Earlier studies from Szyf's122 laboratory extracted active DNA demethylase activity from a human lung cancer cell line and identified a protein with demethylase activity, which was cloned concurrently by Bird's group and named MBD2.123 Interestingly, the protein, MBD2, was found by Bird's group and others to also associate with a chromatin remodeling complex containing HDAC, which is involved in silencing of gene expression through the recruitment of a repressor complex. The assignment of a demethylase function to a protein that was independently discovered as a recruiter of repressor complexes triggered the expected controversy in the field and reports that MBD2 failed to produce demethylase activity. However, the observation that MBD2/demethylase expression produces the demethylation of some, but not all, promoters in a dose- and time-dependent manner has been confirmed.108,124 Clearly, the contextual factors that determine MBD2 demethylase activity remain to be fully explained. Interestingly, MBD2 increased gene expression in those instances where promoter demethylation occurred, suggesting that not all promoters respond in the same orderly manner. Indeed, the same is true for DNA methylation, which impedes the DNA binding of
