期刊
EMBO JOURNAL
卷 21, 期 22, 页码 6195-6204出版社
NATURE PUBLISHING GROUP
DOI: 10.1093/emboj/cdf625
关键词
alternative splicing; exonic splicing silencer; hnRNP A and B; protein 4.1R
资金
- NCI NIH HHS [CA 13106, P01 CA013106] Funding Source: Medline
- NHLBI NIH HHS [HL 45182, R56 HL045182, R01 HL045182] Funding Source: Medline
A physiologically important alternative pre-mRNA splicing switch, involving activation. of protein 4.1R exon 16 (E16) splicing; is required for the establishment of proper mechanical integrity of the erythrocyte membrane during erythropoiesis. Here we identify a conserved exonic splicing silencer element (CE(16)) in E16 that interacts with hnRNP A/B proteins and plays a role in repression of E16 splicing during early erythropoiesis. Experiments with model pre-mRNAs showed that CE(16) can repress splicing of upstream introns, and that mutagenesis or replacement of CE(16) can relieve this inhibition. An affinity selection assay with biotinylated CE(16) RNA demonstrated specific binding of hnRNP A/B proteins. Depletion of hnRNP A/B proteins from nuclear extract significantly increased E16 inclusion, while repletion with recombinant hnRNP A/B restored E16 silencing. Most importantly, differentiating mouse erythroblasts exhibited a stage-specific activation of the E16 splicing switch in concert with a dramatic and specific down-regulation of hnRNP A/B protein expression. These findings demonstrate that natural developmental changes in hnRNP A/B proteins can effect physiologically important switches in pre-mRNA splicing.
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