An RNA code for the FOX2 splicing regulator revealed by mapping RNA-protein interactions in stem cells
Open accessAbstract
The elucidation of a code for regulated splicing has been a long-standing goal in understanding the control of post-transcriptional gene expression events that are crucial for cell survival, differentiation and development. We decoded functional RNA elements in vivo by constructing an RNA map for the cell type-specific splicing regulator FOX2 (also known as RBM9) via cross-linking immunoprecipitation coupled with high-throughput sequencing (CLIP-seq) in human embryonic stem cells. The map identified a large cohort of specific FOX2 targets, many of which are themselves splicing regulators, and comparison between the FOX2 binding profile and validated splicing events revealed a general rule for FOX2-regulated exon inclusion or skipping in a position-dependent manner. These findings suggest that FOX2 functions as a critical regulator of a splicing network, and we further show that FOX2 is important for the survival of human embryonic stem cells.
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RBFOX1, RBFOX2, and RBFOX3 motifs are conserved in introns downstream of alternative exons, whereas PUM1 and PUM2 sites are most highly conserved in 3' UTRs.
“motifs for the alternative splicing factorsRBFOX1, RBFOX2 and RBFOX3 (ref. 4) are conserved in introns downstream of alternative exons, whereas sites for the stability/translation factors PUM1 and PUM2 are most highly conserved in 3′ UTRs24,25”
From A compendium of RNA-binding motifs for decoding gene regulation (2013) · cites this paper as [24]
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References 32 · Cited by 572
- Authors
- Yeo, G. W., Coufal, N. G., Liang, T. Y., Peng, G. E., Fu, X.-D., & Gage, F. H.
- Affiliations
- Salk Institute for Biological Studies (US)
- University of California San Diego (US)
- Corresponding author
- Yeo, Gene W
- Fu, Xiang-Dong
- Gage, Fred H
- Venue
- Nature Structural & Molecular Biology
- Published
- 2009-01-11
- Volume
- 16
- Issue
- 2
- Pages
- 130-137
- ISSN
- 1545-9985 (ISSN-L)
- 1545-9993
- PMC
- PMC2735254
- OpenAlex
- W2162727919
- Cited by
- 572
- References
- 32
- Citations by year
- 2026: 10 · 2025: 13 · 2024: 27 · 2023: 16 · 2022: 26 · 2021: 33 · 2020: 21 · 2019: 18 · 2018: 25 · 2017: 40 · 2016: 37 · 2015: 41 · 2014: 47 · 2013: 46 · 2012: 58
- FWCI
- 22.97
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Structural & Molecular Biology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Human Genome Research Institute (HG004659, R01HG004659)
- National Institute of General Medical Sciences (GM049369, R01GM049369)
- National Center for Research Resources (S10RR025547)
- 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, RNA-protein interactions, human embryonic stem cells, CLIP-seq, splicing regulators, stem cell survival, cell death
- MeSH terms
- RNA Splicing Factors, Cell Survival, Exons, Humans, Repressor Proteins, RNA-Binding Proteins, Alternative Splicing, Sequence Analysis, RNA, RNA Splice Sites, Immunoprecipitation, Embryonic Stem Cells
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