Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B

Abstract SCNN1B encodes the beta subunit of the epithelial sodium channel ENaC. Previously, we reported an association between SNP markers of SCNN1B gene and disease severity in cystic fibrosis-affected sibling pairs. We hypothesized that factors interacting with the SCNN1B genomic sequence are resp...

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Autores principales:	Tim Becker, Andreas Pich, Stephanie Tamm, Silke Hedtfeld, Mohammed Ibrahim, Janine Altmüller, Nina Dalibor, Mohammad Reza Toliat, Sabina Janciauskiene, Burkhard Tümmler, Frauke Stanke
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/dcc752896878496ebfa52dadd5b3f362
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spelling	oai:doaj.org-article:dcc752896878496ebfa52dadd5b3f3622021-12-02T13:46:46ZGenetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B10.1038/s41598-020-79804-y2045-2322https://doaj.org/article/dcc752896878496ebfa52dadd5b3f3622020-12-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-79804-yhttps://doaj.org/toc/2045-2322Abstract SCNN1B encodes the beta subunit of the epithelial sodium channel ENaC. Previously, we reported an association between SNP markers of SCNN1B gene and disease severity in cystic fibrosis-affected sibling pairs. We hypothesized that factors interacting with the SCNN1B genomic sequence are responsible for intrapair discordance. Concordant and discordant pairs differed at six SCNN1B markers (Praw = 0.0075, Pcorr = 0.0397 corrected for multiple testing). To identify the factors binding to these six SCNN1B SNPs, we performed an electrophoretic mobility shift assay and captured the DNA–protein complexes. Based on protein mass spectrometry data, the epithelial splicing regulatory protein ESRP2 was identified when using SCNN1B-derived probes and the ESRP2-SCNN1B interaction was independently confirmed by coimmunoprecipitation assays. We observed an alternative SCNN1B transcript and demonstrated in 16HBE14o− cells that levels of this transcript are decreased upon ESRP2 silencing by siRNA. Furthermore, we confirmed that mildly and severely affected siblings have different ESPR2 genetic backgrounds and that ESRP2 markers are linked to the response of CF patients’ nasal epithelium to amiloride, indicating ENaC involvement (Pbest = 0.0131, Pcorr = 0.068 for multiple testing). Our findings demonstrate that sibling pairs clinically discordant for CF can be used to identify meaningful DNA regulatory elements and interacting factors.Tim BeckerAndreas PichStephanie TammSilke HedtfeldMohammed IbrahimJanine AltmüllerNina DaliborMohammad Reza ToliatSabina JanciauskieneBurkhard TümmlerFrauke StankeNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-19 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Tim Becker Andreas Pich Stephanie Tamm Silke Hedtfeld Mohammed Ibrahim Janine Altmüller Nina Dalibor Mohammad Reza Toliat Sabina Janciauskiene Burkhard Tümmler Frauke Stanke Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B
description	Abstract SCNN1B encodes the beta subunit of the epithelial sodium channel ENaC. Previously, we reported an association between SNP markers of SCNN1B gene and disease severity in cystic fibrosis-affected sibling pairs. We hypothesized that factors interacting with the SCNN1B genomic sequence are responsible for intrapair discordance. Concordant and discordant pairs differed at six SCNN1B markers (Praw = 0.0075, Pcorr = 0.0397 corrected for multiple testing). To identify the factors binding to these six SCNN1B SNPs, we performed an electrophoretic mobility shift assay and captured the DNA–protein complexes. Based on protein mass spectrometry data, the epithelial splicing regulatory protein ESRP2 was identified when using SCNN1B-derived probes and the ESRP2-SCNN1B interaction was independently confirmed by coimmunoprecipitation assays. We observed an alternative SCNN1B transcript and demonstrated in 16HBE14o− cells that levels of this transcript are decreased upon ESRP2 silencing by siRNA. Furthermore, we confirmed that mildly and severely affected siblings have different ESPR2 genetic backgrounds and that ESRP2 markers are linked to the response of CF patients’ nasal epithelium to amiloride, indicating ENaC involvement (Pbest = 0.0131, Pcorr = 0.068 for multiple testing). Our findings demonstrate that sibling pairs clinically discordant for CF can be used to identify meaningful DNA regulatory elements and interacting factors.
format	article
author	Tim Becker Andreas Pich Stephanie Tamm Silke Hedtfeld Mohammed Ibrahim Janine Altmüller Nina Dalibor Mohammad Reza Toliat Sabina Janciauskiene Burkhard Tümmler Frauke Stanke
author_facet	Tim Becker Andreas Pich Stephanie Tamm Silke Hedtfeld Mohammed Ibrahim Janine Altmüller Nina Dalibor Mohammad Reza Toliat Sabina Janciauskiene Burkhard Tümmler Frauke Stanke
author_sort	Tim Becker
title	Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B
title_short	Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B
title_full	Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B
title_fullStr	Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B
title_full_unstemmed	Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B
title_sort	genetic information from discordant sibling pairs points to esrp2 as a candidate trans-acting regulator of the cf modifier gene scnn1b
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/dcc752896878496ebfa52dadd5b3f362
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Genetic information from discordant sibling pairs points to ESRP2 as a candidate trans-acting regulator of the CF modifier gene SCNN1B

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