Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins
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 altern...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2012-02-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124712000435 |
| _version_ | 1818389298106335232 |
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| author | 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, Jr. Gene W. Yeo |
| author_facet | 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, Jr. Gene W. Yeo |
| author_sort | Stephanie C. Huelga |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-14T04:39:30Z |
| format | Article |
| id | doaj.art-5ea4085bf35e4d778e21aa158cbf14f8 |
| institution | Directory Open Access Journal |
| issn | 2211-1247 |
| language | English |
| last_indexed | 2024-12-14T04:39:30Z |
| publishDate | 2012-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj.art-5ea4085bf35e4d778e21aa158cbf14f82022-12-21T23:16:50ZengElsevierCell Reports2211-12472012-02-011216717810.1016/j.celrep.2012.02.001Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP ProteinsStephanie C. Huelga0Anthony Q. Vu1Justin D. Arnold2Tiffany Y. Liang3Patrick P. Liu4Bernice Y. Yan5John Paul Donohue6Lily Shiue7Shawn Hoon8Sydney Brenner9Manuel Ares, Jr.10Gene W. Yeo11Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USADepartment of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USADepartment of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USADepartment of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USADepartment of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USADepartment of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USARNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, 95064, USARNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, 95064, USAMolecular Engineering Lab, Agency for Science Technology and Research, SingaporeMolecular Engineering Lab, Agency for Science Technology and Research, SingaporeRNA Center, Department of Molecular, Cell and Developmental Biology, Sinsheimer Labs, University of California, Santa Cruz, California, 95064, USADepartment of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, 92093, USAUnderstanding 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.http://www.sciencedirect.com/science/article/pii/S2211124712000435 |
| spellingShingle | 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, Jr. Gene W. Yeo Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins Cell Reports |
| title | Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins |
| title_full | Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins |
| title_fullStr | Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins |
| title_full_unstemmed | Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins |
| title_short | Integrative Genome-wide Analysis Reveals Cooperative Regulation of Alternative Splicing by hnRNP Proteins |
| title_sort | integrative genome wide analysis reveals cooperative regulation of alternative splicing by hnrnp proteins |
| url | http://www.sciencedirect.com/science/article/pii/S2211124712000435 |
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