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| Status |
Public on May 25, 2022 |
| Title |
HOX epi-mutations, driven by maternal SMCHD1 or LRIF1 haploinsufficiency, trigger homeotic transformations in genetically wildtype offspring |
| Organism |
Danio rerio |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
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 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.
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| Overall design |
RNA-seq of wt and smchd1 maternal zygotic null zebrafish embryos at 4-cell and sphere stages
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| Contributor(s) |
Xue S, Ly T, Vijayakar RS, Chen J, Ng J, Mathuru AS, Magdinier F, Reversade B |
| Citation(s) |
35739109 |
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| Submission date |
Apr 28, 2021 |
| Last update date |
Jun 30, 2022 |
| Contact name |
Shifeng Xue |
| E-mail(s) |
dbsxues@nus.edu.sg
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| Organization name |
National University of Singapore
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| Lab |
S1A #05-05
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| Street address |
14 Science Drive 4
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| City |
Singapore |
| ZIP/Postal code |
117543 |
| Country |
Singapore |
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| Platforms (1) |
| GPL21741 |
Illumina HiSeq 4000 (Danio rerio) |
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| Samples (12)
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| Relations |
| BioProject |
PRJNA725967 |
| SRA |
SRP316871 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE173462_RAW.tar |
7.8 Mb |
(http)(custom) |
TAR (of RESULTS) |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data provided as supplementary file |
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