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Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors.

ABSTRACT: Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological phenomena by applying engineered transcription factors to selectively modify chromatin at a specific mouse gene in vivo. We found that histone methylation or acetylation at the Fosb locus in nucleus accumbens, a brain reward region, was sufficient to control drug- and stress-evoked transcriptional and behavioral responses via interactions with the endogenous transcriptional machinery. This approach allowed us to relate the epigenetic landscape at a given gene directly to regulation of its expression and to its subsequent effects on reward behavior.

SUBMITTER: Heller EA

PROVIDER: S-EPMC4241193 | biostudies-literature | 2014 Dec

REPOSITORIES: biostudies-literature

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Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors.

Heller Elizabeth A EA Cates Hannah M HM Peña Catherine J CJ Sun Haosheng H Shao Ningyi N Feng Jian J Golden Sam A SA Herman James P JP Walsh Jessica J JJ Mazei-Robison Michelle M Ferguson Deveroux D Knight Scott S Gerber Mark A MA Nievera Christian C Han Ming-Hu MH Russo Scott J SJ Tamminga Carol S CS Neve Rachael L RL Shen Li L Zhang H Steve HS Zhang Feng F Nestler Eric J EJ

Nature neuroscience 20141027 12

Chronic exposure to drugs of abuse or stress regulates transcription factors, chromatin-modifying enzymes and histone post-translational modifications in discrete brain regions. Given the promiscuity of the enzymes involved, it has not yet been possible to obtain direct causal evidence to implicate the regulation of transcription and consequent behavioral plasticity by chromatin remodeling that occurs at a single gene. We investigated the mechanism linking chromatin dynamics to neurobiological p ...[more]

PMID: 25347353

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Project description:IntroductionDepressive emotions can lead to subsequent unhealthy behaviors such as Internet addiction, especially in female adolescents; therefore, studies that examine the relationships among depression, health‑related behaviors, and Internet addiction in female adolescents are warranted.PurposeTo examine (1) the relationship between depression and health-related behaviors and (2) the relationship between depression and Internet addiction.MethodA cross-sectional study design was adopted using a structured questionnaire to measure depression, health-related behaviors, and Internet addiction in female adolescents. The data were collected from students of a junior college in southern Taiwan using convenience sampling to select the participants. The questionnaire was divided into four sections: demographics, the Center for Epidemiologic Studies Depression Scale (CES-D), the Health Promoting Lifestyle Profile (HPLP), and the Internet Addiction Test (IAT).ResultsThe final sample comprised 503 female junior college students, with the participants mainly aged between 15 to 22 years (mean age = 17.30 years, SD = 1.34). Regarding the HPLP scores, the overall score, nutrition subscale score, and self-actualization subscale score were significantly and negatively associated with the CES-D depression score (p < 0.05-0.01). In other words, depression level was lower in students who exhibited more healthy behaviors, put more emphasis on dietary health, and had higher levels of self-admiration and confidence toward life. Regarding the IAT scores, the overall score and six domain scores were all positively associated (p < 0.01) to the CES-D depression score. In other words, the higher an individual's Internet addiction score was, the higher her depression level was.ConclusionsThe results confirmed the relationship between depression, health-related behaviors, and Internet addiction. The cultivation of health-related behaviors may help in lowering depressive symptoms. Teenagers with depression have higher risks of developing Internet addiction, and such addiction is likely to affect their daily functioning.

Project description:Testicular germ cell tumors (TGCTs) are aggressive but sensitive to cisplatin-based chemotherapy. Alternative therapies are needed for tumors refractory to cisplatin with hypomethylating agents providing one possibility. The mechanisms of cisplatin hypersensitivity and resistance in TGCTs remain poorly understood. Recently, it has been shown that TGCTs, even those resistant to cisplatin, are hypersensitive to very low doses of hypomethylating agents including 5-aza deoxy-cytosine (5-aza) and guadecitabine. We undertook a pharmacogenomic approach in order to better understand mechanisms of TGCT hypomethylating agent hypersensitivity by generating a panel of acquired 5-aza-resistant TGCT cells and contrasting these to previously generated acquired isogenic cisplatin-resistant cells from the same parent. Interestingly, there was a reciprocal relationship between cisplatin and 5-aza sensitivity, with cisplatin resistance associated with increased sensitivity to 5-aza and 5-aza resistance associated with increased sensitivity to cisplatin. Unbiased transcriptome analysis revealed 5-aza-resistant cells strongly downregulated polycomb target gene expression, the exact opposite of the finding for cisplatin-resistant cells, which upregulated polycomb target genes. This was associated with a dramatic increase in H3K27me3 and decrease in DNMT3B levels in 5-aza-resistant cells, the exact opposite changes seen in cisplatin-resistant cells. Evidence is presented that reciprocal regulation of polycomb and DNMT3B may be initiated by changes in DNMT3B levels as DNMT3B knockdown alone in parental cells resulted in increased expression of H3K27me3, EZH2, and BMI1, conferred 5-aza resistance and cisplatin sensitization, and mediated genome-wide repression of polycomb target gene expression. Finally, genome-wide analysis revealed that 5-aza-resistant, cisplatin-resistant, and DNMT3B-knockdown cells alter the expression of a common set of polycomb target genes. This study highlights that reciprocal epigenetic changes mediated by DNMT3B and polycomb may be a key driver of the unique cisplatin and 5-aza hypersensitivity of TGCTs and suggests that distinct epigenetic vulnerabilities may exist for pharmacological targeting of TGCTs.

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Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors.

Publications

Locus-specific epigenetic remodeling controls addiction- and depression-related behaviors.

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