Apr 3, 2020

Successful generation of epigenetic disease model mice by targeted demethylation of the epigenome

Genome Biology
Takuro HoriiIzuho Hatada

Abstract

Epigenetic modifications, including DNA methylation, play an important role in gene silencing and genome stability. Consequently, epigenetic dysregulation can cause several diseases, such as cancer, obesity, diabetes, autism, and imprinting disorders. We validate three methods for the generation of epigenome-edited mice using the dCas9-SunTag and single-chain variable fragment-TET1 catalytic domain. We generate model mice for Silver-Russell syndrome (SRS), an imprinting disorder, by target-specific DNA demethylation in the H19 differentially methylated region. Like SRS patients, these mice show H19 upregulation and Igf2 downregulation, leading to severe intrauterine and postnatal growth retardation. This is the first report of an imprinting disease model animal generated by targeted demethylation of specific loci of the epigenome in fertilized eggs. Epigenome-edited animals are also useful for exploring the causative epimutations in epigenetic diseases.

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Mentioned in this Paper

Malignant Neoplasms
Obesity
Russell-Silver Syndrome
Up-Regulation (Physiology)
DNA
Diabetes
Epigenetic Process
Catalytic Domain
Imprinting (Psychology)
Structure of Zygote

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