Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization
Name
jcb_202307026.pdf
Description
Published version
Size
6.49 MB
Format
Adobe PDF
Checksum (MD5)
148bccfcf58dde3ddcfc8749763f1094
Author(s)
Scelfo, Andrea
Barra, Viviana
Abdennur, Nezar
Spracklin, George
Busato, Florence
Salinas-Luypaert, Catalina
Bonaiti, Elena
Velasco, Guillaume
Bonhomme, Frédéric
Chipont, Anna
Date Issued
February 20, 2024
Journal
Journal of Cell Biology
Publisher
Rockefeller University Press
Citation
Andrea Scelfo, Viviana Barra, Nezar Abdennur, George Spracklin, Florence Busato, Catalina Salinas-Luypaert, Elena Bonaiti, Guillaume Velasco, Frédéric Bonhomme, Anna Chipont, Andréa E. Tijhuis, Diana C.J. Spierings, Coralie Guérin, Paola Arimondo, Claire Francastel, Floris Foijer, Jӧrg Tost, Leonid Mirny, Daniele Fachinetti; Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization. J Cell Biol 1 April 2024; 223 (4): e202307026.
Version
Final published version
Abstract
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.
MIT Department
Institute for Medical Engineering and Science
Massachusetts Institute of Technology. Department of Physics
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Creative Commons Attribution-Noncommercial-ShareAlike
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DOI of Published Version
https://doi.org/10.1083/jcb.202307026
