Postdoctoral Fellow, Friedman Brain Institute at Mount Sinai School of Medicine
Mechanisms of epigenetic priming – a scientific problem relevant to a human mental health crisis
At the heart of cellular identity lies the capacity to store information over long periods of time. In the adult brain, epigenetic signatures that govern gene expression preserve cellular memory. These epigenetic processes can integrate environmental information to permanently adapt neuronal gene transcription and identity. Currently, the precise mechanisms underlying such plasticity remain opaque. An important context of permanently altered neuronal gene regulation relevant to human health are states of addiction. Drug addiction is a neuropsychiatric disorder with severe health, financial and societal consequences. The critical need for deep insights into mechanisms of addiction is driven by the sharp recent increases in drug abuse. Drugs of abuse, in addition to their acute effects, cause persistent aberrations in neuronal activity and gene expression. In the nucleus accumbens - the key brain region of reward learning - we found that cocaine permanently alters the inducibility of key genes to future stimuli, referred to as gene priming and desensitization. We hypothesize that drug-induced changes in the epigenetic landscape underlie such latent transcriptional dysregulation. A critical challenge is to determine which neuronal subtypes are responsible: the nucleus accumbens is principally composed of two functionally exclusive types of medium spiny neurons (MSNs), the D1 and D2 dopamine receptor-expressing subtypes. First, we investigated the differential transcriptional priming caused by cocaine in D1 and D2 MSNs. We then identified the long-lasting aberrations in chromatin structure that underlie epigenetic priming and altered MSN activity. Using ATAC-seq, we surveyed chromatin accessibility genome-wide and differentiate acute from permanent changes induced by cocaine in D1 vs D2 MSNs. An advanced understanding of the epigenetic processes that regulate priming and neural identity will ultimately identify novel targets for epigenetic therapies of psychiatric diseases.
Abstract: Drug-induced alterations in gene expression throughout the reward circuitry of the brain are likely components of the persistence of the drug-addicted state. Recent studies examining the molecular mechanisms controlling drug-induced transcriptional, behavioral, and synaptic plasticity have indicated a direct role for chromatin remodeling in the regulation and stability of drug-mediated neuronal gene programs, and the subsequent promulgation of addictive behaviors. In this review, we discuss recent advances in our understanding of chromatin phenomena--or epigenetics, by one definition--that contribute to drug addiction, with the hope that such mechanistic insights may aid in the development of novel therapeutics for future treatments of addiction.
Pub.: 29 Jan '11, Pinned: 17 Aug '17
Abstract: Drug addiction involves potentially life-long behavioral abnormalities that are caused in vulnerable individuals by repeated exposure to a drug of abuse. The persistence of these behavioral changes suggests that long-lasting changes in gene expression, within particular regions of the brain, may contribute importantly to the addiction phenotype. Work over the past decade has demonstrated a crucial role for epigenetic mechanisms in driving lasting changes in gene expression in diverse tissues, including brain. This has prompted recent research aimed at characterizing the influence of epigenetic regulatory events in mediating the lasting effects of drugs of abuse on the brain in animal models of drug addiction. This review provides a progress report of this still early work in the field. As will be seen, there is robust evidence that repeated exposure to drugs of abuse induces changes within the brain's reward regions in three major modes of epigenetic regulation-histone modifications such as acetylation and methylation, DNA methylation, and non-coding RNAs. In several instances, it has been possible to demonstrate directly the contribution of such epigenetic changes to addiction-related behavioral abnormalities. Studies of epigenetic mechanisms of addiction are also providing an unprecedented view of the range of genes and non-genic regions that are affected by repeated drug exposure and the precise molecular basis of that regulation. Work is now needed to validate key aspects of this work in human addiction and evaluate the possibility of mining this information to develop new diagnostic tests and more effective treatments for addiction syndromes. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'.
Pub.: 07 May '13, Pinned: 17 Aug '17
Abstract: Cell growth is attuned to nutrient availability to sustain homeostatic biosynthetic processes. In unfavorable environments, cells enter a nonproliferative state termed quiescence but rapidly return to the cell cycle once conditions support energetic needs. Changing cellular metabolite pools are proposed to directly alter the epigenome via histone acetylation. Here we studied the relationship between histone modification dynamics and the dramatic transcriptional changes that occur during nutrient-induced cell cycle reentry from quiescence in the yeast Saccharomyces cerevisiae. SILAC (stable isotope labeling by amino acids in cell culture)-based mass spectrometry showed that histone methylation-in contrast to histone acetylation-is surprisingly static during quiescence exit. Chromatin immunoprecipitation followed by massive parallel sequencing (ChIP-seq) revealed genome-wide shifts in histone acetylation at growth and stress genes as cells exit quiescence and transcription dramatically changes. Strikingly, however, the patterns of histone methylation remain intact. We conclude that the functions of histone methylation and acetylation are remarkably distinct during quiescence exit: acetylation rapidly responds to metabolic state, while methylation is independent. Thus, the initial burst of growth gene reactivation emerging from quiescence involves dramatic increases of histone acetylation but not of histone methylation.
Pub.: 27 Aug '14, Pinned: 17 Aug '17
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