Abstract
A wide variety of nuclear regulators and enzymes are subjected to acetylation of the lysine residue, which regulates different aspects of protein functions. The MYST family histone acetyltransferase, human ortholog of MOF (hMOF), plays critical roles in transcription activation by acetylating nucleosomal H4K16. In this study, we found that hMOF acetylates itself in vitro and in vivo, and the acetylation is restricted to the conserved MYST domain (C2HC zinc finger and HAT), of which the K274 residue is the major autoacetylation site. Furthermore, the class III histone deacetylase SIRT1 was found to interact with the MYST domain of hMOF through the deacetylase catalytic region and deacetylate autoacetylated hMOF. In vitro binding assays showed that non-acetylated hMOF robustly binds to nucleosomes while acetylation decreases the binding ability. In HeLa cells, the recruitment of hMOF to the chromatin increases in response to SIRT1 overexpression and decreases after knockdown of SIRT1. The acetylation mimic mutation K274Q apparently decreases the chromatin recruitment of hMOF as well as the global H4K16Ac level in HeLa cells. Finally, upon SIRT1 knockdown, hMOF recruitment to the gene body region of its target gene HoxA9 decreases, accompanied with decrease of H4K16Ac at the same region and repression of HoxA9 transcription. These results suggest a dynamic interplay between SIRT1 and hMOF in regulating H4K16 acetylation.
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Acknowledgements
This work was supported by the National Basic Research Program Grants 2011CB965203, 2011CB964803 and 2011CB503902, Hi-Tech Research and Development Program of China Grant 2007AA021206 and the National Natural Science Foundation of China Grants 31030026 and 31021091.
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
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Supplementary information, Figure S1
In vitro autoacetylation of hMOF. (PDF 987 kb)
Supplementary information, Figure S2
In vitro autoacetylation of GST-hMOF constructs. (PDF 920 kb)
Supplementary information, Figure S3
In vitro HAT assay was carried out using FLAG-IP purified mammalian hMOF-K274R complex. (PDF 1163 kb)
Supplementary information, Figure S4
Measurement of H4K16Ac levels from blank HeLa cells and HeLa cells with ectopic hMOF expression. (PDF 988 kb)
Supplementary information, Table S1
Primers used in this study. (PDF 24 kb)
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Lu, L., Li, L., Lv, X. et al. Modulations of hMOF autoacetylation by SIRT1 regulate hMOF recruitment and activities on the chromatin. Cell Res 21, 1182–1195 (2011). https://doi.org/10.1038/cr.2011.71
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DOI: https://doi.org/10.1038/cr.2011.71
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