ‘readers, writers, and erasers’ of the epigenome. For example, the EDC bisphenol A (BPA) engages NHRs to activate PI3K/AKT signaling, phosphorylating the histone methyltransferase MLL to increase the active H3K4 histone mark at reprogrammed genes. This developmental reprogramming persists into adulthood, long after the initial environmental exposure occurred, resulting in changes in gene expression that increase disease risk. Interestingly, the impact of epigenetic reprogramming may be silent until challenged with another, later life exposure. For example, altered gene expression associated with an increase in active H3K4me1 or H3K4me3 marks may not occur until the promoters of reprogrammed genes are engaged by transcription factors, as is the case for hormone-responsive genes that become hyper-responsive to estrogen or testosterone. Alternatively, reprogramming of specific transcription factors, such as the transcription factor EGR-1 (which is activated by high-fat diet), can drive an exaggerated transcriptional response to high-fat diet in EGR-1 target genes. Thus, while epigenetic alterations induced by environmental exposures persist into adult life, their effect on gene expression may be conditional on later life events, which then reveal the impact of developmental reprogramming and promote adult onset disease.