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SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at t...

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Autores principales: Tapia del Fierro, Andres, den Hamer, Bianca, Benetti, Natalia, Jansz, Natasha, Chen, Kelan, Beck, Tamara, Vanyai, Hannah, Gurzau, Alexandra D., Daxinger, Lucia, Xue, Shifeng, Ly, Thanh Thao Nguyen, Wanigasuriya, Iromi, Iminitoff, Megan, Breslin, Kelsey, Oey, Harald, Krom, Yvonne D., van der Hoorn, Dinja, Bouwman, Linde F., Johanson, Timothy M., Ritchie, Matthew E., Gouil, Quentin A., Reversade, Bruno, Prin, Fabrice, Mohun, Timothy, van der Maarel, Silvère M., McGlinn, Edwina, Murphy, James M., Keniry, Andrew, de Greef, Jessica C., Blewitt, Marnie E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519958/
https://www.ncbi.nlm.nih.gov/pubmed/37749075
http://dx.doi.org/10.1038/s41467-023-40992-6
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author Tapia del Fierro, Andres
den Hamer, Bianca
Benetti, Natalia
Jansz, Natasha
Chen, Kelan
Beck, Tamara
Vanyai, Hannah
Gurzau, Alexandra D.
Daxinger, Lucia
Xue, Shifeng
Ly, Thanh Thao Nguyen
Wanigasuriya, Iromi
Iminitoff, Megan
Breslin, Kelsey
Oey, Harald
Krom, Yvonne D.
van der Hoorn, Dinja
Bouwman, Linde F.
Johanson, Timothy M.
Ritchie, Matthew E.
Gouil, Quentin A.
Reversade, Bruno
Prin, Fabrice
Mohun, Timothy
van der Maarel, Silvère M.
McGlinn, Edwina
Murphy, James M.
Keniry, Andrew
de Greef, Jessica C.
Blewitt, Marnie E.
author_facet Tapia del Fierro, Andres
den Hamer, Bianca
Benetti, Natalia
Jansz, Natasha
Chen, Kelan
Beck, Tamara
Vanyai, Hannah
Gurzau, Alexandra D.
Daxinger, Lucia
Xue, Shifeng
Ly, Thanh Thao Nguyen
Wanigasuriya, Iromi
Iminitoff, Megan
Breslin, Kelsey
Oey, Harald
Krom, Yvonne D.
van der Hoorn, Dinja
Bouwman, Linde F.
Johanson, Timothy M.
Ritchie, Matthew E.
Gouil, Quentin A.
Reversade, Bruno
Prin, Fabrice
Mohun, Timothy
van der Maarel, Silvère M.
McGlinn, Edwina
Murphy, James M.
Keniry, Andrew
de Greef, Jessica C.
Blewitt, Marnie E.
author_sort Tapia del Fierro, Andres
collection PubMed
description The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1’s role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease.
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spelling pubmed-105199582023-09-27 SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease Tapia del Fierro, Andres den Hamer, Bianca Benetti, Natalia Jansz, Natasha Chen, Kelan Beck, Tamara Vanyai, Hannah Gurzau, Alexandra D. Daxinger, Lucia Xue, Shifeng Ly, Thanh Thao Nguyen Wanigasuriya, Iromi Iminitoff, Megan Breslin, Kelsey Oey, Harald Krom, Yvonne D. van der Hoorn, Dinja Bouwman, Linde F. Johanson, Timothy M. Ritchie, Matthew E. Gouil, Quentin A. Reversade, Bruno Prin, Fabrice Mohun, Timothy van der Maarel, Silvère M. McGlinn, Edwina Murphy, James M. Keniry, Andrew de Greef, Jessica C. Blewitt, Marnie E. Nat Commun Article The interplay between 3D chromatin architecture and gene silencing is incompletely understood. Here, we report a novel point mutation in the non-canonical SMC protein SMCHD1 that enhances its silencing capacity at endogenous developmental targets. Moreover, it also results in enhanced silencing at the facioscapulohumeral muscular dystrophy associated macrosatellite-array, D4Z4, resulting in enhanced repression of DUX4 encoded by this repeat. Heightened SMCHD1 silencing perturbs developmental Hox gene activation, causing a homeotic transformation in mice. Paradoxically, the mutant SMCHD1 appears to enhance insulation against other epigenetic regulators, including PRC2 and CTCF, while depleting long range chromatin interactions akin to what is observed in the absence of SMCHD1. These data suggest that SMCHD1’s role in long range chromatin interactions is not directly linked to gene silencing or insulating the chromatin, refining the model for how the different levels of SMCHD1-mediated chromatin regulation interact to bring about gene silencing in normal development and disease. Nature Publishing Group UK 2023-09-25 /pmc/articles/PMC10519958/ /pubmed/37749075 http://dx.doi.org/10.1038/s41467-023-40992-6 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as 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 images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Tapia del Fierro, Andres
den Hamer, Bianca
Benetti, Natalia
Jansz, Natasha
Chen, Kelan
Beck, Tamara
Vanyai, Hannah
Gurzau, Alexandra D.
Daxinger, Lucia
Xue, Shifeng
Ly, Thanh Thao Nguyen
Wanigasuriya, Iromi
Iminitoff, Megan
Breslin, Kelsey
Oey, Harald
Krom, Yvonne D.
van der Hoorn, Dinja
Bouwman, Linde F.
Johanson, Timothy M.
Ritchie, Matthew E.
Gouil, Quentin A.
Reversade, Bruno
Prin, Fabrice
Mohun, Timothy
van der Maarel, Silvère M.
McGlinn, Edwina
Murphy, James M.
Keniry, Andrew
de Greef, Jessica C.
Blewitt, Marnie E.
SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
title SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
title_full SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
title_fullStr SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
title_full_unstemmed SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
title_short SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
title_sort smchd1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10519958/
https://www.ncbi.nlm.nih.gov/pubmed/37749075
http://dx.doi.org/10.1038/s41467-023-40992-6
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