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HOX epimutations driven by maternal SMCHD1/LRIF1 haploinsufficiency trigger homeotic transformations in genetically
Shifeng Xue1,2, Thanh Thao Nguyen Ly3,4, Raunak S Vijayakar5
1Department of Biological Sciences, National University of Singapore, Singapore, Singapore. dbsxues@nus.edu.sg.
Nature Communications
|June 23, 2022
Summary
Maternal SMCHD1 is crucial for correct HOX gene expression in offspring. Loss of this protein leads to developmental defects and epigenetic changes, revealing a novel form of inter-generational inheritance.
Area of Science:
- Developmental Biology
- Epigenetics
- Genetics
Background:
- The animal body plan relies on the HOX code, a conserved genetic system transcribed after zygotic genome activation (ZGA).
- SMCHD1, a chromatin modifier, is essential for X-inactivation in mammals and plays a role in gene regulation.
Purpose of the Study:
- To investigate the maternal role of SMCHD1 in regulating HOX gene expression and animal development.
- To understand the mechanisms underlying SMCHD1-mediated HOX gene regulation and its inheritance patterns.
Main Methods:
- Utilized zebrafish and mouse models with Smchd1 knockout.
- Analyzed HOX gene transcription, DNA methylation, and protein interactions.
- Examined patient-derived fibroblasts from FSHD2 patients.
Main Results:
- Smchd1 deficiency caused precocious and ectopic HOX transcription during oogenesis and embryogenesis.
- Maternal Smchd1 loss resulted in vertebrate patterning defects in wild-type offspring, linked to aberrant DNA methylation and HOX epi-mutations.
- SMCHD1/LRIF1 complex mediates the epigenetic state of HOX loci, with inheritance persisting beyond maternal effects.
Conclusions:
- Maternal SMCHD1/LRIF1 establishes a heritable epigenetic state at HOX loci, reset only in the germline.
- This inter-generational inheritance mechanism, where phenotype is uncoupled from genotype, offers new insights into Mendelian diseases.
- The findings highlight a novel regulatory pathway impacting early development and disease etiology.
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