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Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 [Mouse RNA-seq]

ABSTRACT: Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 [Mouse RNA-seq]

PROVIDER: PRJNA596243 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10721505_1.fastq.gz	Fastqsanger.gz
	SRR10721505_2.fastq.gz	Fastqsanger.gz
	SRR10721506_1.fastq.gz	Fastqsanger.gz
	SRR10721506_2.fastq.gz	Fastqsanger.gz
	SRR10721507_1.fastq.gz	Fastqsanger.gz

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Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1

Project description:Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1

| PRJNA385812 | ENA

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.

2020-07-07 | GSE98646 | GEO

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

2020-07-07 | GSE141114 | GEO

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

2020-07-07 | GSE142834 | GEO

Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 [Mouse RNA-seq]

2020-07-07 | GSE142223 | GEO

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

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

| PRJNA598572 | ENA

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

Project description:Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1 (Zebrafish)

| PRJNA592151 | ENA

Structural basis of epigenetic protection of mouse lymphoid progenitor cells by Dnmt1

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-07-07 | GSE98648 | GEO

Epigenetic Protection of Vertebrate Lymphoid Progenitor Cells by Dnmt1.

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 loss of DNMT1 is lethal, a pan-organismic analysis of DNMT1 function is lacking. We identified new recessive dnmt1 alleles in medaka and zebrafish and, guided by the structures of mutant proteins, generated a recessive variant of mouse Dnmt1. Each of the three missense mutations studied here distorts the catalytic pocket and reduces enzymatic activity. Because all three DNMT1 mutant animals are viable, it was possible to examine their phenotypes throughout life. The consequences of genome-wide hypomethylation of DNA of somatic tissues in the Dnmt1 mutants are surprisingly mild but consistently affect the development of the lymphoid lineage. Our findings indicate that developing lymphocytes in vertebrates are sensitive to perturbations of DNA maintenance methylation.

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Structural basis for activation of DNMT1.

Project description:DNMT1 is an essential enzyme that maintains genomic DNA methylation, and its function is regulated by mechanisms that are not yet fully understood. Here, we report the cryo-EM structure of human DNMT1 bound to its two natural activators: hemimethylated DNA and ubiquitinated histone H3. We find that a hitherto unstudied linker, between the RFTS and CXXC domains, plays a key role for activation. It contains a conserved α-helix which engages a crucial "Toggle" pocket, displacing a previously described inhibitory linker, and allowing the DNA Recognition Helix to spring into the active conformation. This is accompanied by large-scale reorganization of the inhibitory RFTS and CXXC domains, allowing the enzyme to gain full activity. Our results therefore provide a mechanistic basis for the activation of DNMT1, with consequences for basic research and drug design.

| S-EPMC9681727 | biostudies-literature

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