PUBLICATION
HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring
- Authors
- Xue, S., Ly, T.T.N., Vijayakar, R.S., Chen, J., Ng, J., Mathuru, A.S., Magdinier, F., Reversade, B.
- ID
- ZDB-PUB-220625-1
- Date
- 2022
- Source
- Nature communications 13: 3583 (Journal)
- Registered Authors
- Mathuru, Ajay, REVERSADE, Bruno, Xue, Shifeng
- Keywords
- none
- Datasets
- GEO:GSE173462
- MeSH Terms
-
- Animals
- Chromatin/genetics
- Chromosomal Proteins, Non-Histone*/genetics
- Chromosomal Proteins, Non-Histone*/metabolism
- Epigenesis, Genetic
- Genes, Homeobox*
- Haploinsufficiency*
- Humans
- Mice
- Muscular Dystrophy, Facioscapulohumeral*/genetics
- Zebrafish/genetics
- Zebrafish/metabolism
- Zebrafish Proteins/genetics
- PubMed
- 35739109 Full text @ Nat. Commun.
Citation
Xue, S., Ly, T.T.N., Vijayakar, R.S., Chen, J., Ng, J., Mathuru, A.S., Magdinier, F., Reversade, B. (2022) HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically wildtype offspring. Nature communications. 13:3583.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping