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

Academic Article
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Overview

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, Sydney
  • Ares Jr., M.
  • Yeo, G. W.

publication date

  • February 2012

journal

  • Cell Reports  Journal

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.

subject areas

  • Alternative Splicing
  • Base Sequence
  • Binding Sites
  • Blotting, Western
  • Exons
  • Fibroblasts
  • Genes, Neoplasm
  • Genome, Human
  • HEK293 Cells
  • Heterogeneous-Nuclear Ribonucleoproteins
  • Humans
  • Molecular Sequence Data
  • Nucleotide Motifs
  • Oligonucleotide Array Sequence Analysis
  • Organ Specificity
  • Protein Binding
  • Protein Interaction Mapping
  • RNA Precursors
  • Reproducibility of Results
  • Reverse Transcriptase Polymerase Chain Reaction
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Identity

PubMed Central ID

  • PMC3345519

International Standard Serial Number (ISSN)

  • 2211-1247

Digital Object Identifier (DOI)

  • 10.1016/j.celrep.2012.02.001

PubMed ID

  • 22574288
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Additional Document Info

start page

  • 167

end page

  • 178

volume

  • 1

issue

  • 2

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