Format

Send to

Choose Destination
Mol Cell. 2017 Feb 2;65(3):539-553.e7. doi: 10.1016/j.molcel.2017.01.011.

Multilayered Control of Alternative Splicing Regulatory Networks by Transcription Factors.

Author information

1
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada.
2
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada.
3
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge CB2 0QH, UK.
4
Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
5
Department of Pharmaceutical Sciences, University of Toronto, Toronto, ON M5S 3M2, Canada.
6
Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada; Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON M5G 1X5, Canada.
7
Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: b.blencowe@utoronto.ca.

Abstract

Networks of coordinated alternative splicing (AS) events play critical roles in development and disease. However, a comprehensive knowledge of the factors that regulate these networks is lacking. We describe a high-throughput system for systematically linking trans-acting factors to endogenous RNA regulatory events. Using this system, we identify hundreds of factors associated with diverse regulatory layers that positively or negatively control AS events linked to cell fate. Remarkably, more than one-third of the regulators are transcription factors. Further analyses of the zinc finger protein Zfp871 and BTB/POZ domain transcription factor Nacc1, which regulate neural and stem cell AS programs, respectively, reveal roles in controlling the expression of specific splicing regulators. Surprisingly, these proteins also appear to regulate target AS programs via binding RNA. Our results thus uncover a large "missing cache" of splicing regulators among annotated transcription factors, some of which dually regulate AS through direct and indirect mechanisms.

KEYWORDS:

RNA interference; SPAR-seq; alternative splicing; chromatin; embryonic stem cells; high-throughput screening; neuroblastoma cells; spliceosome; splicing factors; transcription factors

PMID:
28157508
DOI:
10.1016/j.molcel.2017.01.011
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center