Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins
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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.
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Very different motifs have been previously described for different HNRNPA family members from human and Drosophila, whereas RNAcompete motifs for the same proteins are closely related.
“very different motifs have been previously described for different HNRNPA family members from human and Drosophila19–22, whereas the RNAcompete motifs for the same proteins are closely related”
From A compendium of RNA-binding motifs for decoding gene regulation (2013) · cites this paper as [19]
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- Authors
- Huelga, S. C., Vu, A. Q., Arnold, J. D., Liang, T. Y., Liu, P. P., Yan, B. Y., Donohue, J. P., Shiue, L., Hoon, S., Brenner, S., Ares, M., & Yeo, G. W.
- Affiliations
- University of California San Diego (US)
- University of California, Santa Cruz (US)
- Agency for Science, Technology and Research (SG)
- Corresponding author
- Yeo, Gene W.
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2012-02
- Volume
- 1
- Issue
- 2
- Pages
- 167-178
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC3345519
- OpenAlex
- W1999609473
- Cited by
- 470
- References
- 52
- Citations by year
- 2026: 21 · 2025: 21 · 2024: 31 · 2023: 29 · 2022: 18 · 2021: 29 · 2020: 38 · 2019: 31 · 2018: 38 · 2017: 31 · 2016: 45 · 2015: 51 · 2014: 41 · 2013: 33 · 2012: 13
- FWCI
- 17.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
- Funders
- National Science Foundation
- National Institutes of Health
- National Human Genome Research Institute (HG004659, R01HG004659)
- National Institute of General Medical Sciences (R01GM084317, GM084317)
- National Institute of Neurological Disorders and Stroke (R01NS075449)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA regulation and disease
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer-related molecular mechanisms research
- Keywords
- alternative splicing, hnRNP proteins, RNA-binding proteins, splicing regulation, cooperative regulation, protein-protein interaction, consensus binding site, cross-regulation, autoregulation, cancer genes
- MeSH terms
- Base Sequence, Binding Sites, Exons, Fibroblasts, Humans, Molecular Sequence Data, Organ Specificity, Protein Binding, RNA Precursors, Blotting, Western, Reproducibility of Results, Genome, Human, Alternative Splicing, Reverse Transcriptase Polymerase Chain Reaction, Oligonucleotide Array Sequence Analysis, Protein Interaction Mapping, Heterogeneous-Nuclear Ribonucleoproteins, Genes, Neoplasm, HEK293 Cells, Nucleotide Motifs
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