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DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose

SMCHD1 mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (...

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Autores principales: Inoue, Kaoru, Bostan, Hamed, Browne, MaKenna R., Bevis, Owen F., Bortner, Carl D., Moore, Steven A., Stence, Aaron A., Martin, Negin P., Chen, Shih-Heng, Burkholder, Adam B., Li, Jian-Liang, Shaw, Natalie D.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for the Advancement of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9937577/
https://www.ncbi.nlm.nih.gov/pubmed/36800423
http://dx.doi.org/10.1126/sciadv.abq7744
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author Inoue, Kaoru
Bostan, Hamed
Browne, MaKenna R.
Bevis, Owen F.
Bortner, Carl D.
Moore, Steven A.
Stence, Aaron A.
Martin, Negin P.
Chen, Shih-Heng
Burkholder, Adam B.
Li, Jian-Liang
Shaw, Natalie D.
author_facet Inoue, Kaoru
Bostan, Hamed
Browne, MaKenna R.
Bevis, Owen F.
Bortner, Carl D.
Moore, Steven A.
Stence, Aaron A.
Martin, Negin P.
Chen, Shih-Heng
Burkholder, Adam B.
Li, Jian-Liang
Shaw, Natalie D.
author_sort Inoue, Kaoru
collection PubMed
description SMCHD1 mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (human nose progenitors). Here, we show that upon SMCHD1 ablation, DUX4 becomes derepressed in H9 human embryonic stem cells (hESCs) as they differentiate toward a placode cell fate, triggering cell death. Arhinia and FSHD2 patient-derived induced pluripotent stem cells (iPSCs) express DUX4 when converted to placode cells and demonstrate variable degrees of cell death, suggesting an environmental disease modifier. HSV-1 may be one such modifier as herpesvirus infection amplifies DUX4 expression in SMCHD1 KO hESC and patient iPSC. These studies suggest that arhinia, like FSHD2, is due to compromised SMCHD1 repressive activity in a cell-specific context and provide evidence for an environmental modifier.
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spelling pubmed-99375772023-02-18 DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose Inoue, Kaoru Bostan, Hamed Browne, MaKenna R. Bevis, Owen F. Bortner, Carl D. Moore, Steven A. Stence, Aaron A. Martin, Negin P. Chen, Shih-Heng Burkholder, Adam B. Li, Jian-Liang Shaw, Natalie D. Sci Adv Biomedicine and Life Sciences SMCHD1 mutations cause congenital arhinia (absent nose) and a muscular dystrophy called FSHD2. In FSHD2, loss of SMCHD1 repressive activity causes expression of double homeobox 4 (DUX4) in muscle tissue, where it is toxic. Studies of arhinia patients suggest a primary defect in nasal placode cells (human nose progenitors). Here, we show that upon SMCHD1 ablation, DUX4 becomes derepressed in H9 human embryonic stem cells (hESCs) as they differentiate toward a placode cell fate, triggering cell death. Arhinia and FSHD2 patient-derived induced pluripotent stem cells (iPSCs) express DUX4 when converted to placode cells and demonstrate variable degrees of cell death, suggesting an environmental disease modifier. HSV-1 may be one such modifier as herpesvirus infection amplifies DUX4 expression in SMCHD1 KO hESC and patient iPSC. These studies suggest that arhinia, like FSHD2, is due to compromised SMCHD1 repressive activity in a cell-specific context and provide evidence for an environmental modifier. American Association for the Advancement of Science 2023-02-17 /pmc/articles/PMC9937577/ /pubmed/36800423 http://dx.doi.org/10.1126/sciadv.abq7744 Text en Copyright © 2023 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC). https://creativecommons.org/licenses/by-nc/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license (https://creativecommons.org/licenses/by-nc/4.0/) , which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.
spellingShingle Biomedicine and Life Sciences
Inoue, Kaoru
Bostan, Hamed
Browne, MaKenna R.
Bevis, Owen F.
Bortner, Carl D.
Moore, Steven A.
Stence, Aaron A.
Martin, Negin P.
Chen, Shih-Heng
Burkholder, Adam B.
Li, Jian-Liang
Shaw, Natalie D.
DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
title DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
title_full DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
title_fullStr DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
title_full_unstemmed DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
title_short DUX4 double whammy: The transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
title_sort dux4 double whammy: the transcription factor that causes a rare muscular dystrophy also kills the precursors of the human nose
topic Biomedicine and Life Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9937577/
https://www.ncbi.nlm.nih.gov/pubmed/36800423
http://dx.doi.org/10.1126/sciadv.abq7744
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