Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice
Abstract
Abstract Background Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the Na V 1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency; however, putative causal non-coding promoter mutations have been identified. Methods To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior. Results Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and Na V 1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits. Conclusions This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A . We identified the 1b region as amore »
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- Publication Date:
- Research Org.:
- Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH)
- OSTI Identifier:
- 1780196
- Alternate Identifier(s):
- OSTI ID: 1808528
- Grant/Contract Number:
- AC02-05CH11231; T32-GM008799; T32-GM007377; F31 MH119789-01; R24HL123879; U01DE024427; R01HG003988; U54HG006997; UM1HL098166
- Resource Type:
- Published Article
- Journal Name:
- Genome Medicine
- Additional Journal Information:
- Journal Name: Genome Medicine Journal Volume: 13 Journal Issue: 1; Journal ID: ISSN 1756-994X
- Publisher:
- Springer Science + Business Media
- Country of Publication:
- United Kingdom
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Haigh, Jessica L., Adhikari, Anna, Copping, Nycole A., Stradleigh, Tyler, Wade, A. Ayanna, Catta-Preta, Rinaldo, Su-Feher, Linda, Zdilar, Iva, Morse, Sarah, Fenton, Timothy A., Nguyen, Anh, Quintero, Diana, Agezew, Samrawit, Sramek, Michael, Kreun, Ellie J., Carter, Jasmine, Gompers, Andrea, Lambert, Jason T., Canales, Cesar P., Pennacchio, Len A., Visel, Axel, Dickel, Diane E., Silverman, Jill L., and Nord, Alex S. Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice. United Kingdom: N. p., 2021.
Web. doi:10.1186/s13073-021-00884-0.
Haigh, Jessica L., Adhikari, Anna, Copping, Nycole A., Stradleigh, Tyler, Wade, A. Ayanna, Catta-Preta, Rinaldo, Su-Feher, Linda, Zdilar, Iva, Morse, Sarah, Fenton, Timothy A., Nguyen, Anh, Quintero, Diana, Agezew, Samrawit, Sramek, Michael, Kreun, Ellie J., Carter, Jasmine, Gompers, Andrea, Lambert, Jason T., Canales, Cesar P., Pennacchio, Len A., Visel, Axel, Dickel, Diane E., Silverman, Jill L., & Nord, Alex S. Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice. United Kingdom. https://doi.org/10.1186/s13073-021-00884-0
Haigh, Jessica L., Adhikari, Anna, Copping, Nycole A., Stradleigh, Tyler, Wade, A. Ayanna, Catta-Preta, Rinaldo, Su-Feher, Linda, Zdilar, Iva, Morse, Sarah, Fenton, Timothy A., Nguyen, Anh, Quintero, Diana, Agezew, Samrawit, Sramek, Michael, Kreun, Ellie J., Carter, Jasmine, Gompers, Andrea, Lambert, Jason T., Canales, Cesar P., Pennacchio, Len A., Visel, Axel, Dickel, Diane E., Silverman, Jill L., and Nord, Alex S. Mon .
"Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice". United Kingdom. https://doi.org/10.1186/s13073-021-00884-0.
@article{osti_1780196,
title = {Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice},
author = {Haigh, Jessica L. and Adhikari, Anna and Copping, Nycole A. and Stradleigh, Tyler and Wade, A. Ayanna and Catta-Preta, Rinaldo and Su-Feher, Linda and Zdilar, Iva and Morse, Sarah and Fenton, Timothy A. and Nguyen, Anh and Quintero, Diana and Agezew, Samrawit and Sramek, Michael and Kreun, Ellie J. and Carter, Jasmine and Gompers, Andrea and Lambert, Jason T. and Canales, Cesar P. and Pennacchio, Len A. and Visel, Axel and Dickel, Diane E. and Silverman, Jill L. and Nord, Alex S.},
abstractNote = {Abstract Background Genes with multiple co-active promoters appear common in brain, yet little is known about functional requirements for these potentially redundant genomic regulatory elements. SCN1A, which encodes the Na V 1.1 sodium channel alpha subunit, is one such gene with two co-active promoters. Mutations in SCN1A are associated with epilepsy, including Dravet syndrome (DS). The majority of DS patients harbor coding mutations causing SCN1A haploinsufficiency; however, putative causal non-coding promoter mutations have been identified. Methods To determine the functional role of one of these potentially redundant Scn1a promoters, we focused on the non-coding Scn1a 1b regulatory region, previously described as a non-canonical alternative transcriptional start site. We generated a transgenic mouse line with deletion of the extended evolutionarily conserved 1b non-coding interval and characterized changes in gene and protein expression, and assessed seizure activity and alterations in behavior. Results Mice harboring a deletion of the 1b non-coding interval exhibited surprisingly severe reductions of Scn1a and Na V 1.1 expression throughout the brain. This was accompanied by electroencephalographic and thermal-evoked seizures, and behavioral deficits. Conclusions This work contributes to functional dissection of the regulatory wiring of a major epilepsy risk gene, SCN1A . We identified the 1b region as a critical disease-relevant regulatory element and provide evidence that non-canonical and seemingly redundant promoters can have essential function.},
doi = {10.1186/s13073-021-00884-0},
journal = {Genome Medicine},
number = 1,
volume = 13,
place = {United Kingdom},
year = {Mon Apr 26 00:00:00 EDT 2021},
month = {Mon Apr 26 00:00:00 EDT 2021}
}
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