In 1991, Adrian Bird proposed two models52 to explain how CpG methylation might cause transcriptional repression. Put simply, he postulated in one model— the "d/recf" model, that essential transcription factors saw 5mC as a mutation in their binding site and so were unable to bind, while the other model—the "indirect" model, postulated that methylated DNA sites physically blocked the binding of transcriptional factors. Subsequently, two proteins were identified, MeCP1 and MeCP2, that bound specifically to DNA-containing methyl-CpG (MBD1) sites.52,53 Both proteins were widely expressed in mammalian cells, but MeCP2 was more abundant and more tightly bound in the nucleus than MeCP1, and most importantly was associated with chromatin. Subsequently, MeCP2 was shown to contain both a methyl-CpG-binding domain (MBD) and a transcriptional repression domain (TRD).54 Bird55 and colleagues proposed that MeCP2 could bind methylated DNA in the context of chromatin and they suspected this protein contributed to the long-term silencing of gene activity. While this evidence supported inhibition of transcription by the indirect mechanism, it did not clarify the mechanism by which cytosine methylation affected the structure of chromatin.
Searches of the EST database with the MBD sequence as the query enabled Cross et al.56 to identify the MBD sequence, named MBD1, as a component of MeCP1. Subsequently Hendrich and Bird54 identified three new human and mouse proteins (MBD2, MBD3, and MBD4) that contain the methyl-CpG-binding domain (Figure 6.5). MBD1, MBD2, and MBD4 were all shown to bind methylated DNA via its MBD region and to repress transcription. The precise significance of MBD3 in mammals was unclear.
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