The methyl-CpG-binding protein MeCP2 links DNA methylation to histone methylation.
DNA methylation plays an important role in mammalian development and correlates with chromatin-associated gene silencing. The recruitment of MeCP2 to methylated CpG dinucleotides represents a major mechanism by which DNA methylation can repress transcription. MeCP2 silences gene expression partly by recruiting histone deacetylase (HDAC) activity, resulting in chromatin remodeling. Here, we show that MeCP2 associates with histone methyltransferase activity in vivo and that this activity is directed against Lys(9) of histone H3. Two characterized repression domains of MeCP2 are involved in tethering the histone methyltransferase to MeCP2. We asked if MeCP2 can deliver Lys(9) H3 methylation to the H19 gene, whose activity it represses. We show that the presence of MeCP2 on nucleosomes within the repressor region of the H19 gene (the differentially methylated domain) coincides with an increase in H3 Lys(9) methylation. Our data provide evidence that MeCP2 reinforces a repressive chromatin state by acting as a bridge between two global epigenetic modifications, DNA methylation and histone methylation.
Fuks
Francois
F
Wellcome/Cancer Research UK Institute and Department of Pathology, University of Cambridge, Tennis Court Road, United Kingdom.
Hurd
Paul J
PJ
Wolf
Daniel
D
Nan
Xinsheng
X
Bird
Adrian P
AP
Kouzarides
Tony
T
D000818:Animals; D002460:Cell Line; D002868:Chromosomal Proteins, Non-Histone; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006655:Histone Deacetylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2; D008745:Methylation; D051379:Mice; D011233:Precipitin Tests; D011994:Recombinant Proteins / Q000378:metabolism; D012097:Repressor Proteins; D020133:Reverse Transcriptase Polymerase Chain Reaction
D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D006657:Histones; C497392:MECP2 protein, human; C497393:Mecp2 protein, mouse; D051783:Methyl-CpG-Binding Protein 2; D011994:Recombinant Proteins; D012097:Repressor Proteins; D006655:Histone Deacetylases