Cargando…

Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons

BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA trans...

Descripción completa

Detalles Bibliográficos
Autores principales: Ruble, Cara L., Smith, Ryan M., Calley, John, Munsie, Leanne, Airey, David C., Gao, Yuan, Shin, Joo Heon, Hyde, Thomas M., Straub, Richard E., Weinberger, Daniel R., Nisenbaum, Laura K.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702415/
https://www.ncbi.nlm.nih.gov/pubmed/26738766
http://dx.doi.org/10.1186/s12863-015-0325-6
_version_ 1782408637514252288
author Ruble, Cara L.
Smith, Ryan M.
Calley, John
Munsie, Leanne
Airey, David C.
Gao, Yuan
Shin, Joo Heon
Hyde, Thomas M.
Straub, Richard E.
Weinberger, Daniel R.
Nisenbaum, Laura K.
author_facet Ruble, Cara L.
Smith, Ryan M.
Calley, John
Munsie, Leanne
Airey, David C.
Gao, Yuan
Shin, Joo Heon
Hyde, Thomas M.
Straub, Richard E.
Weinberger, Daniel R.
Nisenbaum, Laura K.
author_sort Ruble, Cara L.
collection PubMed
description BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans. RESULTS: We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5’ untranslated region of HTR2A. CONCLUSIONS: Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-015-0325-6) contains supplementary material, which is available to authorized users.
format Online
Article
Text
id pubmed-4702415
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher BioMed Central
record_format MEDLINE/PubMed
spelling pubmed-47024152016-01-07 Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons Ruble, Cara L. Smith, Ryan M. Calley, John Munsie, Leanne Airey, David C. Gao, Yuan Shin, Joo Heon Hyde, Thomas M. Straub, Richard E. Weinberger, Daniel R. Nisenbaum, Laura K. BMC Genet Research Article BACKGROUND: The serotonin 2A receptor is widely implicated in genetic association studies and remains an important drug target for psychiatric, neurological, and cardiovascular conditions. RNA sequencing redefined the architecture of the serotonin 2A receptor gene (HTR2A), revealing novel mRNA transcript isoforms utilizing unannotated untranslated regions of the gene. Expression of these untranslated regions is modulated by common single nucleotide polymorphisms (SNPs), namely rs6311. Previous studies did not fully capture the complexity of the sense- and antisense-encoded transcripts with respect to novel exons in the HTR2A gene locus. Here, we comprehensively catalogued exons and RNA isoforms for both HTR2A and HTR2A-AS1 using RNA-Seq from human prefrontal cortex and multiple mouse tissues. We subsequently tested associations between expression of newfound gene features and common SNPs in humans. RESULTS: We find that the human HTR2A gene spans ~66 kilobases and consists of 7, rather than 4 exons. Furthermore, the revised human HTR2A-AS1 gene spans ~474 kilobases and consists of 18, rather than 3 exons. Three HTR2A exons directly overlap with HTR2A-AS1 exons, suggesting potential for complementary nucleotide interactions. The repertoire of possible mouse Htr2a splice isoforms is remarkably similar to humans and we also find evidence for overlapping sense-antisense transcripts in the same relative positions as the human transcripts. rs6311 and SNPs in high linkage disequilibrium are associated with HTR2A-AS1 expression, in addition to previously described associations with expression of the extended 5’ untranslated region of HTR2A. CONCLUSIONS: Our proposed HTR2A and HTR2A-AS1 gene structures dramatically differ from current annotations, now including overlapping exons on the sense and anti-sense strands. We also find orthologous transcript isoforms expressed in mice, providing opportunities to elucidate the biological roles of the human isoforms using a model system. Associations between rs6311 and expression of HTR2A and HTR2A-AS1 suggest this polymorphism is capable of modulating the expression of the sense or antisense transcripts. Still unclear is whether these SNPs act directly on the expression of the sense or antisense transcripts and whether overlapping exons are capable of interacting through complimentary base-pairing. Additional studies are necessary to determine the extent and nature of interactions between the SNPs and the transcripts prior to interpreting these findings in the context of phenotypes associated with HTR2A. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12863-015-0325-6) contains supplementary material, which is available to authorized users. BioMed Central 2016-01-06 /pmc/articles/PMC4702415/ /pubmed/26738766 http://dx.doi.org/10.1186/s12863-015-0325-6 Text en © Ruble et al. 2016 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research Article
Ruble, Cara L.
Smith, Ryan M.
Calley, John
Munsie, Leanne
Airey, David C.
Gao, Yuan
Shin, Joo Heon
Hyde, Thomas M.
Straub, Richard E.
Weinberger, Daniel R.
Nisenbaum, Laura K.
Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons
title Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons
title_full Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons
title_fullStr Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons
title_full_unstemmed Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons
title_short Genomic structure and expression of the human serotonin 2A receptor gene (HTR2A) locus: identification of novel HTR2A and antisense (HTR2A-AS1) exons
title_sort genomic structure and expression of the human serotonin 2a receptor gene (htr2a) locus: identification of novel htr2a and antisense (htr2a-as1) exons
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4702415/
https://www.ncbi.nlm.nih.gov/pubmed/26738766
http://dx.doi.org/10.1186/s12863-015-0325-6
work_keys_str_mv AT rublecaral genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT smithryanm genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT calleyjohn genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT munsieleanne genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT aireydavidc genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT gaoyuan genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT shinjooheon genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT hydethomasm genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT straubricharde genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT weinbergerdanielr genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons
AT nisenbaumlaurak genomicstructureandexpressionofthehumanserotonin2areceptorgenehtr2alocusidentificationofnovelhtr2aandantisensehtr2aas1exons