Methylcytosine in the promoter of a rRNA gene binds MBD2 (and possibly other Methyl Domain Binding Proteins) and prevents the transcription factor UBF-1 from binding. In mouse, methylation of the cytosine 133 nucleotides upstream of the start of transcription is sufficient. In the human rRNA promoter methylation of cytosines 9, 102, and 347 nucleotides upstream inhibit transcription.
UBF-1 binds directly to the CORE and UCE elements of the ribosomal DNA promoter. This binding is mediated by the HMG boxes (primarily HMG box1). Phosphorylation may play a role in the modulation of UBF's DNA binding activity, as well as in subsequent steps. UBF is thought to bind DNA in a conformation specific manner (as opposed to a sequence specific manner). The binding of UBF to the minor groove of DNA induces strong DNA bending.