Splicing activates transcription from weak promoters upstream of alternative exons.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
10 06 2023
10 06 2023
Historique:
received:
19
10
2022
accepted:
02
06
2023
medline:
12
6
2023
pubmed:
11
6
2023
entrez:
10
6
2023
Statut:
epublish
Résumé
Transcription and splicing are intrinsically coupled. Alternative splicing of internal exons can fine-tune gene expression through a recently described phenomenon called exon-mediated activation of transcription starts (EMATS). However, the association of this phenomenon with human diseases remains unknown. Here, we develop a strategy to activate gene expression through EMATS and demonstrate its potential for treatment of genetic diseases caused by loss of expression of essential genes. We first identified a catalog of human EMATS genes and provide a list of their pathological variants. To test if EMATS can be used to activate gene expression, we constructed stable cell lines expressing a splicing reporter based on the alternative splicing of motor neuron 2 (SMN2) gene. Using small molecules and antisense oligonucleotides (ASOs) currently used for treatment of spinal muscular atrophy, we demonstrated that increase of inclusion of alternative exons can trigger an activation of gene expression up to 45-fold by enhancing transcription in EMATS-like genes. We observed the strongest effects in genes under the regulation of weak human promoters located proximal to highly included skipped exons.
Identifiants
pubmed: 37301863
doi: 10.1038/s41467-023-39200-2
pii: 10.1038/s41467-023-39200-2
pmc: PMC10256964
doi:
Substances chimiques
Survival of Motor Neuron 1 Protein
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
3435Subventions
Organisme : NIGMS NIH HHS
ID : R35 GM147254
Pays : United States
Informations de copyright
© 2023. The Author(s).
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