Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.

More than 300 genetic risk loci have been identified for male pattern baldness (MPB) but little is known about the exact molecular mechanisms through which the associated variants exert their effects on MPB pathophysiology. Here, we aimed at further elucidating the regulatory architecture of the MPB...

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Autores principales:	Lara M Hochfeld, Marta Bertolini, David Broadley, Natalia V Botchkareva, Regina C Betz, Susanne Schoch, Markus M Nöthen, Stefanie Heilmann-Heimbach
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/73204e71959b4dd0bf12d58f9788dc84
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spelling	oai:doaj.org-article:73204e71959b4dd0bf12d58f9788dc842021-12-02T20:14:42ZEvidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.1932-620310.1371/journal.pone.0256846https://doaj.org/article/73204e71959b4dd0bf12d58f9788dc842021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0256846https://doaj.org/toc/1932-6203More than 300 genetic risk loci have been identified for male pattern baldness (MPB) but little is known about the exact molecular mechanisms through which the associated variants exert their effects on MPB pathophysiology. Here, we aimed at further elucidating the regulatory architecture of the MPB risk locus on chromosome (chr.) 2q35, where we have previously reported a regulatory effect of the MPB lead variant on the expression of WNT10A. A HaploReg database research for regulatory annotations revealed that the association signal at 2q35 maps to a binding site for the transcription factor EBF1, whose gene is located at a second MPB risk locus on chr. 5q33.3. To investigate a potential interaction between EBF1 and WNT10A during MPB development, we performed in vitro luciferase reporter assays as well as expression analyses and immunofluorescence co-stainings in microdissected human hair follicles. Our experiments confirm that EBF1 activates the WNT10A promoter and that the WNT10A/EBF1 interaction is impacted by the allelic expression of the MPB risk allele at 2q35. Expression analyses across different hair cycle phases and immunhistochemical (co)stainings against WNT10A and EBF1 suggest a predominant relevance of EBF1/WNT10A interaction for hair shaft formation during anagen. Based on these findings we suggest a functional mechanism at the 2q35 risk locus for MPB, where an MPB-risk allele associated reduction in WNT10A promoter activation via EBF1 results in a decrease in WNT10A expression that eventually results in anagen shortening, that is frequently observed in MPB affected hair follicles. To our knowledge, this study is the first follow-up study on MPB that proves functional interaction between two MPB risk loci and sheds light on the underlying pathophysiological mechanism at these loci.Lara M HochfeldMarta BertoliniDavid BroadleyNatalia V BotchkarevaRegina C BetzSusanne SchochMarkus M NöthenStefanie Heilmann-HeimbachPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 9, p e0256846 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Lara M Hochfeld Marta Bertolini David Broadley Natalia V Botchkareva Regina C Betz Susanne Schoch Markus M Nöthen Stefanie Heilmann-Heimbach Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.
description	More than 300 genetic risk loci have been identified for male pattern baldness (MPB) but little is known about the exact molecular mechanisms through which the associated variants exert their effects on MPB pathophysiology. Here, we aimed at further elucidating the regulatory architecture of the MPB risk locus on chromosome (chr.) 2q35, where we have previously reported a regulatory effect of the MPB lead variant on the expression of WNT10A. A HaploReg database research for regulatory annotations revealed that the association signal at 2q35 maps to a binding site for the transcription factor EBF1, whose gene is located at a second MPB risk locus on chr. 5q33.3. To investigate a potential interaction between EBF1 and WNT10A during MPB development, we performed in vitro luciferase reporter assays as well as expression analyses and immunofluorescence co-stainings in microdissected human hair follicles. Our experiments confirm that EBF1 activates the WNT10A promoter and that the WNT10A/EBF1 interaction is impacted by the allelic expression of the MPB risk allele at 2q35. Expression analyses across different hair cycle phases and immunhistochemical (co)stainings against WNT10A and EBF1 suggest a predominant relevance of EBF1/WNT10A interaction for hair shaft formation during anagen. Based on these findings we suggest a functional mechanism at the 2q35 risk locus for MPB, where an MPB-risk allele associated reduction in WNT10A promoter activation via EBF1 results in a decrease in WNT10A expression that eventually results in anagen shortening, that is frequently observed in MPB affected hair follicles. To our knowledge, this study is the first follow-up study on MPB that proves functional interaction between two MPB risk loci and sheds light on the underlying pathophysiological mechanism at these loci.
format	article
author	Lara M Hochfeld Marta Bertolini David Broadley Natalia V Botchkareva Regina C Betz Susanne Schoch Markus M Nöthen Stefanie Heilmann-Heimbach
author_facet	Lara M Hochfeld Marta Bertolini David Broadley Natalia V Botchkareva Regina C Betz Susanne Schoch Markus M Nöthen Stefanie Heilmann-Heimbach
author_sort	Lara M Hochfeld
title	Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.
title_short	Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.
title_full	Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.
title_fullStr	Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.
title_full_unstemmed	Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.
title_sort	evidence for a functional interaction of wnt10a and ebf1 in male-pattern baldness.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/73204e71959b4dd0bf12d58f9788dc84
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Evidence for a functional interaction of WNT10A and EBF1 in male-pattern baldness.

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