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J. Biol. Chem., Vol. 277, Issue 3, 1897-1905, January 18, 2002

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Methylation of Promoter Proximal-transcribed Sequences of an Embryonic Globin Gene Inhibits Transcription in Primary Erythroid Cells and Promotes Formation of a Cell Type-specific Methyl Cytosine Binding Complex^*

Rakesh Singal, Shou Zhen Wang^§, Thanh Sargent^§, Sheng Zu Zhu^§, and Gordon D. Ginder^§¶

From the ^§ Massey Cancer Center and Departments of Internal Medicine and Human Genetics, Virginia Commonwealth University, Richmond, Virginia 23298-0037 and  Department of Medicine, Overton Brooks Veterans Affairs Medical Center and Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, Louisiana 71101-4295

The methylation pattern of a 248-base pair proximal transcribed region (248) of the avian embryonic -globin gene was found to correlate inversely with stage-specific expression in avian erythroid cells. In vitro methylation of the 248 segment alone (in the absence of promoter methylation) resulted in a 5-fold inhibition of transcription in a transient transfection assay in primary erythroid cells in which the transfected gene is packaged into nucleosomal chromatin. This effect was observed if the 248 segment was positioned adjacent to the promoter but not when it was located 2.7 kilobases downstream. Fully methylated but not unmethylated 248 formed a novel cell type-specific methyl cytosine-binding protein complex (MeCPC) that contained methyl binding domain protein-2 (MBD-2) and histone deacetylase 1 proteins but differed from MeCP-1. The histone deacetylase inhibitor trichostatin A failed to relieve methylation-mediated repression of transcription from the -gene promoter, supporting the notion of the dominance of methylation over histone deacetylation in silencing through CpG-rich sequences at this locus. These data demonstrate that site-specific methylation of a vertebrate gene 5'-transcribed region alone at the exact CpGs that are methylated in vivo can suppress transcription in homologous primary cells and facilitate binding to a cell type-specific MeCPC.

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