Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Disrupting SUMOylation potentiates transactivation function and ameliorates polyglutamine AR-mediated disease

ABSTRACT: Our findings demonstrate beneficial effects of enhancing transactivation function of the ligand-activated polyQ AR and indicate that the SUMOylation pathway may provide new targets for therapeutic intervention. We mutated conserved lysines in the polyQ AR that are targeted by SUMO, a modification that inhibits AR transactivation function.

ORGANISM(S): Mus musculus

SUBMITTER: Richard McEachin

PROVIDER: E-GEOD-60691 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.

Chua Jason P JP Reddy Satya L SL Yu Zhigang Z Giorgetti Elisa E Montie Heather L HL Mukherjee Sarmistha S Higgins Jake J McEachin Richard C RC Robins Diane M DM Merry Diane E DE Iñiguez-Lluhí Jorge A JA Lieberman Andrew P AP

The Journal of clinical investigation 20150120 2

Expansion of the polyglutamine (polyQ) tract within the androgen receptor (AR) causes neuromuscular degeneration in individuals with spinobulbar muscular atrophy (SBMA). PolyQ AR has diminished transcriptional function and exhibits ligand-dependent proteotoxicity, features that have both been implicated in SBMA; however, the extent to which altered AR transcriptional function contributes to pathogenesis remains controversial. Here, we sought to dissociate effects of diminished AR function from p ...[more]

PMID: 25607844

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Project description:Consumption of a protein containing meal by a fasted animal promotes protein accretion in skeletal muscle, in part through leucine stimulation of protein synthesis and indirectly through repression of protein degradation mediated by its metabolite, Î±-ketoisocaproate. Mice lacking the mitochondrial branched-chain aminotransferase (BCATm/Bcat2), that interconverts leucine and Î±-ketoisocaproate, exhibit elevated protein turnover. Here, the transcriptomes of gastrocnemius muscle from BCATm knockout (KO) and wildtype mice were compared using Next Generation RNA-Sequencing (RNA-Seq) to identify potential adaptations associated with their persistently altered nutrient signaling. Statistically significant changes in the abundance of 1486/~39,010 genes were identified. Bioinformatics analysis of the RNA-Seq data indicated that pathways involved in protein synthesis (eIF2, mTOR, eIF4 and p70S6K pathways including 40S and 60S ribosomal proteins), protein breakdown (e.g., ubiquitin mediated), and muscle degeneration (apoptosis, atrophy, myopathy and cell death) were up-regulated. Also in agreement with our previous observations, the abundance of mRNAs associated with reduced body size, glycemia, plasma insulin, and lipid signaling pathways were observed in BCATm KO mice. Consistently, genes encoding anaerobic and/or oxidative metabolism of carbohydrate, fatty acids and BCAAs were modestly but systematically reduced. Although there was no indication that muscle fiber type was different between KO and wildtype mice, a difference in the abundance of mRNAs associated with a muscular dystrophy phenotype was observed, consistent with the published exercise intolerance of these mice. The results suggest transcriptional adaptations occur in BCATm KO mice that along with altered nutrient signaling may contribute to their previously reported protein turnover, metabolic and exercise phenotypes. Comparison of wildtype and BCATm KO gastrocnemius biological replicates

Dataset Information

Disrupting SUMOylation potentiates transactivation function and ameliorates polyglutamine AR-mediated disease

Publications

Disrupting SUMOylation enhances transcriptional function and ameliorates polyglutamine androgen receptor-mediated disease.

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