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The non-canonical SMC protein SmcHD1 antagonises TAD formation and compartmentalisation on the inactive X chromosome

Author

Listed:
  • Michal R. Gdula

    (University of Oxford)

  • Tatyana B. Nesterova

    (University of Oxford)

  • Greta Pintacuda

    (University of Oxford)

  • Jonathan Godwin

    (University of Oxford)

  • Ye Zhan

    (University of Massachusetts Medical School, Howard Hughes Medical Institute)

  • Hakan Ozadam

    (University of Massachusetts Medical School, Howard Hughes Medical Institute)

  • Michael McClellan

    (University of Oxford)

  • Daniella Moralli

    (University of Oxford)

  • Felix Krueger

    (Bioinformatics Group, The Babraham Institute)

  • Catherine M. Green

    (University of Oxford)

  • Wolf Reik

    (Epigenetics Program, The Babraham Institute)

  • Skirmantas Kriaucionis

    (University of Oxford)

  • Edith Heard

    (Institut Curie, PSL Research University, CNRS UMR3215, INSERM U934, UPMC Paris-Sorbonne)

  • Job Dekker

    (University of Massachusetts Medical School, Howard Hughes Medical Institute)

  • Neil Brockdorff

    (University of Oxford)

Abstract

The inactive X chromosome (Xi) in female mammals adopts an atypical higher-order chromatin structure, manifested as a global loss of local topologically associated domains (TADs), A/B compartments and formation of two mega-domains. Here we demonstrate that the non-canonical SMC family protein, SmcHD1, which is important for gene silencing on Xi, contributes to this unique chromosome architecture. Specifically, allelic mapping of the transcriptome and epigenome in SmcHD1 mutant cells reveals the appearance of sub-megabase domains defined by gene activation, CpG hypermethylation and depletion of Polycomb-mediated H3K27me3. These domains, which correlate with sites of SmcHD1 enrichment on Xi in wild-type cells, additionally adopt features of active X chromosome higher-order chromosome architecture, including A/B compartments and partial restoration of TAD boundaries. Xi chromosome architecture changes also occurred following SmcHD1 knockout in a somatic cell model, but in this case, independent of Xi gene derepression. We conclude that SmcHD1 is a key factor in defining the unique chromosome architecture of Xi.

Suggested Citation

  • 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.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-018-07907-2
    DOI: 10.1038/s41467-018-07907-2
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    Cited by:

    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. 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.

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