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HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring

Author

Listed:
  • 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)

  • Raunak S. Vijayakar

    (Yale-NUS College)

  • Jingyi Chen

    (National University of Singapore)

  • Joel Ng

    (National University of Singapore)

  • Ajay S. Mathuru

    (Institute of Molecular and Cell Biology, A*STAR
    Yale-NUS College
    National University of Singapore)

  • Frederique Magdinier

    (Aix-Marseille University, INSERM, Marseille Medical Genetics)

  • Bruno Reversade

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

Abstract

The body plan of animals is laid out by an evolutionary-conserved HOX code which is colinearly transcribed after zygotic genome activation (ZGA). Here we report that SMCHD1, a chromatin-modifying enzyme needed for X-inactivation in mammals, is maternally required for timely HOX expression. Using zebrafish and mouse Smchd1 knockout animals, we demonstrate that Smchd1 haplo-insufficiency brings about precocious and ectopic HOX transcription during oogenesis and embryogenesis. Unexpectedly, wild-type offspring born to heterozygous knockout zebrafish smchd1 mothers exhibited patent vertebrate patterning defects. The loss of maternal Smchd1 was accompanied by HOX epi-mutations driven by aberrant DNA methylation. We further show that this regulation is mediated by Lrif1, a direct interacting partner of Smchd1, whose knockout in zebrafish phenocopies that of Smchd1. Rather than being a short-lived maternal effect, HOX mis-regulation is stably inherited through cell divisions and persists in cultured fibroblasts derived from FSHD2 patients haploinsufficient for SMCHD1. We conclude that maternal SMCHD1/LRIF1 sets up an epigenetic state in the HOX loci that can only be reset in the germline. Such an unusual inter-generational inheritance, whereby a phenotype can be one generation removed from its genotype, casts a new light on how unresolved Mendelian diseases may be interpreted.

Suggested Citation

  • Shifeng Xue & Thanh Thao Nguyen Ly & Raunak S. Vijayakar & Jingyi Chen & Joel Ng & Ajay S. Mathuru & Frederique Magdinier & Bruno Reversade, 2022. "HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31185-8
    DOI: 10.1038/s41467-022-31185-8
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    1. Monkol Lek & Konrad J. Karczewski & Eric V. Minikel & Kaitlin E. Samocha & Eric Banks & Timothy Fennell & Anne H. O’Donnell-Luria & James S. Ware & Andrew J. Hill & Beryl B. Cummings & Taru Tukiainen , 2016. "Analysis of protein-coding genetic variation in 60,706 humans," Nature, Nature, vol. 536(7616), pages 285-291, August.
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    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.

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