Abstract
DNA methylation is essential for development in the mouse and plays an important role in inactivation of the X chromosome and genomic imprinting. MeCP2 is the founder member of a family of methyl-CpG-binding proteins. MeCP2 directly binds to the co-repressor mSin3, which interacts with class I histone deacetylase, recruiting them to methyl-CpG regions to suppress transcription. Here, we report that MeCP2 directly binds to two co-repressors, c-Ski and N-CoR, in addition to mSin3A, and that the c-Ski, which is encoded by the c-ski proto-onocogene, is required for MeCP2-mediated transcriptional repression. The two regions of c-Ski, including the C-terminal coiled-coil region, interact with the transcriptional repression domain in the center of the MeCP2 molecule. The immunostaining signals for c-Ski and MeCP2 overlap in the nuclear heterochromatin region, suggesting the co-localization of the two proteins. The degree of transcriptional repression mediated by a Gal4-MeCP2 fusion protein was abrogated by overexpression of the putative dominant negative form of c-Ski. Furthermore, injection of antibodies against c-Ski and Sno almost completely abolished the transcriptional repression mediated by the Gal4-MeCP2 fusion protein. These results suggest that the ski gene family is involved in methyl CpG-mediated transcriptional repression.
Highlights
DNA methylation is essential for development in the mouse and plays an important role in inactivation of the X chromosome and genomic imprinting
These results suggest that the ski gene family is involved in methyl CpG-mediated transcriptional repression
N-CoR and SMRT were originally identified as co-repressors that mediate transcriptional repression by nuclear hormone receptors [5, 6] and form a complex with the class II histone deacetylases (HDACs)1 [7,8,9,10]. mSin3 was originally
Summary
DNA methylation is essential for development in the mouse and plays an important role in inactivation of the X chromosome and genomic imprinting. N-CoR and SMRT were originally identified as co-repressors that mediate transcriptional repression by nuclear hormone receptors [5, 6] and form a complex with the class II histone deacetylases (HDACs)1 [7,8,9,10]. MeCP2 is an abundant 486-amino acid protein that contains two functional domains, a MBD essential for its binding to methyl-CpG, and a transcriptional repression domain (TRD) that mediates gene silencing. Recruitment of the HDAC complex by MeCP2 is thought to be an important mechanism of the transcriptional repression mediated by methyl-CpG This is consistent with the observation that densely methylated DNA associates with transcriptionally repressed chromatin characterized by the presence of underacetylated histones [36, 37]. We have found that c-Ski directly binds to MeCP2 and is required for the transcriptional repression mediated by MeCP2
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