Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

B-Catenin Mediates the Development of Behavioral Resilience [smallRNA-Seq]

ABSTRACT: Here we show that ?-catenin mediates pro-resilient and anxiolytic effects in mice in the nucleus accumbens (NAc), a key brain reward region, an effect that is mediated by ?-catenin signaling in D2-type medium spiny neurons (MSNs) specifically. Conversely, blocking ?-catenin function in NAc promotes susceptibility to chronic stress, and we show evidence of robust suppression of ?-catenin transcriptional activity in the NAc both of depressed humans examined postmortem as well as of mice that display a susceptible phenotype after chronic stress, with a converse upregulation in mice that are stress resilient. Using ChIP-seq, we demonstrate a global, genome-wide enrichment of ?-catenin in the NAc of resilient mice, and specifically identify Dicer1—important in small RNA (e.g., microRNA [miRNA]) biogenesis—as a critical ?-catenin target gene involved in mediating a resilient phenotype. Small RNA-seq after excising ?-catenin from the NAc in the context of chronic stress reveals dynamic ?-catenin-dependent miRNA regulation associated with resilience. GFP_Control: 12 samples, GFP_Resilient: 12 samples, GFP_Susceptible: 4 samples; CRE_Control: 12 samples, CRE_Susceptible: 8 samples.

ORGANISM(S): Mus musculus

SUBMITTER: Li Shen

PROVIDER: E-GEOD-61295 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

β-catenin mediates stress resilience through Dicer1/microRNA regulation.

Dias Caroline C Feng Jian J Sun Haosheng H Shao Ning Yi NY Mazei-Robison Michelle S MS Damez-Werno Diane D Scobie Kimberly K Bagot Rosemary R LaBonté Benoit B Ribeiro Efrain E Liu XiaoChuan X Kennedy Pamela P Vialou Vincent V Ferguson Deveroux D Peña Catherine C Calipari Erin S ES Koo Ja Wook JW Mouzon Ezekiell E Ghose Subroto S Tamminga Carol C Neve Rachael R Shen Li L Nestler Eric J EJ

Nature 20141112 7529

β-catenin is a multi-functional protein that has an important role in the mature central nervous system; its dysfunction has been implicated in several neuropsychiatric disorders, including depression. Here we show that in mice β-catenin mediates pro-resilient and anxiolytic effects in the nucleus accumbens, a key brain reward region, an effect mediated by D2-type medium spiny neurons. Using genome-wide β-catenin enrichment mapping, we identify Dicer1-important in small RNA (for example, microRN ...[more]

PMID: 25383518

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Project description:Despite depression being one of the most prevalent and debilitating disorders worldwide, it has been difficult to understand its pathophysiology and to develop more effective treatments. Maladaptive transcriptional regulation within limbic neural circuits, including reward processing regions such as the nucleus accumbens (NAc), in response to chronic stress is thought to be a major contributor to the development of the syndrome. Epigenetic events?in particular, histone writers and erasers?that alter chromatin structure to regulate programs of gene expression have increasingly been associated with depression-related behavioral abnormalities in animal models and in depressed humans examined postmortem. However, very little is known about the ATP-dependent chromatin remodelers that control nucleosome positioning and the packing state of chromatin. Here we show that the ACF complex, part of the ISWI family of chromatin remodelers, is persistently and selectively upregulated in the NAc of mice that are susceptible to chronic social stress, as well as in the NAc of depressed human. We further establish that ACF induction is both necessary and sufficient for susceptibility to stress-induced depressive-like behaviors. Using ChIP-seq, we demonstrate that altered ACF binding after chronic stress is strongly correlated with altered nucleosome positioning, in particular, around the transcriptional start sites of affected genes. These alterations in ACF binding and nucleosome repositioning are associated with repressed expression of a subset of genes in animals that are susceptible to chronic stress. Together, these findings establish that active ATP-dependent chromatin remodeling by the ACF complex is a key regulator in the repression of genes that mediate susceptibility to social stress, and provide novel candidate targets for improved therapeutics of depression and other stress-related disorders. c57bl/6 mice underwent chronic social defeat stress (CSDS), and social interaction test was used to separate animals into control, susceptible and resilient groups. Nucleus accumbens (NAc) tissue was collected 48 hours after the last defeat session, and then Acf1, SNF2H ChIP-seq or H3 MNase-seq were performed based on the control, susceptible, and resilient groups. Three sequencing replicates were performed on each group.

Dataset Information

B-Catenin Mediates the Development of Behavioral Resilience [smallRNA-Seq]

Publications

β-catenin mediates stress resilience through Dicer1/microRNA regulation.

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