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

Shifeng Xue (), Thanh Thao Nguyen Ly, Raunak S. Vijayakar, Jingyi Chen, Joel Ng, Ajay S. Mathuru, Frederique Magdinier and Bruno Reversade ()
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Shifeng Xue: National University of Singapore
Thanh Thao Nguyen Ly: National University of Singapore
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
Frederique Magdinier: Aix-Marseille University, INSERM, Marseille Medical Genetics
Bruno Reversade: Institute of Molecular and Cell Biology, A*STAR

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-022-31185-8

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