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

• Published in: Nature communications Vol. 13; no. 1; p. 3583
• Main Authors: Xue, Shifeng, Ly, Thanh Thao Nguyen, Vijayakar, Raunak S, Chen, Jingyi, Ng, Joel, Mathuru, Ajay S, Magdinier, Frederique, Reversade, Bruno
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 23.06.2022; Nature Publishing Group UK; Nature Portfolio
• Subjects: Animals; Chromatin; Chromatin - genetics; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Danio rerio; DNA methylation; Embryogenesis; Embryonic growth stage; Epigenesis, Genetic; Epigenetics; Evolutionary conservation; Fibroblasts; Genes, Homeobox; Genetics; Genomes; Genotypes; Haploinsufficiency; HOX gene; Humans; Inactivation; Life Sciences; Mice; Muscular Dystrophy, Facioscapulohumeral - genetics; Mutation; Offspring; Oogenesis; Phenotypes; Spine; Vertebrates; Zebrafish; Zebrafish - genetics; Zebrafish - metabolism; Zebrafish Proteins - genetics
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-31185-8

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.