Methylation-dependent silencing at the H19 imprinting control region by MeCP2

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Abstract
Methylation of CpG dinucleotides is correlated with transcriptional repression of genes, including imprinted genes. In the case of the imprinted H19 gene, a 2 kb imprinting control region (ICR) is subject to differential methylation, as it is methylated only on the silenced paternal allele. This region has previously been shown to act as a silencer element at the endogenous locus. The proteins that bind at the H19 differentially methylated domain (DMD) and mediate transcriptional silencing have yet to be identified, although a family of proteins containing a methyl-CpG-binding domain (MBD), of which MeCP2 is the best characterised, are obvious candidates. MeCP2 can bind to a single methylated CpG dinucleotide through its MBD and also contains a transcriptional repression domain (TRD). The TRD interacts with Sin3a and histone deacetylases (HDACs) in vivo, forming a repressive complex. Here we show that MeCP2 is recruited to the H19 DMD in vivo and can silence a reporter gene regulated by the H19 DMD in a methylation-dependent manner. This repression can be alleviated by deletion of the TRD from MeCP2 or by inhibition of HDAC activity. These data indicate that transcriptional silencing from the H19 ICR involves recruitment of MeCP2 and presumably an associated protein complex with deacetylase activity. This complex may also be recruited to the ICR in vivo, resulting in a compact, repressive chromatin structure capable of silencing the paternal H19 allele.