Transcriptional activators differ in their abilities to control alternative splicing

Promoter and enhancer elements can influence alter. native splicing, but the basis for this phenomenon is not well understood. Here we investigated how different transcriptional activators affect the decision between inclusion and exclusion (skipping) of the fibronectin EDI exon. A mutant of the aci...

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Autores principales:	Nogués, G., Kadener, S., Cramer, P., Bentley, D., Kornblihtt, A.R.
Formato:	JOUR
Materias:	Enzyme inhibition Enzymes Genes RNA Viruses Transcriptional activators Biochemistry 5,6 dichlorobenzimidazole riboside fibronectin histone deacetylase inhibitor mutant protein transactivator protein transcription factor Sp1 trichostatin A alternative RNA splicing animal cell article correlation analysis enhancer region exon nonhuman priority journal promoter region protein domain protein folding Alternative Splicing Animals Antigens, Polyomavirus Transforming Cercopithecus aethiops COS Cells Enhancer Elements (Genetics) Exons Fibronectins Gene Expression Regulation, Viral Replication Origin RNA Polymerase II Simian virus 40 Trans-Activators Transcription, Genetic Transfection Animalia Human immunodeficiency virus
Acceso en línea:	http://hdl.handle.net/20.500.12110/paper_00219258_v277_n45_p43110_Nogues
Aporte de:	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA) de Universidad de Buenos Aires

id	todo:paper_00219258_v277_n45_p43110_Nogues
record_format	dspace
spelling	todo:paper_00219258_v277_n45_p43110_Nogues2023-10-03T14:23:02Z Transcriptional activators differ in their abilities to control alternative splicing Nogués, G. Kadener, S. Cramer, P. Bentley, D. Kornblihtt, A.R. Enzyme inhibition Enzymes Genes RNA Viruses Transcriptional activators Biochemistry 5,6 dichlorobenzimidazole riboside fibronectin histone deacetylase inhibitor mutant protein transactivator protein transcription factor Sp1 trichostatin A alternative RNA splicing animal cell article correlation analysis enhancer region exon nonhuman priority journal promoter region protein domain protein folding Alternative Splicing Animals Antigens, Polyomavirus Transforming Cercopithecus aethiops COS Cells Enhancer Elements (Genetics) Exons Fibronectins Gene Expression Regulation, Viral Replication Origin RNA Polymerase II Simian virus 40 Trans-Activators Transcription, Genetic Transfection Animalia Human immunodeficiency virus Promoter and enhancer elements can influence alter. native splicing, but the basis for this phenomenon is not well understood. Here we investigated how different transcriptional activators affect the decision between inclusion and exclusion (skipping) of the fibronectin EDI exon. A mutant of the acidic VP16 activation domain called SW6 that preferentially inhibits polymerase II (pol II) elongation caused a reduction in EDI exon skipping. Exon skipping was fully restored in the presence of the SW6 mutant by either the SV40 enhancer in cis or the human immunodeficiency virus (HIV) Tat in trans, both of which specifically stimulate pol II elongation. HIV Tat also cooperated with the Spl and CTF activation domains to enhance transcript elongation and EDI skipping. The extent of exon skipping correlated with the efficiency with which pol II transcripts reach the 3′ end of the gene but not with the overall fold increase in transcript levels caused by different activators. The ability of activators to enhance elongation by RNA polymerase II therefore correlates with their ability to enhance exon skipping. Consistent with this observation, the elongation inhibitor dichlororibofurano-sylbenzimldazole (DRB) enhanced EDI inclusion. Conversely, the histone deacetylase inhibitor trichostatin A that is thought to stimulate elongation caused a modest inhibition of EDI inclusion. Together our results support a kinetic coupling model in which the rate of transcript elongation determines the outcome of two competing splicing reactions that occur co-transcriptionally. Rapid, highly processive transcription favors EDI exon skipping, whereas slower, less processive transcription favors inclusion. JOUR info:eu-repo/semantics/openAccess http://creativecommons.org/licenses/by/2.5/ar http://hdl.handle.net/20.500.12110/paper_00219258_v277_n45_p43110_Nogues
institution	Universidad de Buenos Aires
institution_str	I-28
repository_str	R-134
collection	Biblioteca Digital - Facultad de Ciencias Exactas y Naturales (UBA)
topic	Enzyme inhibition Enzymes Genes RNA Viruses Transcriptional activators Biochemistry 5,6 dichlorobenzimidazole riboside fibronectin histone deacetylase inhibitor mutant protein transactivator protein transcription factor Sp1 trichostatin A alternative RNA splicing animal cell article correlation analysis enhancer region exon nonhuman priority journal promoter region protein domain protein folding Alternative Splicing Animals Antigens, Polyomavirus Transforming Cercopithecus aethiops COS Cells Enhancer Elements (Genetics) Exons Fibronectins Gene Expression Regulation, Viral Replication Origin RNA Polymerase II Simian virus 40 Trans-Activators Transcription, Genetic Transfection Animalia Human immunodeficiency virus
spellingShingle	Enzyme inhibition Enzymes Genes RNA Viruses Transcriptional activators Biochemistry 5,6 dichlorobenzimidazole riboside fibronectin histone deacetylase inhibitor mutant protein transactivator protein transcription factor Sp1 trichostatin A alternative RNA splicing animal cell article correlation analysis enhancer region exon nonhuman priority journal promoter region protein domain protein folding Alternative Splicing Animals Antigens, Polyomavirus Transforming Cercopithecus aethiops COS Cells Enhancer Elements (Genetics) Exons Fibronectins Gene Expression Regulation, Viral Replication Origin RNA Polymerase II Simian virus 40 Trans-Activators Transcription, Genetic Transfection Animalia Human immunodeficiency virus Nogués, G. Kadener, S. Cramer, P. Bentley, D. Kornblihtt, A.R. Transcriptional activators differ in their abilities to control alternative splicing
topic_facet	Enzyme inhibition Enzymes Genes RNA Viruses Transcriptional activators Biochemistry 5,6 dichlorobenzimidazole riboside fibronectin histone deacetylase inhibitor mutant protein transactivator protein transcription factor Sp1 trichostatin A alternative RNA splicing animal cell article correlation analysis enhancer region exon nonhuman priority journal promoter region protein domain protein folding Alternative Splicing Animals Antigens, Polyomavirus Transforming Cercopithecus aethiops COS Cells Enhancer Elements (Genetics) Exons Fibronectins Gene Expression Regulation, Viral Replication Origin RNA Polymerase II Simian virus 40 Trans-Activators Transcription, Genetic Transfection Animalia Human immunodeficiency virus
description	Promoter and enhancer elements can influence alter. native splicing, but the basis for this phenomenon is not well understood. Here we investigated how different transcriptional activators affect the decision between inclusion and exclusion (skipping) of the fibronectin EDI exon. A mutant of the acidic VP16 activation domain called SW6 that preferentially inhibits polymerase II (pol II) elongation caused a reduction in EDI exon skipping. Exon skipping was fully restored in the presence of the SW6 mutant by either the SV40 enhancer in cis or the human immunodeficiency virus (HIV) Tat in trans, both of which specifically stimulate pol II elongation. HIV Tat also cooperated with the Spl and CTF activation domains to enhance transcript elongation and EDI skipping. The extent of exon skipping correlated with the efficiency with which pol II transcripts reach the 3′ end of the gene but not with the overall fold increase in transcript levels caused by different activators. The ability of activators to enhance elongation by RNA polymerase II therefore correlates with their ability to enhance exon skipping. Consistent with this observation, the elongation inhibitor dichlororibofurano-sylbenzimldazole (DRB) enhanced EDI inclusion. Conversely, the histone deacetylase inhibitor trichostatin A that is thought to stimulate elongation caused a modest inhibition of EDI inclusion. Together our results support a kinetic coupling model in which the rate of transcript elongation determines the outcome of two competing splicing reactions that occur co-transcriptionally. Rapid, highly processive transcription favors EDI exon skipping, whereas slower, less processive transcription favors inclusion.
format	JOUR
author	Nogués, G. Kadener, S. Cramer, P. Bentley, D. Kornblihtt, A.R.
author_facet	Nogués, G. Kadener, S. Cramer, P. Bentley, D. Kornblihtt, A.R.
author_sort	Nogués, G.
title	Transcriptional activators differ in their abilities to control alternative splicing
title_short	Transcriptional activators differ in their abilities to control alternative splicing
title_full	Transcriptional activators differ in their abilities to control alternative splicing
title_fullStr	Transcriptional activators differ in their abilities to control alternative splicing
title_full_unstemmed	Transcriptional activators differ in their abilities to control alternative splicing
title_sort	transcriptional activators differ in their abilities to control alternative splicing
url	http://hdl.handle.net/20.500.12110/paper_00219258_v277_n45_p43110_Nogues
work_keys_str_mv	AT noguesg transcriptionalactivatorsdifferintheirabilitiestocontrolalternativesplicing AT kadeners transcriptionalactivatorsdifferintheirabilitiestocontrolalternativesplicing AT cramerp transcriptionalactivatorsdifferintheirabilitiestocontrolalternativesplicing AT bentleyd transcriptionalactivatorsdifferintheirabilitiestocontrolalternativesplicing AT kornblihttar transcriptionalactivatorsdifferintheirabilitiestocontrolalternativesplicing
_version_	1782029678203109376

Transcriptional activators differ in their abilities to control alternative splicing

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