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

• Published in: Nature communications 2022-06, Vol.13 (1), p.3583-3583, Article 3583
• Main Authors: Xue, Shifeng, Ly, Thanh Thao Nguyen, Vijayakar, Raunak S., Chen, Jingyi, Ng, Joel, Mathuru, Ajay S., Magdinier, Frederique, Reversade, Bruno
• Format: Article
• Language: English
• Subjects: 13/1; 13/106; 38/77; 38/91; 631/136/2442; 631/136/756; 631/208; 631/337/176/1988; 64/110; 64/116; 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; Humanities and Social Sciences; Humans; Inactivation; Life Sciences; Mice; multidisciplinary; Muscular Dystrophy, Facioscapulohumeral - genetics; Mutation; Offspring; Oogenesis; Phenotypes; Science; Science (multidisciplinary); 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. Hox genes are known to control anteroposterior patterning, including the vertebrate spine. Here Xue et al. show that maternal Smchd1 regulates Hox expression in an epigenetic manner, and that wild type offspring from heterozygous mothers show skeletal homeotic transformations as a result of this dysregulation.