Characterization of the bidirectional activity of the human TET2 gene promoters

Abstract

Abstract Tet methylcytosine dioxygenase 2 (TET2) is a tumor suppressor gene that is inactivated in a wide range of hematological cancers. TET2 enzymatic activity converts 5-methylcytosine (5-mC) into 5-hydroxymethylcytosine (5-hmC), an essential step in DNA demethylation. Human TET2 is highly expressed in pluripotent cells and down-regulated in differentiated cells. However, transcriptional regulation of the human TET2 gene underlying functional and biological implications has not been investigated in detail. We previously reported three promoters, designated as Pro1, Pro2, and Pro3, generate three alternative first exons, and their presence in TET2 mRNAs varies with cell type and developmental stage. In the present study, we found that the human TET2 promoters has in transcriptional activity in either orientation. The functional identification of these promoters was performed and the results showed distinct bidirectional expression by a broad range of tissues. The antisense activity from Pro2 is significantly higher than Pro1 or Pro3 promoters. The distinct properties and bidirectional nature of the human TET2 promoter elements may play an important role in human cancer development and differentiation and should provide new insights into understanding pathogenesis and development of new therapeutic approaches.