GSE86038
GSE GEOHNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_Arrays_human_Fibs_2]
Relations
Summary
HnRNPA2B1 encodes an RNA binding protein associated with neurodegenerative disorders. However, its function in the nervous system is unclear. Transcriptome-wide cross-linking and immunoprecipitation in mouse spinal cord discover UAGG motifs enriched within ~2,500 hnRNP A2/B1 binding sites and an unexpected role for hnRNP A2/B1 in alternative polyadenylation. Loss of hnRNP A2/B1 results in alternative splicing, including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. Inclusion of the DAO exon is also reduced in transgenic ALS mice models. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells demonstrate gain-of-mutant-dependent splicing differences. Mutant motor neurons also exhibit increased hnRNP A2/B1 localization to cytoplasmic granules during stress, which are abrogated by a small molecule CA43. Our findings and cellular resource identify RNA networks affected in loss of normal and mutated hnRNP A2/B1 with broad relevance to neurodegeneration.
Overall Design
Microarray in human primary fibroblasts from patients with MSP and controls two conrols, two hnRNP A2/B1 D290V patients, and one VCP R155H patient. Three replicates per condition.
Analysis (3 steps)
View Data Processing- Data processed using Affymetrix package (Affy Power Tools) apt-probeset-summarize.
- Iter-plier algorithm used to quantify probesets.
- http://exon.ucsc.edu/documentation/mjay_library/hjay.pgf