Protein-RNA Networks Regulated by Normal and ALS-Associated Mutant HNRNPA2B1 in the Nervous System.
Fernando J Martinez, Gabriel A Pratt, Eric L Van Nostrand, Ranjan Batra, Stephanie C Huelga, Katannya Kapeli, Peter Freese, Seung J Chun, Karen Ling, Chelsea Gelboin-Burkhart, Layla Fijany, Harrison C Wang, Julia K Nussbacher, Sara M Broski, Hong Joo Kim, Rea Lardelli, Balaji Sundararaman, John P Donohue, Ashkan Javaherian, Jens Lykke-Andersen, Steven Finkbeiner, C Frank Bennett, Manuel Ares, Christopher B Burge, J Paul Taylor, Frank Rigo, Gene W Yeo
Neuron · 2016 · Vol. 92 (4) · pp. 780-795
Abstract
HnRNPA2B1 encodes an RNA binding protein associated with neurodegeneration. However, its function in the nervous system is unclear. Transcriptome-wide crosslinking 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. HnRNP A2/B1 loss results in alternative splicing (AS), including skipping of an exon in amyotrophic lateral sclerosis (ALS)-associated D-amino acid oxidase (DAO) that reduces D-serine metabolism. ALS-associated hnRNP A2/B1 D290V mutant patient fibroblasts and motor neurons differentiated from induced pluripotent stem cells (iPSC-MNs) demonstrate abnormal splicing changes, likely due to increased nuclear-insoluble hnRNP A2/B1. Mutant iPSC-MNs display decreased survival in long-term culture and exhibit hnRNP A2/B1 localization to cytoplasmic granules as well as exacerbated changes in gene expression and splicing upon cellular stress. Our findings provide a cellular resource and reveal RNA networks relevant to neurodegeneration, regulated by normal and mutant hnRNP A2/B1. VIDEO ABSTRACT.
Linked datasets 10
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_Arrays_human_iPSC_MN_Stress]
Homo sapiens
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_Arrays_human_iPSC_MN_ASO]
Homo sapiens
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [iCLIP-seq]
Mus musculus
2 data files
| File | Type | Size |
|---|---|---|
| 2_NoIndex_L002_R1.R16.randomer.fastq.gz | RIP-Seq | 2.2 GB |
| SRR4175327_GSM2292522 | RIP-Seq | 2.2 GB |
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_Arrays_human_Fibs_2]
Homo sapiens
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons
Mus musculus
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_Arrays_human_Fibs_1]
Homo sapiens
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_small_rnaseq]
Mus musculus
24 data files
| File | Type | Size |
|---|---|---|
| B7P80-501-1_S7_L001_R1_001.fastq | ncRNA-Seq | 27.6 MB |
| B7P80-501-2_S1_L001_R1_001.fastq | ncRNA-Seq | 20.9 MB |
| B7P80-501-3_S3_L001_R1_001.fastq | ncRNA-Seq | 20.5 MB |
| B7P80-A1_S2_L001_R1_001.fastq | ncRNA-Seq | 24.5 MB |
| B7P80-A2_S9_L001_R1_001.fastq | ncRNA-Seq | 21.6 MB |
| B7P80-A3_S11_L001_R1_001.fastq | ncRNA-Seq | 21.1 MB |
| B7P80-C-1_S4_L001_R1_001.fastq | ncRNA-Seq | 20.3 MB |
| B7P80-C-2_S5_L001_R1_001.fastq | ncRNA-Seq | 18.1 MB |
| B7P80-C-3_S6_L001_R1_001.fastq | ncRNA-Seq | 21.2 MB |
| B7P80-D1_S12_L001_R1_001.fastq | ncRNA-Seq | 22.6 MB |
| B7P80-D2_S13_L001_R1_001.fastq | ncRNA-Seq | 20.3 MB |
| B7P80-D3_S8_L001_R1_001.fastq | ncRNA-Seq | 35.8 MB |
| SRR4175377_GSM2298799 | ncRNA-Seq | 24.0 MB |
| SRR4175378_GSM2298800 | ncRNA-Seq | 21.0 MB |
| SRR4175379_GSM2298801 | ncRNA-Seq | 21.0 MB |
| SRR4175380_GSM2298802 | ncRNA-Seq | 22.0 MB |
| SRR4175381_GSM2298803 | ncRNA-Seq | 20.0 MB |
| SRR4175382_GSM2298804 | ncRNA-Seq | 35.0 MB |
| SRR4175383_GSM2298805 | ncRNA-Seq | 20.0 MB |
| SRR4175384_GSM2298806 | ncRNA-Seq | 18.0 MB |
| SRR4175385_GSM2298807 | ncRNA-Seq | 21.0 MB |
| SRR4175386_GSM2298808 | ncRNA-Seq | 27.0 MB |
| SRR4175387_GSM2298809 | ncRNA-Seq | 20.0 MB |
| SRR4175388_GSM2298810 | ncRNA-Seq | 20.0 MB |
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_Arrays_mouse_SC]
Mus musculus
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_RNA-seq_mouse_SC]
Mus musculus
14 data files
| File | Type | Size |
|---|---|---|
| A1-SC_ATTACTCG_L002_R1.fastq.gz | RNA-Seq | 5.8 GB |
| A2-SC_TCCGGAGA_L002_R1.fastq.gz | RNA-Seq | 5.2 GB |
| A3-SC_CGCTCATT_L002_R1.fastq.gz | RNA-Seq | 467.8 MB |
| D1-SC_GAGATTCC_L002_R1.fastq.gz | RNA-Seq | 1.3 GB |
| D2-SC_ATTCAGAA-TATAGCCT_L003_R1.fastq.gz | RNA-Seq | 1.7 GB |
| D3-SC_GAATTCGT-TATAGCCT_L003_R1.fastq.gz | RNA-Seq | 725.8 MB |
| D4-SC_CTGAAGCT-TATAGCCT_L003_R1.fastq.gz | RNA-Seq | 1.2 GB |
| SRR4175328_GSM2292523 | RNA-Seq | 5.8 GB |
| SRR4175329_GSM2292524 | RNA-Seq | 5.2 GB |
| SRR4175330_GSM2292525 | RNA-Seq | 467.0 MB |
| SRR4175331_GSM2292526 | RNA-Seq | 1.3 GB |
| SRR4175332_GSM2292527 | RNA-Seq | 1.7 GB |
| SRR4175333_GSM2292528 | RNA-Seq | 725.0 MB |
| SRR4175334_GSM2292529 | RNA-Seq | 1.2 GB |
HNRNPA2B1 regulates alternative RNA processing in the nervous system and accumulates in granules in ALS IPSC-derived motor neurons [hnRNPA2B1_eCLIP_human_iPSC_MN]
Homo sapiens
42 data files
| File | Type | Size |
|---|---|---|
| F1_IN_A2B1_ATTACTCG-TATAGCCT_L008_R1.unassigned.randomer.fa… | RIP-Seq | 606.4 MB |
| F1_IP_A2B1_TCCGGAGA-TATAGCCT_L008_R1.A01_F1_IP_mnCLIP_A2B1_… | RIP-Seq | 225.5 MB |
| F1_IP_A2B1_TCCGGAGA-TATAGCCT_L008_R1.B06_F1_IP_mnCLIP_A2B1_… | RIP-Seq | 156.4 MB |
| F2_IN_A2B1_CGCTCATT-TATAGCCT_L008_R1.unassigned.randomer.fa… | RIP-Seq | 506.5 MB |
| F2_IP_A2B1_GAGATTCC-TATAGCCT_L008_R1.C01_F2_IP_mnCLIP_A2B1_… | RIP-Seq | 245.9 MB |
| F2_IP_A2B1_GAGATTCC-TATAGCCT_L008_R1.D08fixed_F2_IP_mnCLIP_… | RIP-Seq | 138.8 MB |
| F3_IN_A2B1_ATTCAGAA-TATAGCCT_L008_R1.unassigned.randomer.fa… | RIP-Seq | 733.5 MB |
| F3_IP_A2B1_GAATTCGT-TATAGCCT_L008_R1.A01_F3_IP_mnCLIP_A2B1_… | RIP-Seq | 140.0 MB |
| F3_IP_A2B1_GAATTCGT-TATAGCCT_L008_R1.B06_F3_IP_mnCLIP_A2B1_… | RIP-Seq | 88.0 MB |
| F4_IN_A2B1_ATTACTCG-ATAGAGGC_L008_R1.unassigned.randomer.fa… | RIP-Seq | 735.2 MB |
| F4_IP_A2B1_TCCGGAGA-ATAGAGGC_L008_R1.C01_F4_IP_mnCLIP_A2B1_… | RIP-Seq | 392.8 MB |
| F4_IP_A2B1_TCCGGAGA-ATAGAGGC_L008_R1.D08fixed_F4_IP_mnCLIP_… | RIP-Seq | 122.7 MB |
| F5_IN_A2B1_CGCTCATT-ATAGAGGC_L008_R1.unassigned.randomer.fa… | RIP-Seq | 447.8 MB |
| F5_IP_A2B1_GAGATTCC-ATAGAGGC_L008_R1.A01_F5_IP_mnCLIP_A2B1_… | RIP-Seq | 282.0 MB |
| F5_IP_A2B1_GAGATTCC-ATAGAGGC_L008_R1.B06_F5_IP_mnCLIP_A2B1_… | RIP-Seq | 108.2 MB |
| F6_IN_A2B1_ATTCAGAA-ATAGAGGC_L008_R1.unassigned.randomer.fa… | RIP-Seq | 340.9 MB |
| F6_IP_A2B1_GAATTCGT-ATAGAGGC_L008_R1.C01_F6_IP_mnCLIP_A2B1_… | RIP-Seq | 315.6 MB |
| F6_IP_A2B1_GAATTCGT-ATAGAGGC_L008_R1.D08fixed_F6_IP_mnCLIP_… | RIP-Seq | 111.7 MB |
| F7_IN_IgG_ATTACTCG-CCTATCCT_L008_R1.unassigned.randomer.fas… | RIP-Seq | 446.3 MB |
| F7_IP_IgG_ATTCAGAA-CCTATCCT_L008_R1.A01_F7_IP_mnCLIP_IgG_hi… | RIP-Seq | 102.4 KB |
| F7_IP_IgG_ATTCAGAA-CCTATCCT_L008_R1.B06_F7_IP_mnCLIP_IgG_hi… | RIP-Seq | 112.6 KB |
| SRR4175306_GSM2292508 | RIP-Seq | 225.0 MB |
| SRR4175307_GSM2292508 | RIP-Seq | 156.0 MB |
| SRR4175308_GSM2292509 | RIP-Seq | 606.0 MB |
| SRR4175309_GSM2292510 | RIP-Seq | 245.0 MB |
| SRR4175310_GSM2292510 | RIP-Seq | 138.0 MB |
| SRR4175311_GSM2292511 | RIP-Seq | 506.0 MB |
| SRR4175312_GSM2292512 | RIP-Seq | 140.0 MB |
| SRR4175313_GSM2292512 | RIP-Seq | 87.0 MB |
| SRR4175314_GSM2292513 | RIP-Seq | 733.0 MB |
| SRR4175315_GSM2292514 | RIP-Seq | 392.0 MB |
| SRR4175316_GSM2292514 | RIP-Seq | 122.0 MB |
| SRR4175317_GSM2292515 | RIP-Seq | 735.0 MB |
| SRR4175318_GSM2292516 | RIP-Seq | 281.0 MB |
| SRR4175319_GSM2292516 | RIP-Seq | 108.0 MB |
| SRR4175320_GSM2292517 | RIP-Seq | 447.0 MB |
| SRR4175321_GSM2292518 | RIP-Seq | 315.0 MB |
| SRR4175322_GSM2292518 | RIP-Seq | 111.0 MB |
| SRR4175323_GSM2292519 | RIP-Seq | 340.0 MB |
| SRR4175324_GSM2292520 | RIP-Seq | |
| SRR4175325_GSM2292520 | RIP-Seq | |
| SRR4175326_GSM2292521 | RIP-Seq | 446.0 MB |
Potentially related datasets 1
These accessions were text-mined from the PMC full text. They may be referenced for comparison, cited from other studies, or otherwise mentioned without being primary data for this paper.
Analysis pipelines 10
| Pipeline | Assay | Steps | Dataset |
|---|---|---|---|
| GSE86038 Microarray Data Processing geo_data_processing | Microarray | 3 | GSE86038 |
| GSE86040 eCLIP Data Processing geo_data_processing | eCLIP | 6 | GSE86040 |
| GSE86041 iCLIP Data Processing geo_data_processing | iCLIP | 7 | GSE86041 |
| GSE86043 RNA-seq Data Processing geo_data_processing | RNA-seq | 8 | GSE86043 |
| GSE86218 Microarray Data Processing geo_data_processing | Microarray | 3 | GSE86218 |
| GSE86223 Microarray Data Processing geo_data_processing | Microarray | 6 | GSE86223 |
| GSE86224 Microarray Data Processing geo_data_processing | Microarray | 3 | GSE86224 |
| GSE86227 RNA-seq Data Processing geo_data_processing | RNA-seq | 5 | GSE86227 |
| GSE86462 Microarray Data Processing geo_data_processing | Microarray | 3 | GSE86462 |
| GSE86464 Microarray Data Processing geo_data_processing | Microarray | 3 | GSE86464 |
Funding 8 grants
| Grant | Funder |
|---|---|
| R01 HG004659 | NHGRI NIH HHS (United States) |
| R35 GM118069 | NIGMS NIH HHS (United States) |
| T32 GM008666 | NIGMS NIH HHS (United States) |
| T32 GM087237 | NIGMS NIH HHS (United States) |
| U54 HG007005 | NHGRI NIH HHS (United States) |
| U54 NS091046 | NINDS NIH HHS (United States) |
| R01 NS075449 | NINDS NIH HHS (United States) |
| R35 NS097974 | NINDS NIH HHS (United States) |