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Blood, 5 November 2009, Vol. 114, No. 19, pp. 4233-4242. Prepublished online as a Blood First Edition Paper on September 3, 2009; DOI 10.1182/blood-2009-02-206219. This Article Full Text Full Text (PDF) Supplemental Table and Figures All Versions of this Article: blood-2009-02-206219v1 114/19/4233    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Huang, S.-C. Articles by Benz, E. J. PubMed PubMed Citation Articles by Huang, S.-C. Articles by Benz, E. J., Jr Related Collections Red Cells, Iron, and Erythropoiesis Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  RED CELLS, IRON, AND ERYTHROPOIESIS Coupled transcription-splicing regulation of mutually exclusive splicing events at the 5' exons of protein 4.1R gene Shu-Ching Huang1,2, Aeri Cho1,*, Stephanie Norton1,*, Eva S. Liu1,*, Jennie Park1,*, Anyu Zhou1,2, Indira D. Munagala1, Alexander C. Ou1, Guang Yang1,2, Amittha Wickrema3, Tang K. Tang4, and Edward J. Benz, Jr1,2,57 1 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA; 2 Department of Medicine, Brigham and Women's Hospital, Boston, MA; 3 Department of Medicine, University of Chicago, IL; 4 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan, China; 5 Dana-Farber/Harvard Cancer Center, Boston, MA; 6 Department of Pathology, Harvard Medical School, Boston, MA; and 7 Department of Pediatrics, Children's Hospital, Boston, MA The tightly regulated production of distinct erythrocyte protein 4.1R isoforms involves differential splicing of 3 mutually exclusive first exons (1A, 1B, 1C) to the alternative 3' splice sites (ss) of exon 2'/2. Here, we demonstrate that exon 1 and 2'/2 splicing diversity is regulated by a transcription-coupled splicing mechanism. We also implicate distinctive regulatory elements that promote the splicing of exon 1A to the distal 3' ss and exon 1B to the proximal 3' ss in murine erythroleukemia cells. A hybrid minigene driven by cytomegalovirus promoter mimicked 1B-promoter–driven splicing patterns but differed from 1A-promoter–driven splicing patterns, suggesting that promoter identity affects exon 2'/2 splicing. Furthermore, splicing factor SF2/ASF ultraviolet (UV) cross-linked to the exon 2'/2 junction CAGAGAA, a sequence that overlaps the distal U2AF35-binding 3' ss. Consequently, depletion of SF2/ASF allowed exon 1B to splice to the distal 3' ss but had no effect on exon 1A splicing. These findings identify for the first time that an SF2/ASF binding site also can serve as a 3' ss in a transcript-dependent manner. Taken together, our results suggest that 4.1R gene expression involves transcriptional regulation coupled with a complex splicing regulatory network. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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