The human DNA methyltransferases (DNMTs) 1, 3a and 3b: coordinate mRNA expression in normal tissues and overexpression in tumors

DNA methylation in mammals is required for embryonic development, X chromos ome inactivation and imprinting. Previous studies have shown that methylati on patterns become abnormal in malignant cells and may contribute to tumori genesis by improper de novo methylation and silencing of the promoters for growth-regulatory genes. RNA and protein levels of the DNA methyltransferas e DNMT1 have been shown to be elevated in tumors, however murine stem cells lacking Dnmt1 are still able to de novo methylate viral DNA, The recent cl oning of a new family of DNA methyltransferases (Dnmt3a and Dnmt3b) in mous e which methylate hemimethylated and unmethylated templates with equal effi ciencies make them candidates for the long sought de novo methyltransferase s. We have investigated the expression of human DNMT1, 3a and 3b and found widespread, coordinate expression of all three transcripts in most normal t issues. Chromosomal mapping placed DNMT3a on chromosome 2p23 and DNMT3b on chromosome 20q11.2. Significant overexpression of DNMT3b was seen in tumors while DNMT1 and DNMT3a were only modestly overexpressed and with lower fre quency. Lastly, several novel alternatively spliced forms of DNMT3b, which may have altered enzymatic activity, were found to be expressed in a tissue -specific manner.