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RUNX1 Associates with Histone Deacetylases and SUV39H1 to Repress Transcription

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RUNX1 Associates with Histone Deacetylases and SUV39H1 to Repress Transcription Oncogene (2006) 25, 5777–5786 & 2006 Nature Publishing Group All rights reserved 0950-9232/06 $30.00 www.nature.com/onc ORIGINAL ARTICLE RUNX1 associates with histone deacetylases and SUV39H1 to repress transcription E Reed-Inderbitzin1,8,9, I Moreno-Miralles1,9, SK Vanden-Eynden1,9, J Xie2, B Lutterbach1,10, KL Durst-Goodwin1,11, KS Luce1, BJ Irvin1,12, ML Cleary3, SJ Brandt2,4,5,6,7 and SW Hiebert1,6 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, USA; 2Department of Medicine, Vanderbilt University School of Medicine, Nashville, TN, USA; 3Stanford University Medical School, Palo Alto, CA, USA; 4Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; 5Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN, USA; 6Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN, USA and 7Tennessee Valley VA Healthcare System, Nashville, TN, USA RUNX1 (AML1) is a gene that is frequently disrupted by Introduction chromosomal translocations in acute leukemia. Like its Drosophila homolog Runt, RUNX1 both activates and Translocations that disrupt the RUNX1 gene are among represses transcription. Both Runt and RUNX1 are the most common aberrations found in human leuke- required for gene silencing during development and a mia. The t(8;21) is found in 10–15% of myeloid central domain of RUNX1, termed repression domain 2 leukemia and gives rise to a fusion protein that contains (RD2), was defined as being required for transcriptional the N-terminal portion of RUNX1 fused to nearly all of repression and for the silencing of CD4 during T-cell myeloid translocation gene on chromosome 8 (MTG8, maturation in thymic organ cultures. Although transcrip- also known as eight-twenty-one (ETO)) (Miyoshi et al., tional co-repressors are known to contact other repression 1991, 1993; Erickson et al., 1994). The fusion protein domains in RUNX1, the factors that bind to RD2 had not appears to function as a transcriptional repressor of been defined. Therefore, we tested whether RD2 contacts RUNX1-regulated genes (Peterson and Zhang, 2004). histone-modifying enzymes that may mediate both repres- The t(12;21) is found in up to 25% of pediatricB-cell sion and gene silencing. We found that RD2 contacts acute leukemia and creates a chimeric gene encoding the SUV39H1, a histone methyltransferase, via two motifs TEL–RUNX1 fusion protein (Golub et al., 1995; and that endogenous Suv39h1 associates with a Runx1- Nucifora et al., 1995; Raynaud et al., 1995; Romana regulated repression element in murine erythroleukemia et al., 1995). TEL–RUNX1 also appears to act as a cells. In addition, one of these SUV39H1-binding motifs is transcriptional repressor that dominantly interferes with also sufficient forbinding to histone deacetylases 1 and 3, RUNX1-specific transactivation (Hiebert et al., 1996; and both of these domains are required for full RUNX1- Chakrabarti and Nucifora, 1999; Fenrick et al., 2000; mediated transcriptional repression. The association Guidez et al., 2000). RUNX1 function is also impaired between RUNX1, histone deacetylases and SUV39H1 by the inv(16), which fuses the RUNX1 associating provides a molecular mechanism for repression and factor, core binding factor b (CBFb or polyoma possibly gene silencing mediated by RUNX1. enhancer binding protein 2 beta) to the smooth muscle Oncogene (2006) 25, 5777–5786. doi:10.1038/sj.onc.1209591; myosin heavy-chain gene MYH11, in approximately 8% published online 1 May 2006 of acute myeloid leukemia (Liu et al., 1993). Like the t(8;21) and the t(12;21), the inv(16) also encodes a Keywords: Suv39h1; RUNX1; AML1; histone; deacetylase transcriptional repressor, but this factor must associate with RUNX1 to regulate transcription (Lutterbach et al., 1999; Durst et al., 2003). RUNX1 is a member of the mammalian Runt domain Correspondence: Dr SW Hiebert, Department of Biochemistry, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of family of transcription factors, which were recently Medicine, Preston Research Building, Rm 512, 23rd and Pierce, renamed the RUNX factors after the Runt protein that Nashville, TN 37232, USA. controls segmentation in the Drosophila embryo (Ger- E-mail: [email protected] gen and Wieschaus, 1985; van Wijnen et al., 2004). Runt 8Current address: University of Oregon Health Sciences Center, either activates or represses transcription in a promoter- Beaverton, OR, USA. 9These authors contributed equally to this work. or enhancer-specific context and cell type-specific 10Current address: Merck Inc., West Point, PA, USA. manner, but more frequently it is required for repressing 11Current address: Indiana University School of Medicine, Indiana- transcription (Wheeler et al., 2002; Swantek and polis, IN, USA. Gergen, 2004). For instance, during embryogenesis 12Current address: The Blood Center of Wisconsin, Milwaukee, WI, USA. the establishment of Runt-mediated repression of Received 19 April 2005; revised 21 February 2006; accepted 28 February engrailed is dependent on the dosage of the zinc-finger- 2006; published online 1 May 2006 containing transcription factor Tramtrack. However, RUNX1 recruits histone-modifying enzymes E Reed-Inderbitzin et al 5778 the maintenance of repression of engrailed is dependent RUNX1 and RUNX3 may associate with factors that on the presence of the Groucho and dCtBP co-repressors regulate the ‘histone code’ (Durst et al., 2003). The and the Rpd3 histone deacetylase (Wheeler et al., 2002). histone code hypothesis suggests that deacetylation of Thus, Runt acts in a context-dependent manner, key lysine residues in the conserved tails of histones is activating or repressing gene expression depending on followed by methylation that allows the association of the constitution of a particular promoter/enhancer or silencing factors such as heterochromatin protein-1 the availability of a given co-factor in a specific cell type. (HP1), which binds to methylated histone H3 (Firestein Likewise, RUNX1 acts as an ‘organizing’ factor for et al., 2000; Jacobs et al., 2001; Jenuwein and Allis, many promoters and enhancers. RUNX1 is a poor 2001; Lachner et al., 2001). Therefore, we asked whether activator of transcription when expressed alone or when SUV39H1, a histone H3 lysine 9-specific methyltrans- tested using artificial promoters containing multiple ferase (Rea et al., 2000), and histone deacetylases RUNX-binding sites. However, in concert with other contact RUNX1 within RD2 or other domains that DNA-binding factors, RUNX family members coop- are known to be required for transcriptional repression erate to activate transcription (Zhang et al., 1996; and gene silencing. We found that both SUV39H1 and Britos-Bray and Friedman, 1997; Goetz et al., 2000; histone deacetylase-1 and -3 contacted RUNX1 within Gu et al., 2000; Cameron and Neil, 2004). By contrast, RD2. Deletion of either of the two SUV39H1 contact RUNX1 is a potent transcriptional repressor, even when sites or the HDAC-binding motif within repression expressed alone, albeit in a cell type-specific manner. In domain 2 of RUNX1 significantly impaired RUNX1- fact, three distinct domains, termed repression domains mediated transcriptional repression. In addition, 1, 2 and 3, are required for RUNX1-mediated repression RUNX1 and RUNX3, but not Runx2, associated with (Aronson et al., 1997; Lutterbach et al., 2000). RUNX1 SUV39H1 and Runx1 recruited Suv39h1 to an endo- recruits the mSin3A co-repressor through a domain genous target gene, which raises the possibility that adjacent to the DNA-binding domain (repression recruitment of histone methyltransferases contributes to domain 1) (Lutterbach et al., 2000). In addition, RUNX1-mediated silencing of gene expression. RUNX1 contacts Groucho family members to repress transcription in a promoter-dependent manner through a C-terminal motif termed repression domain 3 Results (Aronson et al., 1997; Levanon et al., 1998; Javed et al., 2000; Lutterbach et al., 2000; Nishimura et al., 2004). RUNX1 and RUNX3 associate with SUV39H1 Repression domain 2 was simply defined as an As RUNX1 and RUNX3 both contribute to gene approximately 100 amino-acid sequence that was silencing of CD4 at distinct stages of T-cell development required for repression (Lutterbach et al., 2000). (Taniuchi et al., 2002), we tested whether RUNX family In addition to transcriptional repression, genetic members could associate with SUV39H1. Each RUNX studies have implicated Runx1 and Runx3 in the family protein was co-expressed with epitope-tagged silencing of gene transcription. During T-cell develop- SUV39H1 (FLAG-SUV39H1), SUV39H1 was immu- ment, CD4 and CD8 are silent in immature T-cells noprecipitated, and the co-purifying RUNX proteins (CD4À/CD8À), and after these cell surface markers detected by immunoblot analysis (Figure 1a). Both expressed either are CD4 or CD8 are silenced as T-cells RUNX1 and RUNX3, which are required for CD4 move from the ‘double-positive’ to the ‘single-positive’ silencing, associated with SUV39H1 (Figure 1a). By stage (e.g. CD4À/CD8 þ ). Using site-directed mutagen- contrast, Runx2, which does not contribute to CD4 gene esis of the CD4 silencer elements in transgenic mouse silencing, did not co-purify with SUV39H1 under these studies, binding sites for Runx family members were conditions (Figure 1a). In addition, using these same found to be necessary for silencing CD4 expression. conditions we were unable to detect an association Moreover, mice lacking
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