TY - JOUR
T1 - Tunable DNMT1 degradation reveals DNMT1/DNMT3B synergy in DNA methylation and genome organization
AU - Scelfo, Andrea
AU - Barra, Viviana
AU - Abdennur, Nezar
AU - Spracklin, George
AU - Busato, Florence
AU - Salinas-Luypaert, Catalina
AU - Bonaiti, Elena
AU - Velasco, Guillaume
AU - Bonhomme, Frédéric
AU - Chipont, Anna
AU - Tijhuis, Andréa E
AU - Spierings, Diana C J
AU - Guérin, Coralie
AU - Arimondo, Paola
AU - Francastel, Claire
AU - Foijer, Floris
AU - Tost, Jӧrg
AU - Mirny, Leonid
AU - Fachinetti, Daniele
N1 - © 2024 Scelfo et al.
PY - 2024/4/1
Y1 - 2024/4/1
N2 - 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.
AB - 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.
KW - Humans
KW - DNA Methylation
KW - Cell Division
KW - Epigenomics
KW - Heterochromatin/genetics
U2 - 10.1083/jcb.202307026
DO - 10.1083/jcb.202307026
M3 - Article
C2 - 38376465
SN - 0021-9525
VL - 223
JO - The Journal of Cell Biology
JF - The Journal of Cell Biology
IS - 4
M1 - e202307026
ER -