The DNA methyltransferase-like protein DNMT3L stimulates de novo methylation by Dnmt3a.
Dnmt3L is required for the establishment of maternal methylation imprints at imprinting centers (ICs). Dnmt3L, however, lacks the conserved catalytic domain common to DNA methyltransferases. In an attempt to define its function, we coexpressed DNMT3L with each of the two known de novo methyltransferases, Dnmt3a and DNMT3B, in human cells and monitored de novo methylation by using replicating minichromosomes carrying various ICs as targets. Coexpression of DNMT3L with DNMT3B led to little or no change in target methylation. However, coexpression of DNMT3L with Dnmt3a resulted in a striking stimulation of de novo methylation by Dnmt3a. Stimulation was observed at maternally methylated ICs such as small nuclear ribonucleoprotein polypeptide N (SNRPN), Snrpn, and Igf2rAir, as well as at various nonimprinted sequences present on the episomes. Stimulation of Dnmt3a by DNMT3L was also observed at endogenous sequences in the genome. Therefore, DNMT3L acts as a general stimulatory factor for de novo methylation by Dnmt3a. The implications of these findings for the function of DNMT3L and Dnmt3a in DNA methylation and genomic imprinting are discussed.
Chedin
Frederic
F
Departments of Pathology, Biochemistry and Molecular Biology, and Urology, Norris Comprehensive Cancer Center, Room 5420, Keck School of Medicine, University of Southern California, Los Angeles, CA 90089, USA.
Lieber
Michael R
MR
Hsieh
Chih-Lin
CL
D002460:Cell Line; D018899:CpG Islands; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000502:physiology*; D019175:DNA Methylation; D000090205:DNA Methyltransferase 3A; D006801:Humans; D014162:Transfection
C000717967:DNMT3A protein, human; C412484:DNMT3L protein, human; D004248:DNA (Cytosine-5-)-Methyltransferases; D000090205:DNA Methyltransferase 3A