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Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins.

Stephanie C Huelga, Anthony Q Vu, Justin D Arnold, Tiffany Y Liang, Patrick P Liu, Bernice Y Yan, John Paul Donohue, Lily Shiue, Shawn Hoon, Sydney Brenner, Manuel Ares, Gene W Yeo

Cell reports · 2012 · Vol. 1 (2) · pp. 167-78

PubMed ↗ DOI ↗ PMC full text ↗

Abstract

Understanding how RNA binding proteins control the splicing code is fundamental to human biology and disease. Here, we present a comprehensive study to elucidate how heterogeneous nuclear ribonucleoparticle (hnRNP) proteins, among the most abundant RNA binding proteins, coordinate to regulate alternative pre-mRNA splicing (AS) in human cells. Using splicing-sensitive microarrays, crosslinking and immunoprecipitation coupled with high-throughput sequencing (CLIP-seq), and cDNA sequencing, we find that more than half of all AS events are regulated by multiple hnRNP proteins and that some combinations of hnRNP proteins exhibit significant synergy, whereas others act antagonistically. Our analyses reveal position-dependent RNA splicing maps, in vivo consensus binding sites, a surprising level of cross- and autoregulation among hnRNP proteins, and the coordinated regulation by hnRNP proteins of dozens of other RNA binding proteins and genes associated with cancer. Our findings define an unprecedented degree of complexity and compensatory relationships among hnRNP proteins and their splicing targets that likely confer robustness to cells.

Linked datasets 4

GSE34996 GSE · via ncbi_elink
GEO ↗

Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins

Homo sapiens

GSE34995 GSE · via ncbi_elink
GEO ↗

Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins (RNA-Seq)

Homo sapiens

67 data files
FileTypeSize
control_293T_RNAseq_1_sequence.txt RNA-Seq 485.3 MB
control_293T_RNAseq_2_sequence.txt RNA-Seq 397.3 MB
control_293T_RNAseq_3_sequence.txt RNA-Seq 557.7 MB
control_293T_RNAseq_4_sequence.txt RNA-Seq 547.7 MB
control_293T_RNAseq_4_sequence.txt RNA-Seq 547.7 MB
control_293T_RNAseq_5_sequence.txt RNA-Seq 751.5 MB
control_293T_RNAseq_6_sequence.txt RNA-Seq 790.2 MB
hnRNPA1_293T_RNAseq_KD1a_sequence.txt RNA-Seq 266.9 MB
hnRNPA1_293T_RNAseq_KD2a_sequence.txt RNA-Seq 315.5 MB
hnRNPA1_293T_RNAseq_KD3a_sequence.txt RNA-Seq 258.7 MB
hnRNPA1_293T_RNAseq_KD3b_sequence.txt RNA-Seq 1.2 GB
hnRNPA1_293T_RNAseq_KD3c_sequence.txt RNA-Seq 760.1 MB
hnRNPA1_293T_RNAseq_KD3d_sequence.txt RNA-Seq 769.1 MB
hnRNPA2B1_293T_RNAseq_KD1a_sequence.txt RNA-Seq 629.9 MB
hnRNPA2B1_293T_RNAseq_KD2a_sequence.txt RNA-Seq 447.6 MB
hnRNPF_293T_RNAseq_KD1a_sequence.txt RNA-Seq 446.9 MB
hnRNPF_293T_RNAseq_KD1b_sequence.txt RNA-Seq 720.1 MB
hnRNPF_293T_RNAseq_KD2a_sequence.txt RNA-Seq 670.7 MB
hnRNPF_293T_RNAseq_KD2b_sequence.txt RNA-Seq 779.5 MB
hnRNPF_293T_RNAseq_KD2c_sequence.txt RNA-Seq 767.9 MB
hnRNPH1_293T_RNAseq_KD1a_sequence.txt RNA-Seq 688.8 MB
hnRNPH1_293T_RNAseq_KD2a_sequence.txt RNA-Seq 1.2 GB
hnRNPM_293T_RNAseq_KD1a_sequence.txt RNA-Seq 340.2 MB
hnRNPM_293T_RNAseq_KD1b_sequence.txt RNA-Seq 1.1 GB
hnRNPM_293T_RNAseq_KD1c_sequence.txt RNA-Seq 688.6 MB
hnRNPM_293T_RNAseq_KD1d_sequence.txt RNA-Seq 684.9 MB
hnRNPM_293T_RNAseq_KD2a_sequence.txt RNA-Seq 324.7 MB
hnRNPM_293T_RNAseq_KD2b_sequence.txt RNA-Seq 320.6 MB
hnRNPU_293T_RNAseq_KD1a_sequence.txt RNA-Seq 449.8 MB
hnRNPU_293T_RNAseq_KD1b_sequence.txt RNA-Seq 1.2 GB
hnRNPU_293T_RNAseq_KD2a_sequence.txt RNA-Seq 762.2 MB
hnRNPU_293T_RNAseq_KD2b_sequence.txt RNA-Seq 3.2 GB
SRR398210_GSM859993 RNA-Seq 266.0 MB
SRR398211_GSM859994 RNA-Seq 315.0 MB
SRR398212_GSM859995 RNA-Seq 258.0 MB
SRR398213_GSM859996 RNA-Seq 1.2 GB
SRR398214_GSM859998 RNA-Seq 760.0 MB
SRR398215 RNA-Seq 769.1 MB
SRR398215_GSM859999 RNA-Seq 769.0 MB
SRR398216_GSM860001 RNA-Seq 629.0 MB
SRR398217_GSM860004 RNA-Seq 447.0 MB
SRR398218_GSM860007 RNA-Seq 446.0 MB
SRR398219_GSM860009 RNA-Seq 720.0 MB
SRR398220_GSM860011 RNA-Seq 670.0 MB
SRR398221_GSM860012 RNA-Seq 779.0 MB
SRR398222_GSM860013 RNA-Seq 767.0 MB
SRR398223_GSM860014 RNA-Seq 688.0 MB
SRR398224 RNA-Seq 1.2 GB
SRR398224_GSM860015 RNA-Seq 1.2 GB
SRR398225_GSM860016 RNA-Seq 340.0 MB
SRR398226_GSM860017 RNA-Seq 1.1 GB
SRR398227_GSM860018 RNA-Seq 688.0 MB
SRR398228_GSM860019 RNA-Seq 684.0 MB
SRR398229_GSM860020 RNA-Seq 324.0 MB
SRR398230 RNA-Seq 320.6 MB
SRR398230_GSM860021 RNA-Seq 320.0 MB
SRR398231_GSM860022 RNA-Seq 449.0 MB
SRR398232_GSM860023 RNA-Seq 1.2 GB
SRR398233_GSM860024 RNA-Seq 762.0 MB
SRR398234 RNA-Seq 3.2 GB
SRR398234_GSM860025 RNA-Seq 3.2 GB
SRR398235_GSM860026 RNA-Seq 485.0 MB
SRR398236_GSM860027 RNA-Seq 397.0 MB
SRR398237_GSM860028 RNA-Seq 557.0 MB
SRR398238_GSM860029 RNA-Seq 547.0 MB
SRR398239_GSM860030 RNA-Seq 751.0 MB
SRR398240_GSM860031 RNA-Seq 790.0 MB
GSE34992 GSE · via ncbi_elink
GEO ↗

Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins (splicing arrays)

Homo sapiens

GSE34993 GSE · via ncbi_elink
GEO ↗

Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins (CLIP-Seq)

Homo sapiens

34 data files
FileTypeSize
hnRNPA1_293T_CLIPseq_1_sequence.txt RNA-Seq 54.6 MB
hnRNPA1_293T_CLIPseq_2_sequence.txt RNA-Seq 83.2 MB
hnRNPA1_293T_CLIPseq_3_sequence.txt RNA-Seq 80.7 MB
hnRNPA1_293T_CLIPseq_4_sequence.txt RNA-Seq 409.6 KB
hnRNPA2B1_293T_CLIPseq_1_sequence.txt RNA-Seq 475.5 MB
HnRNPF_293T_CLIPseq_1_sequence.txt RNA-Seq 145.5 MB
HnRNPF_293T_CLIPseq_2_sequence.txt RNA-Seq 155.0 MB
HnRNPF_293T_CLIPseq_3_sequence.txt RNA-Seq 216.1 MB
HnRNPF_293T_CLIPseq_4_sequence.txt RNA-Seq 418.5 MB
HnRNPM_293T_CLIPseq_1_sequence.txt RNA-Seq 144.1 MB
HnRNPM_293T_CLIPseq_2_sequence.txt RNA-Seq 140.6 MB
HnRNPU_293T_CLIPseq_1_sequence.txt RNA-Seq 149.6 MB
HnRNPU_293T_CLIPseq_2_sequence.txt RNA-Seq 86.0 MB
HnRNPU_293T_CLIPseq_3_sequence.txt RNA-Seq 64.8 MB
HnRNPU_293T_CLIPseq_4_sequence.txt RNA-Seq 392.5 MB
SRR398195_GSM859978 RNA-Seq 54.0 MB
SRR398196 RNA-Seq 83.2 MB
SRR398196_GSM859979 RNA-Seq 83.0 MB
SRR398197_GSM859980 RNA-Seq 80.0 MB
SRR398198_GSM859981 RNA-Seq
SRR398199_GSM859982 RNA-Seq 475.0 MB
SRR398200_GSM859983 RNA-Seq 145.0 MB
SRR398201 RNA-Seq 155.0 MB
SRR398201_GSM859984 RNA-Seq 155.0 MB
SRR398202 RNA-Seq 216.1 MB
SRR398202_GSM859985 RNA-Seq 216.0 MB
SRR398203 RNA-Seq 418.5 MB
SRR398203_GSM859986 RNA-Seq 418.0 MB
SRR398204_GSM859987 RNA-Seq 144.0 MB
SRR398205_GSM859988 RNA-Seq 140.0 MB
SRR398206_GSM859989 RNA-Seq 149.0 MB
SRR398207_GSM859990 RNA-Seq 85.0 MB
SRR398208_GSM859991 RNA-Seq 64.0 MB
SRR398209_GSM859992 RNA-Seq 392.0 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.

Accession Source Title
GSE34992 GSE · GEO GEO ↗ Integrative genome-wide analysis reveals cooperative regulation of alternative splicing by hnRNP proteins (splicing arrays)

Analysis pipelines 4

Pipeline Assay Steps Dataset
GSE34992 Microarray Data Processing geo_data_processing Microarray 2 GSE34992
GSE34993 CLIP-seq Data Processing geo_data_processing CLIP-seq 2 GSE34993
GSE34995 RNA-seq Data Processing geo_data_processing RNA-seq 2 GSE34995
GSE34996 Microarray Data Processing geo_data_processing Microarray 2 GSE34996
Funding 5 grants
Grant Funder
R01 HG004659 NHGRI NIH HHS (United States)
R01 NS075449 NINDS NIH HHS (United States)
HG004659 NHGRI NIH HHS (United States)
R01 GM084317 NIGMS NIH HHS (United States)
GM084317 NIGMS NIH HHS (United States)