DNA methyltransferase 3a/3b-dependent non-random DNA segregation in Embryonic Stem Cells
University of California, Berkeley
Embryonic stem cells (ESCs) are of great interest for regenerative medicine because of their infinite potential for asymmetric division; one daughter cell renews the stem cell population, and the other journeys down a specified fate. However, precisely controlling stem cells’ differentiation potential, post-transplantation regulation, and chemical niche depend on our understanding of the molecular mechanisms controlling these processes. We discovered that embryonic stem cells that are in the process of differentiating segregate their DNA asymmetrically at high frequencies, and that ESCs co-segregate their old DNA non-randomly and specifically with the more stem-like cell. This finding immediately suggests that the mechanism is likely epigenetic; using inhibitors of DNA methyltransferase (DNMT) and Histone deacetylase, we found that asymmetric DNA segregation is greatly reduced in differentiating ESCs treated with the DNMT inhibitor, demonstrating a mechanistic dependence of non-random template segregation on DNA methylation. Furthermore, we probed for specific DNA methyltransferase co-segregation with old and new DNA strands and unveiled that DNMT 3a and 3b co-segregate non-randomly with the old DNA. Genetic studies using mice deficient for DNMT 3a/3b validate the link between non-random DNA template segregation and DNA methylation. Taken collectively, we show that DNA methylation affects the propensity of ESCs to segregate their DNA asymmetrically, thus offering a molecular pathway to regulate and control ESC fate and self-renewal.