Signal-dependent nuclear export of a histone deacetylase regulates muscle differentiation

• Published in: Nature (London) 2000-11, Vol.408 (6808), p.106-111
• Main Authors: McKinsey, Timothy A., Zhang, Chun-Li, Lu, Jianrong, Olson, Eric N.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell Differentiation; Cell Line; Cell Nucleus - metabolism; Cell physiology; COS Cells; DNA-Binding Proteins - metabolism; Enzymes; Fundamental and applied biological sciences. Psychology; Genes; HDAC5 protein; Histone Deacetylases - genetics; Histone Deacetylases - metabolism; Histones - metabolism; Humanities and Social Sciences; letter; MEF2 Transcription Factors; Molecular and cellular biology; Molecular biology; multidisciplinary; Muscle, Skeletal - cytology; Muscular system; Mutagenesis; myocyte enhancer factor 2; myogenesis; Myogenic Regulatory Factors; nuclear export; Phosphorylation; Protein Transport; Repressor Proteins - genetics; Repressor Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction; Transcription Factors - metabolism
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/35040593

Members of the myocyte enhancer factor-2 (MEF2) family of transcription factors associate with myogenic basic helix–loop–helix transcription factors such as MyoD to activate skeletal myogenesis 1 . MEF2 proteins also interact with the class II histone deacetylases HDAC4 and HDAC5, resulting in repression of MEF2-dependent genes 2 , 3 , 4 . Execution of the muscle differentiation program requires release of MEF2 from repression by HDACs, which are expressed constitutively in myoblasts and myotubes 5 . Here we show that HDAC5 shuttles from the nucleus to the cytoplasm when myoblasts are triggered to differentiate. Calcium/calmodulin-dependent protein kinase (CaMK) signalling, which stimulates myogenesis 5 and prevents formation of MEF2–HDAC complexes 4 , also induces nuclear export of HDAC4 and HDAC5 by phosphorylation of these transcriptional repressors. An HDAC5 mutant lacking two CaMK phosphorylation sites is resistant to CaMK-mediated nuclear export and acts as a dominant inhibitor of skeletal myogenesis, whereas a cytoplasmic HDAC5 mutant is unable to block efficiently the muscle differentiation program. Our results highlight a mechanism for transcriptional regulation through signal- and differentiation-dependent nuclear export of a chromatin-remodelling enzyme, and suggest that nucleo-cytoplasmic trafficking of HDACs is involved in the control of cellular differentiation.