Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization - Institut Pasteur Accéder directement au contenu
Article Dans Une Revue Journal of Cell Biology Année : 2024

Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization

Andrea Scelfo
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Elena Bonaiti
Anna Chipont
Andréa Tijhuis
Floris Foijer
Leonid Mirny
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Résumé

DNA methylation (DNAme) is a key epigenetic mark that regulates critical biological processes maintaining overall genome stability. Given its pleiotropic function, studies of DNAme dynamics are crucial, but currently available tools to interfere with DNAme have limitations and major cytotoxic side effects. Here, we present cell models that allow inducible and reversible DNAme modulation through DNMT1 depletion. By dynamically assessing whole genome and locus-specific effects of induced passive demethylation through cell divisions, we reveal a cooperative activity between DNMT1 and DNMT3B, but not of DNMT3A, to maintain and control DNAme. We show that gradual loss of DNAme is accompanied by progressive and reversible changes in heterochromatin, compartmentalization, and peripheral localization. DNA methylation loss coincides with a gradual reduction of cell fitness due to G1 arrest, with minor levels of mitotic failure. Altogether, this system allows DNMTs and DNA methylation studies with fine temporal resolution, which may help to reveal the etiologic link between DNAme dysfunction and human disease.

Domaines

Chimie
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Origine : Publication financée par une institution
Licence : CC BY NC SA - Paternité - Pas d'utilisation commerciale - Partage selon les Conditions Initiales

Dates et versions

pasteur-04472433 , version 1 (22-02-2024)

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Paternité - Pas d'utilisation commerciale - Partage selon les Conditions Initiales

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Andrea Scelfo, Viviana Barra, Nezar Abdennur, George Spracklin, Florence Busato, et al.. Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization. Journal of Cell Biology, 2024, 223 (4), pp.e202307026. ⟨10.1083/jcb.202307026⟩. ⟨pasteur-04472433⟩
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