The methyl-CpG binding protein MBD1 is required for PML-RARα function

Raffaella Villa, Lluis Morey, Veronica A. Raker, Marcus Buschbeck, Arantxa Gutierrez, Francesca De Santis, Massimo Corsaro, Florencio Varas, Daniela Bossi, Saverio Minucci, Pier Giuseppe Pelicci, Luciano Di Croce

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

PML-RARα induces a block of hematopoietic differentiation and acute promyelocytic leukemia. This block is based on its capacity to inactivate target genes by recruiting histone deacetylase (HDAC) and DNA methyltransferase activities. Here we report that MBD1, a member of a conserved family of proteins able to bind methylated DNA, cooperates with PML-RARα in transcriptional repression and cellular transformation. PML-RARα recruits MBD1 to its target promoter through an HDAC3-mediated mechanism. Binding of HDAC3 and MBD1 is not confined to the promoter region but instead is spread over the locus. Knock-down of HDAC3 expression by RNA interference in acute promyelocytic leukemia cells alleviates PML-RAR-induced promoter silencing. We further demonstrate that retroviral expression of dominant-negative mutants of MBD1 in hematopoietic precursors compromises the ability of PML-RARα to block their differentiation and thus restored cell differentiation. Our results demonstrate that PML-RARα functions by recruiting an HDAC3-MBD1 complex that contributes to the establishment and maintenance of the silenced chromatin state.

Original languageEnglish (US)
Pages (from-to)1400-1405
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume103
Issue number5
DOIs
StatePublished - Jan 31 2006

    Fingerprint

Keywords

  • Chromatin
  • Epigenetics
  • Leukemia

ASJC Scopus subject areas

  • General

Cite this

Villa, R., Morey, L., Raker, V. A., Buschbeck, M., Gutierrez, A., De Santis, F., Corsaro, M., Varas, F., Bossi, D., Minucci, S., Pelicci, P. G., & Di Croce, L. (2006). The methyl-CpG binding protein MBD1 is required for PML-RARα function. Proceedings of the National Academy of Sciences of the United States of America, 103(5), 1400-1405. https://doi.org/10.1073/pnas.0509343103