MBD3, a component of the NuRD complex, facilitates chromatin alteration and deposition of epigenetic marks.
In plants, as in mammals, mutations in SNF2-like DNA helicases/ATPases were shown to affect not only chromatin structure but also global methylation patterns, suggesting a potential functional link between chromatin structure and epigenetic marks. The SNF2-like ATPase containing nucleosome remodeling and deacetylase corepressor complex (NuRD) is involved in gene transcriptional repression and chromatin remodeling. We have previously shown that the leukemogenic protein PML-RARa represses target genes through recruitment of DNA methytransferases and Polycomb complex. Here, we demonstrate a direct role of the NuRD complex in aberrant gene repression and transmission of epigenetic repressive marks in acute promyelocytic leukemia (APL). We show that PML-RARa binds and recruits NuRD to target genes, including to the tumor-suppressor gene RARbeta2. In turn, the NuRD complex facilitates Polycomb binding and histone methylation at lysine 27. Retinoic acid treatment, which is often used for patients at the early phase of the disease, reduced the promoter occupancy of the NuRD complex. Knockdown of the NuRD complex in leukemic cells not only prevented histone deacetylation and chromatin compaction but also impaired DNA and histone methylation, as well as stable silencing, thus favoring cellular differentiation. These results unveil an important role for NuRD in the establishment of altered epigenetic marks in APL, demonstrating an essential link between chromatin structure and epigenetics in leukemogenesis that could be exploited for therapeutic intervention.
Morey
Lluis
L
Centre de Regulacio Genomica, Universitat Pompeu Fabra, Barcelona, Spain.
Brenner
Carmen
C
Fazi
Francesco
F
Villa
Raffaella
R
Gutierrez
Arantxa
A
Buschbeck
Marcus
M
Nervi
Clara
C
Minucci
Saverio
S
Fuks
Francois
F
Di Croce
Luciano
L
D045744:Cell Line, Tumor; D042002:Chromatin Assembly and Disassembly; D004268:DNA-Binding Proteins / Q000378:metabolism*; D044127:Epigenesis, Genetic; D006655:Histone Deacetylases / Q000378:metabolism*; D006801:Humans; D015473:Leukemia, Promyelocytic, Acute / Q000235:genetics*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D015514:Oncogene Proteins, Fusion / Q000378:metabolism
D004268:DNA-Binding Proteins; C115369:MBD3 protein, human; D015514:Oncogene Proteins, Fusion; C093476:promyelocytic leukemia-retinoic acid receptor alpha fusion oncoprotein; D006655:Histone Deacetylases; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex