Dataset Information

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

ABSTRACT: While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs share less than 50% of their interactions. In the global context of interactome network maps, alternative isoforms tend to behave like distinct proteins rather than minor variants of each other. Interaction partners specific to alternative isoforms tend to be expressed in a highly tissue-specific manner and belong to distinct functional modules. Our strategy, applicable to other functional characteristics, reveals a widespread expansion of protein interaction capabilities through alternative splicing and suggests that many alternative "isoforms" are functionally divergent (i.e., "functional alloforms").

SUBMITTER: Yang X

PROVIDER: S-EPMC4882190 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Publications

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

Yang Xinping X Coulombe-Huntington Jasmin J Kang Shuli S Sheynkman Gloria M GM Hao Tong T Richardson Aaron A Sun Song S Yang Fan F Shen Yun A YA Murray Ryan R RR Spirohn Kerstin K Begg Bridget E BE Duran-Frigola Miquel M MacWilliams Andrew A Pevzner Samuel J SJ Zhong Quan Q Wanamaker Shelly A SA Tam Stanley S Ghamsari Lila L Sahni Nidhi N Yi Song S Rodriguez Maria D MD Balcha Dawit D Tan Guihong G Costanzo Michael M Andrews Brenda B Boone Charles C Zhou Xianghong J XJ Salehi-Ashtiani Kourosh K Charloteaux Benoit B Chen Alyce A AA Calderwood Michael A MA Aloy Patrick P Roth Frederick P FP Hill David E DE Iakoucheva Lilia M LM Xia Yu Y Vidal Marc M

Cell 20160201 4

While alternative splicing is known to diversify the functional characteristics of some genes, the extent to which protein isoforms globally contribute to functional complexity on a proteomic scale remains unknown. To address this systematically, we cloned full-length open reading frames of alternatively spliced transcripts for a large number of human genes and used protein-protein interaction profiling to functionally compare hundreds of protein isoform pairs. The majority of isoform pairs shar ...[more]

PMID: 26871637

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Project description:The spinocerebellar ataxias (SCAs) are a group of dominantly inherited neurodegenerative diseases, several of which are caused by CAG expansion mutations (SCAs 1, 2, 3, 6, 7 and 12) and more broadly belong to the large family of over 40 microsatellite expansion diseases. While dysregulation of alternative splicing is a well defined driver of disease pathogenesis across several microsatellite diseases, the contribution of alternative splicing in CAG expansion SCAs is poorly understood. Furthermore, despite extensive studies on differential gene expression, there remains a gap in our understanding of presymptomatic transcriptomic drivers of disease. We sought to address these knowledge gaps through a comprehensive study of 29 publicly available RNA-sequencing datasets. We identified that dysregulation of alternative splicing is widespread across CAG expansion mouse models of SCAs 1, 3 and 7. These changes were detected presymptomatically, persisted throughout disease progression, were repeat length-dependent, and were present in brain regions implicated in SCA pathogenesis including the cerebellum, pons and medulla. Across disease progression, changes in alternative splicing occurred in genes that function in pathways and processes known to be impaired in SCAs, such as ion channels, synaptic signalling, transcriptional regulation and the cytoskeleton. We validated several key alternative splicing events with known functional consequences, including Trpc3 exon 9 and Kcnma1 exon 23b, in the Atxn1154Q/2Q mouse model. Finally, we demonstrated that alternative splicing dysregulation is responsive to therapeutic intervention in CAG expansion SCAs with Atxn1 targeting antisense oligonucleotide rescuing key splicing events. Taken together, these data demonstrate that widespread presymptomatic dysregulation of alternative splicing in CAG expansion SCAs may contribute to disease onset, early neuronal dysfunction and may represent novel biomarkers across this devastating group of neurodegenerative disorders.

Dataset Information

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

Publications

Widespread Expansion of Protein Interaction Capabilities by Alternative Splicing.

Similar Datasets

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