The metabolic-epigenetic axis
Emerging evidence reveals a diversity of interactions between metabolic and epigenetic pathways, which serve as an important conduit of information between the environment and chromatin to alter gene expression and behavior. In particular, the discovery of a direct metabolic-epigenetic interface represents a paradigm shift in our mechanistic understanding of environmental impacts on transcriptional activity. This direct pathway is mediated by metabolic enzymes—classically thought to reside in mitochondria and cytoplasm—localizing within the nucleus and even binding to chromatin. This surprising location enables the generation of metabolite pools which can fuel epigenetic enzymes directly. Our current knowledge of these critical mechanisms, however, remains limited. Our lab aims to further explore this novel and fascinating area of biology, which will transform our understanding of how the brain adapts to environmental changes.
Substance use disorders (SUDs)
SUDs impose a tremendous burden on society. While we know much about how alcohol and other drugs affect the brain, this knowledge has failed to translate into efficacious treatments. A potential reason is that while these substances are quickly metabolized following intake, the effect of their break-down products on the brain has so far been largely ignored. We have recently shown that alcohol-derived acetate is quickly deposited on histones in the brain, which drives gene expression changes and behavioral phenotypes linked to alcohol use disorder. Building on these observations, we explore the effect of drug metabolites on gene regulation in the brain, and study their role in related molecular and behavioral changes with the potential to identify radically new therapeutic targets.
Developmental exposure to drugs
In utero, alcohol and other abused substances act as environmental teratogens that affect developmental gene expression and elicit numerous postnatal disease phenotypes, most severely fetal alcohol spectrum disorder (FASD). We have recently shown that near-term exposure to alcohol results in the deposition of alcohol-derived acetyl-groups onto histones in fetal brains. We now continue to characterize the role of drug metabolites in utero using mouse models of prenatal exposure to alcohol and other drugs. We explore developmental windows of epigenetic sensitivity to drug metabolites and characterize the effects on transcriptional, cellular and behavioral impairments. This work will elucidate novel mechanisms by which alcohol and other abused substances affect the developing brain.
Neurodegeneration
We are interested in exploring the metabolic and epigenetic underpinnings of neurodegeneration related to Alzheimer’s disease, as well as long-term, repeated exposure to alcohol and other abused substances. Epigenetic mechanisms, and in particular histone acetylation are closely linked to neurodegeneration. We explore how repeated metabolic perturbations lead to persistent epigenetic changes, culminating in detrimental outcomes including neurodegeneration.