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

Andres Tapia del Fierro; Bianca den Hamer; Natalia Benetti; Natasha Jansz; Kelan Chen; Tamara Beck; Hannah Vanyai; Alexandra D. Gurzau; Lucia Daxinger; Shifeng Xue; Thanh Thao Nguyen Ly; Iromi Wanigasuriya; Megan Iminitoff; Kelsey Breslin; Harald Oey; Yvonne D. Krom; Dinja van der Hoorn; Linde F. Bouwman; Timothy M. Johanson; Matthew E. Ritchie; Quentin A. Gouil; Bruno Reversade; Fabrice Prin; Timothy Mohun; Silvère M. van der Maarel; Edwina McGlinn; James M. Murphy; Andrew Keniry; Jessica C. de Greef; Marnie E. Blewitt

doi:10.1038/s41467-023-40992-6

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

Andres Tapia del Fierro, Bianca den Hamer, Natalia Benetti, Natasha Jansz, Kelan Chen, Tamara Beck, Hannah Vanyai, Alexandra D. Gurzau, Lucia Daxinger, Shifeng Xue, Thanh Thao Nguyen Ly, Iromi Wanigasuriya, Megan Iminitoff, Kelsey Breslin, Harald Oey, Yvonne D. Krom, Dinja van der Hoorn, Linde F. Bouwman, Timothy M. Johanson, Matthew E. RitchieQuentin A. Gouil, Bruno Reversade, Fabrice Prin, Timothy Mohun, Silvère M. van der Maarel, Edwina McGlinn, James M. Murphy, Andrew Keniry, Jessica C. de Greef, Marnie E. Blewitt^*

^*Corresponding author for this work

Bioscience

Research output: Contribution to journal › Article › peer-review

7 Scopus citations

Abstract

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.

Original language	English (US)
Article number	5466
Journal	Nature Communications
Volume	14
Issue number	1
DOIs	https://doi.org/10.1038/s41467-023-40992-6
State	Published - Dec 2023

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Tapia del Fierro, A., den Hamer, B., Benetti, N., Jansz, N., Chen, K., Beck, T., Vanyai, H., Gurzau, A. D., Daxinger, L., Xue, S., Ly, T. T. N., Wanigasuriya, I., Iminitoff, M., Breslin, K., Oey, H., Krom, Y. D., van der Hoorn, D., Bouwman, L. F., Johanson, T. M., ... Blewitt, M. E. (2023). SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease. Nature Communications, 14(1), Article 5466. https://doi.org/10.1038/s41467-023-40992-6

@article{5f4a1499707a48878d4170e5001203e6,

title = "SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease",

abstract = "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{\textquoteright}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.",

author = "{Tapia del Fierro}, Andres and {den Hamer}, Bianca and Natalia Benetti and Natasha Jansz and Kelan Chen and Tamara Beck and Hannah Vanyai and Gurzau, {Alexandra D.} and Lucia Daxinger and Shifeng Xue and Ly, {Thanh Thao Nguyen} and Iromi Wanigasuriya and Megan Iminitoff and Kelsey Breslin and Harald Oey and Krom, {Yvonne D.} and {van der Hoorn}, Dinja and Bouwman, {Linde F.} and Johanson, {Timothy M.} and Ritchie, {Matthew E.} and Gouil, {Quentin A.} and Bruno Reversade and Fabrice Prin and Timothy Mohun and {van der Maarel}, {Silv{\`e}re M.} and Edwina McGlinn and Murphy, {James M.} and Andrew Keniry and {de Greef}, {Jessica C.} and Blewitt, {Marnie E.}",

note = "Publisher Copyright: {\textcopyright} 2023, Springer Nature Limited.",

year = "2023",

month = dec,

doi = "10.1038/s41467-023-40992-6",

language = "English (US)",

volume = "14",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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Tapia del Fierro, A, den Hamer, B, Benetti, N, Jansz, N, Chen, K, Beck, T, Vanyai, H, Gurzau, AD, Daxinger, L, Xue, S, Ly, TTN, Wanigasuriya, I, Iminitoff, M, Breslin, K, Oey, H, Krom, YD, van der Hoorn, D, Bouwman, LF, Johanson, TM, Ritchie, ME, Gouil, QA, Reversade, B, Prin, F, Mohun, T, van der Maarel, SM, McGlinn, E, Murphy, JM, Keniry, A, de Greef, JC & Blewitt, ME 2023, 'SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease', Nature Communications, vol. 14, no. 1, 5466. https://doi.org/10.1038/s41467-023-40992-6

TY - JOUR

T1 - SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease

AU - Tapia del Fierro, Andres

AU - den Hamer, Bianca

AU - Benetti, Natalia

AU - Jansz, Natasha

AU - Chen, Kelan

AU - Beck, Tamara

AU - Vanyai, Hannah

AU - Gurzau, Alexandra D.

AU - Daxinger, Lucia

AU - Xue, Shifeng

AU - Ly, Thanh Thao Nguyen

AU - Wanigasuriya, Iromi

AU - Iminitoff, Megan

AU - Breslin, Kelsey

AU - Oey, Harald

AU - Krom, Yvonne D.

AU - van der Hoorn, Dinja

AU - Bouwman, Linde F.

AU - Johanson, Timothy M.

AU - Ritchie, Matthew E.

AU - Gouil, Quentin A.

AU - Reversade, Bruno

AU - Prin, Fabrice

AU - Mohun, Timothy

AU - van der Maarel, Silvère M.

AU - McGlinn, Edwina

AU - Murphy, James M.

AU - Keniry, Andrew

AU - de Greef, Jessica C.

AU - Blewitt, Marnie E.

PY - 2023/12

Y1 - 2023/12

N2 - 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.

AB - 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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DO - 10.1038/s41467-023-40992-6

M3 - Article

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AN - SCOPUS:85172125313

SN - 2041-1723

VL - 14

JO - Nature Communications

JF - Nature Communications

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M1 - 5466

ER -

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

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