Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression

Suzuki, Motoo; Yamada, Toshiyuki; Kihara-Negishi, Fumiko; Sakurai, Takeshi; Oikawa, Tsuneyuki

doi:10.1038/sj.onc.1207182

Cited by 72 publications

(71 citation statements)

References 47 publications

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“…The 35 S-labeled Dnmt3a and Dnmt3b translated in vitro bound to GST-PU.1 fusion protein (Figure 1b). The 35 Slabeled in vitro translated CBP 1890 (1283-1915 amino acids (a.a.)) and MeCP2 used as positive controls bound to GST-PU.1, consistent with our previous reports Suzuki et al, 2003), while the 35 S-labeled luciferase used as a negative control did not bind to GST-PU.1. These results suggest that the interaction between PU.1 and Dnmt3s is direct.…”

Section: Resultssupporting

confidence: 91%

“…Physical interaction between PU.1 and Dnmt3a/b We previously reported that MeCP2 interacts with, and acts as a corepressor for, PU.1 probably by facilitating the formation of a complex with mSin3A and HDACs (Suzuki et al, 2003). There is growing evidence to suggest that Dnmt1 interacts with the methylated DNAbinding protein (MBD) family (Tatematsu et al, 2000) and that Dnmt3s mediate the binding of MBD family members such as MeCP2 to methylated CpG sites (Majumder et al, 2002).…”

Section: Resultsmentioning

confidence: 99%

“…We have also demonstrated that PU.1 binds to the corepressor mSin3A and forms a complex with histone deacetyl transferase (HDAC)1 (Kihara-Negishi et al, 2001). Moreover, we have reported that MeCP2 is a binding partner of the PU.1-mSin3A-HDAC complex, but not of the PU.1-CBP complex (Suzuki et al, 2003).…”

Section: Introductionmentioning

confidence: 98%

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Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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The Ets transcription factor PU.1 is a hematopoietic master regulator essential for the development of myeloid and B-cell lineages. As we previously reported, PU.1 sometimes represses transcription on forming a complex with mSin3A-histone deacetyl transferase-MeCP2. Here, we show an interaction between PU.1 and DNA methyltransferases, DNA methyltransferase (Dnmt)3a and Dnmt3b (Dnmt3s). Glutathione-S-transferase pulldown assay revealed that PU.1 directly interacted with the ATRX domain of Dnmt3s through the ETS domain. Dnmt3s repressed the transcriptional activity of PU.1 on a reporter construct with trimerized PU.1-binding sites. The repression was recovered by addition of 5-aza-deoxycitidine, a DNA methyltransferase inhibitor, but not trichostatin A, a histone deacetylase inhibitor. Bisulfite sequence analysis revealed that several CpG sites in the promoter region neighboring the PU.1-binding sites were methylated when Dnmt3s were coexpressed with PU.1. We also showed that the CpG sites in the p16 INK4A promoter were methylated by overexpression of PU.1 in NIH3T3 cells, accompanied by a downregulation of p16 INK4A gene expression. These results suggest that PU.1 may downregulate its target genes through an epigenetic modification such as DNA methylation.

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Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

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Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

et al. 2005

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“…Recently, Suzuki et al (2003) reported that MeCP2-mediated transcriptional repression of PU.1 involves Sin3A and HDAC1 in a TSA-sensitive manner. Since mt-Ski which can bind to Sin3A (Ueki and Hayman, 2003b) was defective in PU.1 repression, the repression by Ski seems to be Sin3A independent.…”

Section: Discussionmentioning

confidence: 99%

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

2007

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“…45 Recent data also identified Spi-1 binding to enhancers as a primary event that facilitates H3K4me1 deposition. 43 Our work reveals a new mechanism whereby Spi-1 represses gene transcription, by promoting H3K27me3 deposition at chromatin.…”

Section: α-Suz12mentioning

confidence: 99%

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

et al. 2013

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Deregulation of transcriptional networks contributes to haematopoietic malignancies. The transcription factor Spi-1/PU.1 is a master regulator of haematopoiesis and its alteration leads to leukaemia. Spi-1 overexpression inhibits differentiation and promotes resistance to apoptosis in erythroleukaemia. Here, we show that Spi-1 inhibits mitochondrial apoptosis in vitro and in vivo through the transcriptional repression of Bim, a proapoptotic factor. BIM interacts with MCL-1 that behaves as a major player in the survival of the preleukaemic cells. The repression of BIM expression reduces the amount of BIM-MCL-1 complexes, thus increasing the fraction of potentially active antiapoptotic MCL-1. We then demonstrate that Spi-1 represses Bim transcription by binding to the Bim promoter and by promoting the trimethylation of histone 3 on lysine 27 (H3K27me3, a repressive histone mark) on the Bim promoter. The PRC2 repressive complex of Polycomb is directly responsible for the deposit of H3K27me3 mark at the Bim promoter. SUZ12 and the histone methyltransferase EZH2, two PRC2 subunits bind to the Bim promoter at the same location than H3K27me3, distinct of the Spi-1 DNA binding site. As Spi-1 interacts with SUZ12 and EZH2, these results indicate that Spi-1 modulates the activity of PRC2 without directly recruiting the complex to the site of its activity on the chromatin. Our results identify a new mechanism whereby Spi-1 represses transcription and provide mechanistic insights on the antiapoptotic function of a transcription factor mediated by the epigenetic control of gene expression. Cell Death and Differentiation (2013) 20, 1268-1278; doi:10.1038/cdd.2013.88; published online 12 July 2013Acute myeloid leukaemia (AML) develops through a multistep process driven by the progressive accumulation of mutations, leading to deregulation of cell proliferation and differentiation. Most frequently, abnormalities in cell differentiation are the result of loss-of-function mutations in lineage-specific transcription factors, whereas alterations in cell proliferation are associated with gain-of-function mutations in signalling pathways. 1 Mutations that target components of the spliceosomal machinery 2 and epigenetic regulators 3 have been identified as well, although their functional consequences in leukaemogenesis are not clear. To date, AML treatments are largely determined by the nature of the identified mutated proteins and a major challenge is to design molecules that can target each molecular alteration contributing to transformation. For that, understanding the molecular mechanisms controlled by an oncoprotein is one essential step. We have previously described a mouse model of erythroleukaemia (Spi-1 transgenic mice) that recapitulates the multistep development of human AML. 4 Spi-1 is a master transcription factor of haematopoiesis that is also involved in pre-mRNA splicing regulation. 5 During the preleukaemic stage of the disease, the differentiation blockage of the erythroid progenitors is the first oncogenic mark assoc...

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Direct association between PU.1 and MeCP2 that recruits mSin3A-HDAC complex for PU.1-mediated transcriptional repression

Cited by 72 publications

References 47 publications

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Site-specific DNA methylation by a complex of PU.1 and Dnmt3a/b

Ski can negatively regulates macrophage differentiation through its interaction with PU.1

Epigenetic silencing of Bim transcription by Spi-1/PU.1 promotes apoptosis resistance in leukaemia

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