Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, United States
Jui-Hung Hung
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United States
Taylor L Hickman
Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, United States
Andrew H Coles
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, United States
James F Carey
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, United States
Zhiping Weng
Program in Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, United States; Department of Biochemistry and Molecular Pharmacology, University of Massachusetts Medical School, Worcester, United States
Feixia Chu
Department of Molecular, Cellular and Biomedical Sciences, University of New Hampshire, Durham, United States
Thomas G Fazzio
Program in Gene Function and Expression, University of Massachusetts Medical School, Worcester, United States; Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, United States
In embryonic stem cells (ESCs), the Tip60 histone acetyltransferase activates genes required for proliferation and silences genes that promote differentiation. Here we show that the class II histone deacetylase Hdac6 co-purifies with Tip60-p400 complex from ESCs. Hdac6 is necessary for regulation of most Tip60-p400 target genes, particularly those repressed by the complex. Unlike differentiated cells, where Hdac6 is mainly cytoplasmic, Hdac6 is largely nuclear in ESCs, neural stem cells (NSCs), and some cancer cell lines, and interacts with Tip60-p400 in each. Hdac6 localizes to promoters bound by Tip60-p400 in ESCs, binding downstream of transcription start sites. Surprisingly, Hdac6 does not appear to deacetylate histones, but rather is required for Tip60-p400 binding to many of its target genes. Finally, we find that, like canonical subunits of Tip60-p400, Hdac6 is necessary for robust ESC differentiation. These data suggest that Hdac6 plays a major role in the modulation of Tip60-p400 function in stem cells.
