title: TCERG1 regulates alternative splicing of the Bcl-x gene by modulating the rate of RNA polymerase II transcription.
abstract: Complex functional coupling exists between transcriptional elongation and pre-mRNA alternative splicing. Pausing sites and changes in the rate of transcription by RNA polymerase II (RNAPII) may therefore have fundamental impacts in the regulation of alternative splicing. Here, we show that the elongation and splicing-related factor TCERG1 regulates alternative splicing of the apoptosis gene Bcl-x in a promoter-dependent manner. TCERG1 promotes the splicing of the short isoform of Bcl-x (Bcl-x(s)) through the SB1 regulatory element located in the first half of exon 2. Consistent with these results, we show that TCERG1 associates with the Bcl-x pre-mRNA. A transcription profile analysis revealed that the RNA sequences required for the effect of TCERG1 on Bcl-x alternative splicing coincide with a putative polymerase pause site. Furthermore, TCERG1 modifies the impact of a slow polymerase on Bcl-x alternative splicing. In support of a role for an elongation mechanism in the transcriptional control of Bcl-x alternative splicing, we found that TCERG1 modifies the amount of pre-mRNAs generated at distal regions of the endogenous Bcl-x. Most importantly, TCERG1 affects the rate of RNAPII transcription of endogenous human Bcl-x. We propose that TCERG1 modulates the elongation rate of RNAPII to relieve pausing, thereby activating the proapoptotic Bcl-x(S) 5' splice site.
authors.affiliation: Department of Molecular Biology, Instituto de Parasitología y Biomedicina López Neyra, IPBLN-CSIC, Granada, Spain.
authors.forename: Marta
authors.initials: M
authors.lastname: Montes
authors.forename: Alexandre
authors.initials: A
authors.lastname: Cloutier
authors.forename: Noemí
authors.initials: N
authors.lastname: Sánchez-Hernández
authors.forename: Laetitia
authors.initials: L
authors.lastname: Michelle
authors.forename: Bruno
authors.initials: B
authors.lastname: Lemieux
authors.forename: Marco
authors.initials: M
authors.lastname: Blanchette
authors.forename: Cristina
authors.initials: C
authors.lastname: Hernández-Munain
authors.forename: Benoit
authors.initials: B
authors.lastname: Chabot
authors.forename: Carlos
authors.initials: C
authors.lastname: Suñé
mesh_terms: D017398:Alternative Splicing; D017209:Apoptosis / Q000235:genetics; D005091:Exons; D055785:Gene Knockdown Techniques; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D012319:RNA Polymerase II / Q000378:metabolism*; D022821:RNA Splice Sites; D034741:RNA, Small Interfering / Q000235:genetics; D050436:Regulatory Elements, Transcriptional; D014158:Transcription, Genetic; D035602:Transcriptional Elongation Factors / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051020:bcl-X Protein / Q000235:genetics*
chemical_list: C494811:BCL2L1 protein, human; D022821:RNA Splice Sites; D034741:RNA, Small Interfering; C108440:TCERG1 protein, human; D035602:Transcriptional Elongation Factors; D051020:bcl-X Protein; D012319:RNA Polymerase II