Model for the developmental regulation of ρ-globin transcription in chicken erythrocytes. (A) In embryonic day 4 primitive chicken erythrocytes, robust expression of the ρ-globin gene is seen. The presence of positively-acting trans factors such as GATA1 recruits RNA polymerase (RNAPII) and drives high levels of transcription from the unmethylated ρ-globin gene. Histones throughout the gene exhibit high levels of transcriptionally active modifications, such as trimethylation of H3-K4 as well as H3 and H4 acetylation. (B) No transcription of the ρ-globin gene is seen in adult definitive chicken erythrocytes. In these cells there is dense methylation at the promoter, ρ-PTR, and downstream regions of the gene. In this work we have shown that cMBD2 binds to the methylated ρ-globin gene in adult cells. Because cMBD2 can affinity copurify the other components of the MeCPC complex in vivo, it is likely that MBD2 recruits these components to the methylated ρ-globin gene. Indeed, we show that MBD2 and MTA2 occupy the methylated gene in MEL-ρ cells. The complex maintains transcriptional inactivity by remodeling chromatin into a nonpermissive configuration. Coincident with this loss of transcriptional activity is the loss of trimethylation of H3-K4.