SCN1A: Bioinformatically Informed Revised Boundaries for Promoter and Enhancer Regions

Overview

Journal Hum Mol Genet

Specialties Genetics
Molecular Biology

Date 2023 Jan 30

PMID 36715146

Authors

Susanna Pagni

Helena Martins Custodio

Adam Frankish

Jonathan M Mudge

James D Mills

Sanjay M Sisodiya

Affiliations

Soon will be listed here.

Abstract

Pathogenic variations in the sodium voltage-gated channel alpha subunit 1 (SCN1A) gene are responsible for multiple epilepsy phenotypes, including Dravet syndrome, febrile seizures (FS) and genetic epilepsy with FS plus. Phenotypic heterogeneity is a hallmark of SCN1A-related epilepsies, the causes of which are yet to be clarified. Genetic variation in the non-coding regulatory regions of SCN1A could be one potential causal factor. However, a comprehensive understanding of the SCN1A regulatory landscape is currently lacking. Here, we summarized the current state of knowledge of SCN1A regulation, providing details on its promoter and enhancer regions. We then integrated currently available data on SCN1A promoters by extracting information related to the SCN1A locus from genome-wide repositories and clearly defined the promoter and enhancer regions of SCN1A. Further, we explored the cellular specificity of differential SCN1A promoter usage. We also reviewed and integrated the available human brain-derived enhancer databases and mouse-derived data to provide a comprehensive computationally developed summary of SCN1A brain-active enhancers. By querying genome-wide data repositories, extracting SCN1A-specific data and integrating the different types of independent evidence, we created a comprehensive catalogue that better defines the regulatory landscape of SCN1A, which could be used to explore the role of SCN1A regulatory regions in disease.

Citing Articles

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References

Andersson R, Gebhard C, Miguel-Escalada I, Hoof I, Bornholdt J, Boyd M . An atlas of active enhancers across human cell types and tissues. Nature. 2014; 507(7493):455-461. PMC: 5215096. DOI: 10.1038/nature12787. View

Frankish A, Diekhans M, Jungreis I, Lagarde J, Loveland J, Mudge J . GENCODE 2021. Nucleic Acids Res. 2020; 49(D1):D916-D923. PMC: 7778937. DOI: 10.1093/nar/gkaa1087. View

Kuersten M, Tacke M, Gerstl L, Hoelz H, Stulpnagel C, Borggraefe I . Antiepileptic therapy approaches in KCNQ2 related epilepsy: A systematic review. Eur J Med Genet. 2019; 63(1):103628. DOI: 10.1016/j.ejmg.2019.02.001. View

Ishii A, Watkins J, Chen D, Hirose S, Hammer M . Clinical implications of SCN1A missense and truncation variants in a large Japanese cohort with Dravet syndrome. Epilepsia. 2016; 58(2):282-290. DOI: 10.1111/epi.13639. View

Anwar A, Saleem S, Patel U, Arumaithurai K, Malik P . Dravet Syndrome: An Overview. Cureus. 2019; 11(6):e5006. PMC: 6713249. DOI: 10.7759/cureus.5006. View

Soldner F, Stelzer Y, Shivalila C, Abraham B, Latourelle J, Barrasa M . Parkinson-associated risk variant in distal enhancer of α-synuclein modulates target gene expression. Nature. 2016; 533(7601):95-9. PMC: 5042324. DOI: 10.1038/nature17939. View

Haigh J, Adhikari A, Copping N, Stradleigh T, Wade A, Catta-Preta R . Deletion of a non-canonical regulatory sequence causes loss of Scn1a expression and epileptic phenotypes in mice. Genome Med. 2021; 13(1):69. PMC: 8080386. DOI: 10.1186/s13073-021-00884-0. View

Orkin S, Kazazian Jr H, Antonarakis S, Goff S, Boehm C, Sexton J . Linkage of beta-thalassaemia mutations and beta-globin gene polymorphisms with DNA polymorphisms in human beta-globin gene cluster. Nature. 1982; 296(5858):627-31. DOI: 10.1038/296627a0. View

Batut P, Dobin A, Plessy C, Carninci P, Gingeras T . High-fidelity promoter profiling reveals widespread alternative promoter usage and transposon-driven developmental gene expression. Genome Res. 2012; 23(1):169-80. PMC: 3530677. DOI: 10.1101/gr.139618.112. View

10.

Vormstein-Schneider D, Lin J, Pelkey K, Chittajallu R, Guo B, Arias-Garcia M . Viral manipulation of functionally distinct interneurons in mice, non-human primates and humans. Nat Neurosci. 2020; 23(12):1629-1636. PMC: 8015416. DOI: 10.1038/s41593-020-0692-9. View

11.

Gertler T, Calhoun J, Laux L . A single-center, retrospective analysis of genotype-phenotype correlations in children with Dravet syndrome. Seizure. 2019; 75:1-6. PMC: 7112984. DOI: 10.1016/j.seizure.2019.12.009. View

12.

de Lange I, Koudijs M, van t Slot R, Gunning B, Sonsma A, van Gemert L . Mosaicism of de novo pathogenic SCN1A variants in epilepsy is a frequent phenomenon that correlates with variable phenotypes. Epilepsia. 2018; 59(3):690-703. DOI: 10.1111/epi.14021. View

13.

di Iulio J, Bartha I, Wong E, Yu H, Lavrenko V, Yang D . The human noncoding genome defined by genetic diversity. Nat Genet. 2018; 50(3):333-337. DOI: 10.1038/s41588-018-0062-7. View

14.

Li X, Qian X, Wang B, Xia Y, Zheng Y, Du L . Programmable base editing of mutated TERT promoter inhibits brain tumour growth. Nat Cell Biol. 2020; 22(3):282-288. DOI: 10.1038/s41556-020-0471-6. View

15.

Forrest A, Kawaji H, Rehli M, Baillie J, de Hoon M, Haberle V . A promoter-level mammalian expression atlas. Nature. 2014; 507(7493):462-70. PMC: 4529748. DOI: 10.1038/nature13182. View

16.

Huang F, Hodis E, Xu M, Kryukov G, Chin L, Garraway L . Highly recurrent TERT promoter mutations in human melanoma. Science. 2013; 339(6122):957-9. PMC: 4423787. DOI: 10.1126/science.1229259. View

17.

Nakayama T, Ogiwara I, Ito K, Kaneda M, Mazaki E, Osaka H . Deletions of SCN1A 5' genomic region with promoter activity in Dravet syndrome. Hum Mutat. 2010; 31(7):820-9. DOI: 10.1002/humu.21275. View

18.

Martin M, Tang B, Ta N, Escayg A . Characterization of 5' untranslated regions of the voltage-gated sodium channels SCN1A, SCN2A, and SCN3A and identification of cis-conserved noncoding sequences. Genomics. 2007; 90(2):225-35. PMC: 2637551. DOI: 10.1016/j.ygeno.2007.04.006. View

19.

Li W, Schneider A, Scheffer I . Defining Dravet syndrome: An essential pre-requisite for precision medicine trials. Epilepsia. 2021; 62(9):2205-2217. PMC: 9291974. DOI: 10.1111/epi.17015. View

20.

Dong Z, Tang L, Deng G, Zeng T, Liu S, Wan R . Transcription of the human sodium channel SCN1A gene is repressed by a scaffolding protein RACK1. Mol Neurobiol. 2014; 50(2):438-48. DOI: 10.1007/s12035-014-8633-9. View