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Molecular and Cellular Biology, October 2008, p. 5912-5923, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00467-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

MBD3, a Component of the NuRD Complex, Facilitates Chromatin Alteration and Deposition of Epigenetic Marks{triangledown}

Lluis Morey,1,{dagger} Carmen Brenner,2 Francesco Fazi,3 Raffaella Villa,1 Arantxa Gutierrez,1 Marcus Buschbeck,1 Clara Nervi,3 Saverio Minucci,4 Francois Fuks,2 and Luciano Di Croce1,5*

Centre de Regulacio Genomica, Universitat Pompeu Fabra, Barcelona, Spain,1 Free University of Brussels, Brussels, Belgium,2 San Raffaele Bio-Medical Park Foundation, Rome, Italy,3 European Institute of Oncology, Milan, Italy,4 ICREA and Centre de Regulacio Genomica, Barcelona, Spain5

Received 20 March 2008/ Returned for modification 19 April 2008/ Accepted 13 July 2008

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 RARβ2. 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.

* Corresponding author. Mailing address: Centre de Regulacio Genomica, Universitat Pompeu Fabra, Barcelona, Spain. Phone: 34-9331-60132. Fax: 34-93 3160 099. E-mail: luciano.dicroce{at}crg.es

{triangledown} Published ahead of print on 21 July 2008.

{dagger} Present address: Centre for Epigenetics and BRIC, University of Copenhagen, Ole Maaløes Vej 5, 2200 Copenhagen, Denmark.

Molecular and Cellular Biology, October 2008, p. 5912-5923, Vol. 28, No. 19
0270-7306/08/$08.00+0     doi:10.1128/MCB.00467-08
Copyright © 2008, American Society for Microbiology. All Rights Reserved.





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