BackgroundMBD5 and MBD6 are two uncharacterized mammalian proteins that contain a putative Methyl-Binding Domain (MBD). In the proteins MBD1, MBD2, MBD4, and MeCP2, this domain allows the specific recognition of DNA containing methylated cytosine; as a consequence, the proteins serve as interpreters of DNA methylation, an essential epigenetic mark. It is unknown whether MBD5 or MBD6 also bind methylated DNA; this question has interest for basic research, but also practical consequences for human health, as MBD5 deletions are the likely cause of certain cases of mental retardation.Principal FindingsHere we report the first functional characterization of MBD5 and MBD6. We have observed that the proteins colocalize with heterochromatin in cultured cells, and that this localization requires the integrity of their MBD. However, heterochromatic localization is maintained in cells with severely decreased levels of DNA methylation. In vitro, neither MBD5 nor MBD6 binds any of the methylated sequences DNA that were tested.ConclusionsOur data suggest that MBD5 and MBD6 are unlikely to be methyl-binding proteins, yet they may contribute to the formation or function of heterochromatin. One isoform of MBD5 is highly expressed in oocytes, which suggests a possible role in epigenetic reprogramming after fertilization.
CpG islands (CGIs) are regions enriched in the dinucleotide CpG; they constitute the promoter of about 60% of mammalian genes. In cancer cells, some promoter-associated CGIs become heavily methylated on cytosines, and the corresponding genes undergo stable transcriptional silencing. Hypermethylated CGIs attract methyl-CpG-binding proteins (MBPs), which have been shown to recruit chromatin modifiers and cause transcriptional repression. These observations have led to the prevalent model that methyl-CpG-binding proteins are promoter-proximal transcriptional repressors. Recent discoveries challenge this idea and raise a number of questions. Here we discuss the following issues: what are other possible roles for the known MBPs? Why are these proteins not essential in mammals? Are there other MBPs left to discover? Could CpG methylation be nonessential?
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