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Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 [Mouse WGBS]

ABSTRACT: DNA methylation is a universal epigenetic mechanism involved in regulation of gene expression and genome stability. The DNA maintenance methylase DNMT1 ensures that DNA methylation patterns are faithfully transmitted to daughter cells during cell division. Because DNMT1 is essential for cell viability, little is known about its tissue-specific function. To overcome this impediment, forward genetic screens were conducted in medaka and zebrafish to identify viable dnmt1 alleles. The recovered recessive missense mutations lead to distorted structures of the catalytic pocket and reduced enzymatic activities, resulting in hypomethylation of genomic DNA that specifically impairs lymphoid development. The insights gleaned from fish dnmt1 alleles enabled the structure-guided generation of a hypomorphic variant of mouse Dnmt1, which also causes cell-autonomous defects of lymphoid development. The similar phenotypes observed in three distinct species suggest that the unique sensitivity of lymphocytes to perturbations of DNA methylation patterns is an evolutionarily conserved feature of all vertebrates.

ORGANISM(S): Mus musculus

PROVIDER: GSE142834 | GEO | 2020/07/07

REPOSITORIES: GEO

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Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 (Medaka)

Project description:DNA methylation is a universal epigenetic mechanism involved in regulation of gene expression and genome stability. The DNA maintenance methylase DNMT1 ensures that DNA methylation patterns are faithfully transmitted to daughter cells during cell division. Because DNMT1 is essential for cell viability, little is known about its tissue-specific function. To overcome this impediment, forward genetic screens were conducted in medaka and zebrafish to identify viable dnmt1 alleles. The recovered recessive missense mutations lead to distorted structures of the catalytic pocket and reduced enzymatic activities, resulting in hypomethylation of genomic DNA that specifically impairs lymphoid development. The insights gleaned from fish dnmt1 alleles enabled the structure-guided generation of a hypomorphic variant of mouse Dnmt1, which also causes cell-autonomous defects of lymphoid development. The similar phenotypes observed in three distinct species suggest that the unique sensitivity of lymphocytes to perturbations of DNA methylation patterns is an evolutionarily conserved feature of all vertebrates.

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