VEGFA's distal enhancer regulates its alternative splicing in CML.
Journal
NAR cancer
ISSN: 2632-8674
Titre abrégé: NAR Cancer
Pays: England
ID NLM: 101769553
Informations de publication
Date de publication:
Sep 2021
Sep 2021
Historique:
received:
25
01
2021
revised:
21
06
2021
accepted:
27
06
2021
entrez:
28
7
2021
pubmed:
29
7
2021
medline:
29
7
2021
Statut:
epublish
Résumé
Enhancer demethylation in leukemia has been shown to lead to overexpression of genes which promote cancer characteristics. The vascular endothelial growth factor A (VEGFA) enhancer, located 157 Kb downstream of its promoter, is demethylated in chronic myeloid leukemia (CML). VEGFA has several alternative splicing isoforms with different roles in cancer progression. Since transcription and splicing are coupled, we wondered whether VEGFA enhancer activity can also regulate the gene's alternative splicing to contribute to the pathology of CML. Our results show that mutating the VEGFA +157 enhancer promotes exclusion of exons 6a and 7 and activating the enhancer by tethering a chromatin activator has the opposite effect. In line with these results, CML patients present with high expression of +157 eRNA and inclusion of VEGFA exons 6a and 7. In addition, our results show that the positive regulator of RNAPII transcription elongation, CCNT2, binds VEGFA's promoter and enhancer, and its silencing promotes exclusion of exons 6a and 7 as it slows down RNAPII elongation rate. Thus our results suggest that VEGFA's +157 enhancer regulates its alternative splicing by increasing RNAPII elongation rate via CCNT2. Our work demonstrates for the first time a connection between an endogenous enhancer and alternative splicing regulation of its target gene.
Identifiants
pubmed: 34316716
doi: 10.1093/narcan/zcab029
pii: zcab029
pmc: PMC8276762
doi:
Types de publication
Journal Article
Langues
eng
Pagination
zcab029Informations de copyright
© The Author(s) 2021. Published by Oxford University Press on behalf of NAR Cancer.
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