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.
N1 - Funding Information:
We thank Dr. Ruth Arkell for the valuable discussion of the FNP RNA-seq and the WEHI MAGEC facility for recreating the MommeD43 mutation on the Smchd1-GFP background. We thank mouse technicians at WEHI (Jessica Martin) and QIMR (Joanne Sutton) for their work on this project. We thank SAXS beamline staff at the Australian Synchrotron for assistance with data collection. This work was supported by grants and fellowships from the Australian National Health and Medical Research Council (GNT1098290 to M.E.B., J.M.M., and M.E.R., fellowship GNT1194345 to M.E.B., GNT1172929 to J.M.M., GNT1104924 to M.E.R.). N.J. and A.G. were supported by Australian Research Training Program scholarships. MEB was supported by the Bellberry-Viertel fellowship. J.C.G. was funded by a fellowship from the FSHD Society (Sylvia & Leonard Marx Foundation Fellowship FSHS-82017-02). This work was also supported by grants from the Prinses Beatrix Spierfonds (W.OP14-01, W.OR17-04), the US National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases 2R01AR066248), and Spieren voor Spieren. The generation of the MommeD43 mice on the Smchd1-GFP background used in this study was supported by Phenomics Australia (PA) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. Additional support was provided by the Victorian State Government Operational Infrastructure Support, Australian National Health and Medical Research Council IRIISS grant (9000719). The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. S.X. is supported by NMRC (NMRC/OFYIRG/062/2017) and NUS PYP. B.R. is an investigator of the National Research Foundation (NRF, Singapore), Branco Weiss Foundation (Switzerland), and an EMBO Young Investigator, and is supported by an inaugural Use-Inspired Basic Research Fund from the Agency for Science & Technology and Research (A*STAR) in Singapore. B.H., Y.K., S.M., and J.G. are members of the European Reference Network for Rare Neuromuscular Diseases [ERN EURO-NMD].
Funding Information:
We thank Dr. Ruth Arkell for the valuable discussion of the FNP RNA-seq and the WEHI MAGEC facility for recreating the MommeD43 mutation on the Smchd1-GFP background. We thank mouse technicians at WEHI (Jessica Martin) and QIMR (Joanne Sutton) for their work on this project. We thank SAXS beamline staff at the Australian Synchrotron for assistance with data collection. This work was supported by grants and fellowships from the Australian National Health and Medical Research Council (GNT1098290 to M.E.B., J.M.M., and M.E.R., fellowship GNT1194345 to M.E.B., GNT1172929 to J.M.M., GNT1104924 to M.E.R.). N.J. and A.G. were supported by Australian Research Training Program scholarships. MEB was supported by the Bellberry-Viertel fellowship. J.C.G. was funded by a fellowship from the FSHD Society (Sylvia & Leonard Marx Foundation Fellowship FSHS-82017-02). This work was also supported by grants from the Prinses Beatrix Spierfonds (W.OP14-01, W.OR17-04), the US National Institutes of Health (National Institute of Arthritis and Musculoskeletal and Skin Diseases 2R01AR066248), and Spieren voor Spieren. The generation of the MommeD43 mice on the Smchd1-GFP background used in this study was supported by Phenomics Australia (PA) and the Australian Government through the National Collaborative Research Infrastructure Strategy (NCRIS) program. Additional support was provided by the Victorian State Government Operational Infrastructure Support, Australian National Health and Medical Research Council IRIISS grant (9000719). The Australian Regenerative Medicine Institute is supported by grants from the State Government of Victoria and the Australian Government. S.X. is supported by NMRC (NMRC/OFYIRG/062/2017) and NUS PYP. B.R. is an investigator of the National Research Foundation (NRF, Singapore), Branco Weiss Foundation (Switzerland), and an EMBO Young Investigator, and is supported by an inaugural Use-Inspired Basic Research Fund from the Agency for Science & Technology and Research (A*STAR) in Singapore. B.H., Y.K., S.M., and J.G. are members of the European Reference Network for Rare Neuromuscular Diseases [ERN EURO-NMD].
Publisher Copyright:
© 2023, Springer Nature Limited.
PY - 2023/9/25
Y1 - 2023/9/25
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.
UR - http://www.scopus.com/inward/record.url?scp=85172125313&partnerID=8YFLogxK
U2 - 10.1038/s41467-023-40992-6
DO - 10.1038/s41467-023-40992-6
M3 - Article
C2 - 37749075
AN - SCOPUS:85172125313
SN - 2041-1723
VL - 14
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 5466
ER -