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

Heller, Elizabeth A.; Cates, Hannah M.; Peña, Catherine J.; Sun, HaoSheng; Shao, Ning‐Yi; Feng, Jian; Golden, Sam A.; Herman, James P.; Walsh, Jessica J.; Mazei-Robison, Michelle S.; Ferguson, Deveroux; Knight, Scott W.; Gerber, Mark A.; Nievera, Christian; Han, Ming; Russo, Scott J.; Tamminga, Carol; Neve, Rachael L.; Shen, Li; Zhang, H. Steve; Zhang, Feng; Nestler, Eric J.

doi:10.1038/nn.3871

Cited by 193 publications

(181 citation statements)

References 47 publications

(82 reference statements)

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“…Additionally, current FDA-approved and in development histone mark modifying drugs are effective in targeting specific gene loci and pathways [109,145] and for treating diseases such as lung cancer [146]. As a proof of principle for IPF, profibrotic phenotypes have been reversed in primary fibroblasts and the bleomycin mouse model by the Brd4 inhibitor JQ1 [147] as well as HDAC inhibitors Spiruchostatin A (SpA) [148] and suberoylanilide hydroxamic acid (SAHA) [149].…”

Section: Treatment Of Ipfmentioning

confidence: 99%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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Idiopathic pulmonary fibrosis (IPF) is the most common and the most aggressive fibrosing interstitial lung disease (ILD). Despite recent promising clinical trials, IPF remains incurable and largely untreatable. Genetic studies have identified several risk loci for both sporadic and familial forms of IPF. A single variant upstream of MUC5B is predicted to account for more than 30% of all IPF risk. This variant, rs35705950, is associated with expression of MUC5B in healthy lung tissue. However, the mechanism underlying the relationship between rs35705950 and MUC5B expression remains unclear.The first goal of my thesis research was to determine whether rs35705950 is also a risk factor for other forms of ILD. Genomic DNA from individuals with IPF, HP, COPD, iNSIP, and RB-ILD was obtained and genotyped for the common MUC5B promoter variant. In these populations the risk allele was associated with IPF and iNSIP which suggested a potential shared disease mechanism. Additionally, I showed that in the IPF and control populations rs35705950 is associated with lung MUC5B expression.The second goal of my thesis research was to investigate MUC5B promoter DNA methylation which has previously been shown to play a role in MUC5B expression.Methylation analysis of the 4KB region upstream of MUC5B identified two differentially methylated regions (DMRs) associated with IPF, one DMR associated with MUC5B iv expression, and one DMR associated with rs35705950. The IPF, MUC5B expression, and rs35705950 associated DMRs are all differentially methylated at a cluster of 11 CpG motifs. overlapping DMR, including the motif disrupted by rs35705950. These findings suggest that DNA methylation may play a role in MUC5B gene regulation and IPF risk.Next, I used cross species analysis to identify highly conserved domains within the overlapping DMR. Evolutionary conservation indicated selective pressures to maintain sequences overtime and suggests biological importance. The overlapping DMR contains a highly conserved binding motif for FOXA2, a transcription factor. Further analysis using ChIP-qPCR, reporter constructs, and siRNA, established a role for FOXA2 in regulation of MUC5B expression in lung tissue. Additionally, siRNA knock down identified 3 other transcription factors which are associated with MUC5B expression; STAT3, HOXA9 and ZBTB7A. These transcriptional regulators provide insight into possible therapeutic intervention for MUC5B dysregulation and IPF.The form and content of this abstract are approved. I recommend its publication.

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Section: Treatment Of Ipfmentioning

confidence: 99%

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Helling

Gerber

Kadiyala

et al. 2017

Am J Respir Cell Mol Biol

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“…Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3)(4)(5)(6)(7)(8)(9)(10)(11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.…”

mentioning

confidence: 99%

Histone arginine methylation in cocaine action in the nucleus accumbens

Damez-Werno

Sun

Scobie

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Repeated cocaine exposure regulates transcriptional regulation within the nucleus accumbens (NAc), and epigenetic mechanismssuch as histone acetylation and methylation on Lys residues-have been linked to these lasting actions of cocaine. In contrast to Lys methylation, the role of histone Arg (R) methylation remains underexplored in addiction models. Here we show that protein-R-methyltransferase-6 (PRMT6) and its associated histone mark, asymmetric dimethylation of R2 on histone H3 (H3R2me2a), are decreased in the NAc of mice and rats after repeated cocaine exposure, including self-administration, and in the NAc of cocaine-addicted humans. Such PRMT6 down-regulation occurs selectively in NAc medium spiny neurons (MSNs) expressing dopamine D2 receptors (D2-MSNs), with opposite regulation occurring in D1-MSNs, and serves to protect against cocaine-induced addictive-like behavioral abnormalities. Using ChIP-seq, we identified Src kinase signaling inhibitor 1 (Srcin1; also referred to as p140Cap) as a key gene target for reduced H3R2me2a binding, and found that consequent Srcin1 induction in the NAc decreases Src signaling, cocaine reward, and the motivation to self-administer cocaine. Taken together, these findings suggest that suppression of Src signaling in NAc D2-MSNs, via PRMT6 and H3R2me2a down-regulation, functions as a homeostatic brake to restrain cocaine action, and provide novel candidates for the development of treatments for cocaine addiction.histone arginine (R) methylation | drug addiction | medium spiny neurons | ChIP-seq | Src R epeated cocaine exposure is marked by persistent changes in gene expression within the nucleus accumbens (NAc), a central component of the brain's reward circuitry (1, 2). Important aspects of cocaine action appear to be mediated by changes in gene transcription via chromatin regulatory mechanisms such as histone acetylation or methylation on Lys (K) residues (3-11). However, in contrast to K methylation, the functional role of histone Arg (R) methylation remains underexplored in addiction models and poorly understood in the brain in general.The methylation of R residues is catalyzed by the protein R methyltransferase (PRMT) family of enzymes, which can generate different methylated R states with diverse functional consequences, including monomethylarginine (MMA) and dimethylarginine (DMA) residues, the latter of which can be either asymmetric (aDMA) or symmetric (sDMA). PRMTs that catalyze aDMA are designated type I, and those that generate sDMA are designated type II (12, 13). Histone tails are prime targets for these PRMTs, and R methylation induces alterations in chromatin architecture, either condensing or relaxing its structure, thereby creating binding sites for regulatory proteins that contain specialized binding domains (14, 15).PRMT6, a nuclear enzyme that modifies histone tails, is the primary enzyme responsible for asymmetric dimethylation of R2 on histone H3 (H3R2me2a) in mammalian cells (14,16). The H3R2me2a mark is thought to be repressive in nature because of...

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“…Histone subunits are also dynamically regulated through methylation and demethylation of lysine residues. The catalytic regions of histone H3K9 methyltransferases EHMT2 (also known as G9A) and SUV39H1 have been found to repress transcription and alter chromatin status at targeted promoters when fused to ZFs (Snowden et al 2002;Falahi et al 2013;Heller et al 2014) and TALEs . Targeted H3K4 demethylation has also been applied using TALEs or dCas9 fused to the KDM1A protein (also known as LSD1) (Mendenhall et al 2013;Kearns et al 2015), enabling the characterization of known and putative enhancers.…”

Section: Next Generation Genome Engineering: Epigenome Editingmentioning

confidence: 99%

Enabling functional genomics with genome engineering

Hilton

Gersbach

2015

Genome Res.

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Advances in genome engineering technologies have made the precise control over genome sequence and regulation possible across a variety of disciplines. These tools can expand our understanding of fundamental biological processes and create new opportunities for therapeutic designs. The rapid evolution of these methods has also catalyzed a new era of genomics that includes multiple approaches to functionally characterize and manipulate the regulation of genomic information. Here, we review the recent advances of the most widely adopted genome engineering platforms and their application to functional genomics. This includes engineered zinc finger proteins, TALEs/TALENs, and the CRISPR/Cas9 system as nucleases for genome editing, transcription factors for epigenome editing, and other emerging applications. We also present current and potential future applications of these tools, as well as their current limitations and areas for future advances.

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

Cited by 193 publications

References 47 publications

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Regulation of MUC5B Expression in Idiopathic Pulmonary Fibrosis

Histone arginine methylation in cocaine action in the nucleus accumbens

Enabling functional genomics with genome engineering

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