IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v14y2023i1d10.1038_s41467-023-40992-6.html
   My bibliography  Save this article

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

Author

Listed:
  • Andres Tapia del Fierro

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Bianca den Hamer

    (Leiden University Medical Center)

  • Natalia Benetti

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Natasha Jansz

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kelan Chen

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Tamara Beck

    (The Walter and Eliza Hall Institute of Medical Research)

  • Hannah Vanyai

    (The Francis Crick Institute)

  • Alexandra D. Gurzau

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Lucia Daxinger

    (Queensland Institute of Medical Research)

  • Shifeng Xue

    (National University of Singapore
    Institute of Molecular and Cell Biology, A*STAR)

  • Thanh Thao Nguyen Ly

    (National University of Singapore
    Institute of Molecular and Cell Biology, A*STAR)

  • Iromi Wanigasuriya

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Megan Iminitoff

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Kelsey Breslin

    (The Walter and Eliza Hall Institute of Medical Research)

  • Harald Oey

    (Queensland Institute of Medical Research)

  • Yvonne D. Krom

    (Leiden University Medical Center)

  • Dinja van der Hoorn

    (Leiden University Medical Center)

  • Linde F. Bouwman

    (Leiden University Medical Center)

  • Timothy M. Johanson

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Matthew E. Ritchie

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Quentin A. Gouil

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Bruno Reversade

    (Institute of Molecular and Cell Biology, A*STAR
    Genome Institute of Singapore, A*STAR)

  • Fabrice Prin

    (The Francis Crick Institute)

  • Timothy Mohun

    (The Francis Crick Institute)

  • Silvère M. van der Maarel

    (Leiden University Medical Center)

  • Edwina McGlinn

    (Monash University
    Monash University)

  • James M. Murphy

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne
    Monash University)

  • Andrew Keniry

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

  • Jessica C. de Greef

    (Leiden University Medical Center)

  • Marnie E. Blewitt

    (The Walter and Eliza Hall Institute of Medical Research
    University of Melbourne)

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.

Suggested Citation

  • 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 & Ir, 2023. "SMCHD1 has separable roles in chromatin architecture and gene silencing that could be targeted in disease," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40992-6
    DOI: 10.1038/s41467-023-40992-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-023-40992-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-023-40992-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Smyth Gordon K, 2004. "Linear Models and Empirical Bayes Methods for Assessing Differential Expression in Microarray Experiments," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 3(1), pages 1-28, February.
    2. Natalia Benetti & Quentin Gouil & Andres Tapia del Fierro & Tamara Beck & Kelsey Breslin & Andrew Keniry & Edwina McGlinn & Marnie E. Blewitt, 2022. "Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    3. Michal R. Gdula & Tatyana B. Nesterova & Greta Pintacuda & Jonathan Godwin & Ye Zhan & Hakan Ozadam & Michael McClellan & Daniella Moralli & Felix Krueger & Catherine M. Green & Wolf Reik & Skirmantas, 2019. "The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    4. Chen-Yu Wang & David Colognori & Hongjae Sunwoo & Danni Wang & Jeannie T. Lee, 2019. "PRC1 collaborates with SMCHD1 to fold the X-chromosome and spread Xist RNA between chromosome compartments," Nature Communications, Nature, vol. 10(1), pages 1-18, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Natalia Benetti & Quentin Gouil & Andres Tapia del Fierro & Tamara Beck & Kelsey Breslin & Andrew Keniry & Edwina McGlinn & Marnie E. Blewitt, 2022. "Maternal SMCHD1 regulates Hox gene expression and patterning in the mouse embryo," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    2. Aaron C Ericsson & J Wade Davis & William Spollen & Nathan Bivens & Scott Givan & Catherine E Hagan & Mark McIntosh & Craig L Franklin, 2015. "Effects of Vendor and Genetic Background on the Composition of the Fecal Microbiota of Inbred Mice," PLOS ONE, Public Library of Science, vol. 10(2), pages 1-19, February.
    3. Hossain, Ahmed & Beyene, Joseph & Willan, Andrew R. & Hu, Pingzhao, 2009. "A flexible approximate likelihood ratio test for detecting differential expression in microarray data," Computational Statistics & Data Analysis, Elsevier, vol. 53(10), pages 3685-3695, August.
    4. Xiaohong Li & Guy N Brock & Eric C Rouchka & Nigel G F Cooper & Dongfeng Wu & Timothy E O’Toole & Ryan S Gill & Abdallah M Eteleeb & Liz O’Brien & Shesh N Rai, 2017. "A comparison of per sample global scaling and per gene normalization methods for differential expression analysis of RNA-seq data," PLOS ONE, Public Library of Science, vol. 12(5), pages 1-22, May.
    5. Kerr Kathleen F., 2012. "Optimality Criteria for the Design of 2-Color Microarray Studies," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 11(1), pages 1-9, January.
    6. Ambroise Jérôme & Bearzatto Bertrand & Robert Annie & Macq Benoit & Gala Jean-Luc, 2012. "Combining Multiple Laser Scans of Spotted Microarrays by Means of a Two-Way ANOVA Model," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 11(3), pages 1-20, February.
    7. J. McClatchy & R. Strogantsev & E. Wolfe & H. Y. Lin & M. Mohammadhosseini & B. A. Davis & C. Eden & D. Goldman & W. H. Fleming & P. Conley & G. Wu & L. Cimmino & H. Mohammed & A. Agarwal, 2023. "Clonal hematopoiesis related TET2 loss-of-function impedes IL1β-mediated epigenetic reprogramming in hematopoietic stem and progenitor cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    8. Alexandra Gyurdieva & Stefan Zajic & Ya-Fang Chang & E. Andres Houseman & Shan Zhong & Jaegil Kim & Michael Nathenson & Thomas Faitg & Mary Woessner & David C. Turner & Aisha N. Hasan & John Glod & Ro, 2022. "Biomarker correlates with response to NY-ESO-1 TCR T cells in patients with synovial sarcoma," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    9. Sora Yoon & Seon-Young Kim & Dougu Nam, 2016. "Improving Gene-Set Enrichment Analysis of RNA-Seq Data with Small Replicates," PLOS ONE, Public Library of Science, vol. 11(11), pages 1-16, November.
    10. Yu Lianbo & Gulati Parul & Fernandez Soledad & Pennell Michael & Kirschner Lawrence & Jarjoura David, 2011. "Fully Moderated T-statistic for Small Sample Size Gene Expression Arrays," Statistical Applications in Genetics and Molecular Biology, De Gruyter, vol. 10(1), pages 1-22, September.
    11. Sinan Xiong & Jianbiao Zhou & Tze King Tan & Tae-Hoon Chung & Tuan Zea Tan & Sabrina Hui-Min Toh & Nicole Xin Ning Tang & Yunlu Jia & Yi Xiang See & Melissa Jane Fullwood & Takaomi Sanda & Wee-Joo Chn, 2024. "Super enhancer acquisition drives expression of oncogenic PPP1R15B that regulates protein homeostasis in multiple myeloma," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    12. Chaofeng Yuan & Wensheng Zhu & Xuming He & Jianhua Guo, 2019. "A mixture factor model with applications to microarray data," TEST: An Official Journal of the Spanish Society of Statistics and Operations Research, Springer;Sociedad de Estadística e Investigación Operativa, vol. 28(1), pages 60-76, March.
    13. Nan Li & Matthew N. McCall & Zhijin Wu, 2017. "Establishing Informative Prior for Gene Expression Variance from Public Databases," Statistics in Biosciences, Springer;International Chinese Statistical Association, vol. 9(1), pages 160-177, June.
    14. Brian Caffo & Liu Dongmei & Giovanni Parmigiani, 2004. "Power Conjugate Multilevel Models with Applications to Genomics," Johns Hopkins University Dept. of Biostatistics Working Paper Series 1062, Berkeley Electronic Press.
    15. Nott, David J. & Yu, Zeming & Chan, Eva & Cotsapas, Chris & Cowley, Mark J. & Pulvers, Jeremy & Williams, Rohan & Little, Peter, 2007. "Hierarchical Bayes variable selection and microarray experiments," Journal of Multivariate Analysis, Elsevier, vol. 98(4), pages 852-872, April.
    16. Santu Ghosh & Alan M. Polansky, 2022. "Large-Scale Simultaneous Testing Using Kernel Density Estimation," Sankhya A: The Indian Journal of Statistics, Springer;Indian Statistical Institute, vol. 84(2), pages 808-843, August.
    17. Qianxing Mo & Faming Liang, 2010. "Bayesian Modeling of ChIP-chip Data Through a High-Order Ising Model," Biometrics, The International Biometric Society, vol. 66(4), pages 1284-1294, December.
    18. Ahmed Hossain & Hafiz T.A. Khan, 2016. "Identification of genomic markers correlated with sensitivity in solid tumors to Dasatinib using sparse principal components," Journal of Applied Statistics, Taylor & Francis Journals, vol. 43(14), pages 2538-2549, October.
    19. Alexander Kaever & Manuel Landesfeind & Kirstin Feussner & Burkhard Morgenstern & Ivo Feussner & Peter Meinicke, 2014. "Meta-Analysis of Pathway Enrichment: Combining Independent and Dependent Omics Data Sets," PLOS ONE, Public Library of Science, vol. 9(2), pages 1-12, February.
    20. Iqbal Mahmud & Guimei Tian & Jia Wang & Tarun E. Hutchinson & Brandon J. Kim & Nikee Awasthee & Seth Hale & Chengcheng Meng & Allison Moore & Liming Zhao & Jessica E. Lewis & Aaron Waddell & Shangtao , 2023. "DAXX drives de novo lipogenesis and contributes to tumorigenesis," Nature Communications, Nature, vol. 14(1), pages 1-20, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-40992-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.