Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C|[sol]|EBP|[alpha]|

doi:doi:10.1038/sj.leu.2405101

Leukemia (2008) 22, 800–807; doi:10.1038/sj.leu.2405101; published online 31 January 2008

Proteomic identification of the MYST domain histone acetyltransferase TIP60 (HTATIP) as a co-activator of the myeloid transcription factor C/EBP

D Bararia¹, A K Trivedi², A A Peer Zada², P A Greif¹, M A Mulaw¹, M Christopeit², W Hiddemann¹, S K Bohlander^1,3 and G Behre^2,3

¹Department of Medicine III, University of Munich and Clinical Cooperative Group, HelmholtzZentrum 'German Research Center for Environmental Health', Munich, Germany
²Bone Marrow Transplantation Section, Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Halle, Germany

Correspondence: G Behre, Bone Marrow Transplantation Section, Department of Hematology and Oncology, Martin-Luther-University Halle-Wittenberg, Ernst-Grube-Str. 40, Halle 06097, Germany. E-mail: gerhard.behre@medizin.uni-halle.de; SK Bohlander, Clinical Cooperative Group 'Leukemia', GSF 'National Research Center for Environment and Health' and Department of Medicine III, LMU Munich, Marchioninistr. 25, Munich 81377, Germany. E-mail: bohlander@gsf.de

³Joint senior authors.

Received 22 May 2007; Revised 17 December 2007; Accepted 28 December 2007; Published online 31 January 2008.

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Abstract

The transcription factor C/EBP alpha (CEBPA) is a key player in granulopoiesis and leukemogenesis. We have previously reported the interaction of C/EBP alpha with other proteins (utilizing mass spectrometry) in transcriptional regulation. In the present study, we characterized the association of the MYST domain histone acetyltransferase Tat-interactive protein (TIP) 60 (HTATIP) with C/EBP alpha . We show in pull-down and co-precipitation experiments that C/EBP alpha and HTATIP interact. A chromatin immunoprecipitation (ChIP) and a confirmatory Re-ChIP assay revealed in vivo occupancy of the C/EBP alpha and GCSF-R promoter by HTATIP. Reporter gene assays showed that HTATIP is a co-activator of C/EBP alpha . The co-activator function of HTATIP is dependent on its intact histone acetyltransferase (HAT) domain and on the C/EBP alpha DNA-binding domain. The resulting balance between histone acetylation and deacetylation at the C/EBP alpha promoter might represent an important mechanism of C/EBP alpha action. We observed a lower expression of HTATIP mRNA in undifferentiated U937 cells compared to retinoic acid-induced differentiated U937 cells, and correlated expression of CEBPA and HTATIP mRNA levels were observed in leukemia samples. These findings point to a functional synergism between C/EBP alpha and HTATIP in myeloid differentiation and suggest that HTATIP might be an important player in leukemogenesis.