DNMT1 can induce primary germ layer differentiation through de novo DNA methylation

Abstract DNA methyltransferases and TET enzymes dynamically regulate the DNA methylation-demethylation cycles during mouse embryonic development. DNMT1 maintains cell-specific DNA methylation after DNA replication. However, little is known about the physiological significance of the de novo methylation enzymatic potential of DNMT1, which has attracted much attention. Here, we show that the full-length DNMT1 and a mutant form without the N-terminal necessary for its maintenance activity potentially inhibit the differentiation of mouse pluripotent embryonic stem cells lacking Dnmt1, 3a and 3b into primitive endoderm cells. However, the mutant cells could differentiate into epiblast-like cells and beyond, leading to cell-autonomous mesendoderm differentiation. Strikingly, we found that in response to Nodal signalling and the increased concurrent access of DNMT1 and TET enzymes resulting from chromatin relaxation activated primordial germ cell-specific genes. With the precise target selectivity by its N-terminal region, DNMT1 may be involved in gene regulation leading to germline development.