Epigenetics of Drug Addiction

Stewart, Andrew F.; Fulton, Sasha L.; Maze, Ian

doi:10.1101/cshperspect.a040253

Cited by 30 publications

(19 citation statements)

References 89 publications

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“…These TFs include AMP response element-binding protein (CREB), ΔFOSB, nuclear factor κB (NFκB), early growth response protein 3 (EGR3), and nuclear receptor subfamily 4 group a member 1 (NR4A1) ( Hope et al, 1994 ; Carlezon<suffix>Jr.</suffix>, Thome et al, 1998 ; Barrot et al, 2002 ; McClung and Nestler, 2003 ; Zachariou et al, 2006 ; Chandra et al, 2015 ; Carpenter et al, 2020 ). In parallel, numerous studies have begun to uncover chromatin-mediated mechanisms that contribute to behavioral responses to addictive drugs, such as drug-induced post-translational modification of histone proteins ( Stewart et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

et al. 2022

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Substance abuse and addiction represent a significant public health problem that impacts multiple dimensions of society, including healthcare, the economy, and the workforce. In 2021, over 100,000 drug overdose deaths were reported in the US, with an alarming increase in fatalities related to opioids and psychostimulants. Understanding the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bonafide enhancers and highlighted the KLF/SP1, RFX, and AP1 transcription factors families as central to establishing brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, including glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.

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Section: Introductionmentioning

confidence: 99%

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

et al. 2022

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“…These TFs include AMP response element-binding protein (CREB), ΔFOSB, nuclear factor κB (NFκB), early growth response protein 3 (EGR3), and nuclear receptor subfamily 4 group a member 1 (NR4A1) (Hope et al, 1994;Carlezon et al, 1998;Barrot et al, 2002;McClung and Nestler, 2003;Zachariou et al, 2006;Chandra et al, 2015;Carpenter et al, 2020). In parallel, numerous studies have begun to uncover chromatin-mediated mechanisms that contribute to behavioral responses to addictive drugs, such as drug-induced post-translational modification of histone proteins (Stewart et al, 2021). Despite this knowledge, remarkably little is known about the gene regulatory mechanisms that are responsible for driving these changes.…”

Section: Introductionmentioning

confidence: 99%

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Duttke

Montilla‐Perez

Chang

et al. 2022

Preprint

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Substance abuse and addiction represent a major public health problem that impacts multiple dimensions of society, including healthcare, economy, and workforce. In 2021, over 100,000 drug overdose deaths have been reported in the US with an alarming increase in fatalities related to opioids and psychostimulants. Understanding of the fundamental gene regulatory mechanisms underlying addiction and related behaviors could facilitate more effective treatments. To explore how repeated drug exposure alters gene regulatory networks in the brain, we combined capped small (cs)RNA-seq, which accurately captures nascent-like initiating transcripts from total RNA, with Hi-C and single nuclei (sn)ATAC-seq. We profiled initiating transcripts in two addiction-related brain regions, the prefrontal cortex (PFC) and the nucleus accumbens (NAc), from rats that were never exposed to drugs or were subjected to prolonged abstinence after oxycodone or cocaine intravenous self-administration (IVSA). Interrogating over 100,000 active transcription start regions (TSRs) revealed that most TSRs had hallmarks of bona-fide enhancers and highlighted the KLF/SP1, RFX and AP1 transcription factors families as central to establish brain-specific gene regulatory programs. Analysis of rats with addiction-like behaviors versus controls identified addiction-associated repression of transcription at regulatory enhancers recognized by nuclear receptor subfamily 3 group C (NR3C) factors, which include glucocorticoid receptors. Cell-type deconvolution analysis using snATAC-seq uncovered a potential role of glial cells in driving the gene regulatory programs associated with addiction-related phenotypes. These findings highlight the power of advanced transcriptomics methods to provide insight into how addiction perturbs gene regulatory programs in the brain.

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“…However, the underlying mechanism of the association of risk gene variants and opioid addiction remains unknown. Prolonged use of addictive substances could lead to adaptive alterations in neural plasticity in discrete brain regions including the mesocorticolimbic dopamine system which processes the reward and motivation effects (Hyman, Malenka, & Nestler, 2006), resulting in the transition to addicted states (Stewart, Fulton, & Maze, 2021). DNA methylation, one of the epigenetic components, represents a mechanism that affects the plasticity process and then the development of substance addiction by involving environmental stimuli and regulating gene expression patterns (Stewart et al, 2021).…”

Section: Introductionmentioning

confidence: 99%

“…Prolonged use of addictive substances could lead to adaptive alterations in neural plasticity in discrete brain regions including the mesocorticolimbic dopamine system which processes the reward and motivation effects (Hyman, Malenka, & Nestler, 2006), resulting in the transition to addicted states (Stewart, Fulton, & Maze, 2021). DNA methylation, one of the epigenetic components, represents a mechanism that affects the plasticity process and then the development of substance addiction by involving environmental stimuli and regulating gene expression patterns (Stewart et al, 2021). DNA methylation, especially in the promoter region of the gene where is rich with CpG sites and transcriptional factors binding sites, is an important mechanism that regulates gene expression (Pathak, Miller, Morris, Stewart, & Greenberg, 2018).…”

Section: Introductionmentioning

confidence: 99%

Expression Quantitative Trait Locus rs6356 Is Associated with Susceptibility to Heroin Addiction by Potentially Influencing TH Gene Expression in the Hippocampus and Nucleus Accumbens

Wang

Zhang

et al. 2022

J Mol Neurosci

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Opioid addiction is a complicated and highly heritable brain disease. Dysfunction of dopaminergic signaling is involved in the pathogenesis of addictive disorders. Encoding the synthetase of dopamine, tyrosine hydroxylase (TH) gene has long been an interesting candidate in the genetic association studies for opioid addiction. However, the underlying mechanism of the association of risk gene variants and opioid addiction remains unknown. In the present study, we rst analyzed the association between TH gene variants and susceptibility and traits of heroin addiction in 801 patients with heroin addiction and 930 healthy controls. The methylation level in the promoter region of the TH gene was detected and compared between the heroin addiction and healthy control groups. To reveal the potential mechanism of the association of TH gene variants and heroin addiction, correlation between the risk TH SNPs for heroin addiction and the methylation as well expression level of TH gene were examined. Our results demonstrated that SNP rs6356 was associated with the susceptibility of heroin addiction. CpG TH_15 was hypermethylated in the heroin addiction group compared with the healthy control group. Notably, SNP rs6356 was allele-speci c correlated with the expression of TH gene in the hippocampus and nucleus accumbens, but not the methylation level of CpG TH_15. Our ndings suggest that the eQTL rs6356 was associated with the risk of heroin addiction by potentially affecting the expression of TH gene in the mesocorticolimbic dopamine system brain regions including hippocampus and nucleus accumbens.

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Epigenetics of Drug Addiction

Cited by 30 publications

References 89 publications

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Glucocorticoid Receptor-Regulated Enhancers Play a Central Role in the Gene Regulatory Networks Underlying Drug Addiction

Expression Quantitative Trait Locus rs6356 Is Associated with Susceptibility to Heroin Addiction by Potentially Influencing TH Gene Expression in the Hippocampus and Nucleus Accumbens

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