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CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms

DNA methylation (meDNA) is a modulator of alternative splicing, and splicing perturbations are involved in tumorigenesis nearly as frequently as DNA mutations. However, the impact of meDNA on tumorigenesis via splicing-mediated mechanisms has not been thoroughly explored. Here, we found that HCT116...

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Autores principales: Batsché, Eric, Yi, Jia, Mauger, Oriane, Kornobis, Etienne, Hopkins, Benjamin, Hanmer-Lloyd, Charlotte, Muchardt, Christian
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216461/
https://www.ncbi.nlm.nih.gov/pubmed/34086943
http://dx.doi.org/10.1093/nar/gkab437
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author Batsché, Eric
Yi, Jia
Mauger, Oriane
Kornobis, Etienne
Hopkins, Benjamin
Hanmer-Lloyd, Charlotte
Muchardt, Christian
author_facet Batsché, Eric
Yi, Jia
Mauger, Oriane
Kornobis, Etienne
Hopkins, Benjamin
Hanmer-Lloyd, Charlotte
Muchardt, Christian
author_sort Batsché, Eric
collection PubMed
description DNA methylation (meDNA) is a modulator of alternative splicing, and splicing perturbations are involved in tumorigenesis nearly as frequently as DNA mutations. However, the impact of meDNA on tumorigenesis via splicing-mediated mechanisms has not been thoroughly explored. Here, we found that HCT116 colon carcinoma cells inactivated for the DNA methylases DNMT1/3b undergo a partial epithelial to mesenchymal transition associated with increased CD44 variant exon skipping. These skipping events are directly mediated by the loss of intragenic meDNA and the chromatin factors MBD1/2/3 and HP1γ and are also linked to phosphorylation changes in elongating RNA polymerase II. The role of meDNA in alternative splicing was confirmed by using the dCas9/DNMT3b tool. We further tested whether the meDNA level could have predictive value in the MCF10A model for breast cancer progression and in patients with acute lymphoblastic leukemia (B ALL). We found that a small number of differentially spliced genes, mostly involved in splicing and signal transduction, are correlated with the local modulation of meDNA. Our observations suggest that, although DNA methylation has multiple avenues to affect alternative splicing, its indirect effect may also be mediated through alternative splicing isoforms of these meDNA sensors.
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spelling pubmed-82164612021-06-22 CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms Batsché, Eric Yi, Jia Mauger, Oriane Kornobis, Etienne Hopkins, Benjamin Hanmer-Lloyd, Charlotte Muchardt, Christian Nucleic Acids Res Gene regulation, Chromatin and Epigenetics DNA methylation (meDNA) is a modulator of alternative splicing, and splicing perturbations are involved in tumorigenesis nearly as frequently as DNA mutations. However, the impact of meDNA on tumorigenesis via splicing-mediated mechanisms has not been thoroughly explored. Here, we found that HCT116 colon carcinoma cells inactivated for the DNA methylases DNMT1/3b undergo a partial epithelial to mesenchymal transition associated with increased CD44 variant exon skipping. These skipping events are directly mediated by the loss of intragenic meDNA and the chromatin factors MBD1/2/3 and HP1γ and are also linked to phosphorylation changes in elongating RNA polymerase II. The role of meDNA in alternative splicing was confirmed by using the dCas9/DNMT3b tool. We further tested whether the meDNA level could have predictive value in the MCF10A model for breast cancer progression and in patients with acute lymphoblastic leukemia (B ALL). We found that a small number of differentially spliced genes, mostly involved in splicing and signal transduction, are correlated with the local modulation of meDNA. Our observations suggest that, although DNA methylation has multiple avenues to affect alternative splicing, its indirect effect may also be mediated through alternative splicing isoforms of these meDNA sensors. Oxford University Press 2021-06-04 /pmc/articles/PMC8216461/ /pubmed/34086943 http://dx.doi.org/10.1093/nar/gkab437 Text en © The Author(s) 2021. Published by Oxford University Press on behalf of Nucleic Acids Research. https://creativecommons.org/licenses/by/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Gene regulation, Chromatin and Epigenetics
Batsché, Eric
Yi, Jia
Mauger, Oriane
Kornobis, Etienne
Hopkins, Benjamin
Hanmer-Lloyd, Charlotte
Muchardt, Christian
CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms
title CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms
title_full CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms
title_fullStr CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms
title_full_unstemmed CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms
title_short CD44 alternative splicing senses intragenic DNA methylation in tumors via direct and indirect mechanisms
title_sort cd44 alternative splicing senses intragenic dna methylation in tumors via direct and indirect mechanisms
topic Gene regulation, Chromatin and Epigenetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8216461/
https://www.ncbi.nlm.nih.gov/pubmed/34086943
http://dx.doi.org/10.1093/nar/gkab437
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