We doubt that Shakespeare was thinking of DNA methylation and stem cell differentiation when he penned that famous line, and yet somehow it seems to apply here. Recent work led by Frank Rosenbauer at the Max Delbrück Center for Molecular Medicine in Berlin has revealed some of the first insights into the causal relationships between methylation state and stem cell fate through a novel genetic approach allowing for tissue- and cell-specific shutdown of DNMT1.
The investigators explored the interplay between 5-methylcytosine and development in transgenic mice through a loxP-flanked Dnmt1 allele and tissue-specific Cre expression, which allowed them to control the point at which a cell would progressively lose its methylation maintenance machinery. Focusing on hematopoietic (HSC) and cancer (CSC) stem cell populations, the investigators illuminated a delicately methylated balance:
- Complete loss of Dnmt1 was found to rapidly induce apoptosis in HSCs, while hypomorphic Dnmt1 levels reduced HSC repopulation potential.
- Reduced Dnmt1 caused HSCs to preferentially assume myeloid and erythroid over lymphoid cell fates. This bias could be corrected by forced expression or through delayed Dnmt1 loss, suggesting an early-stage regulatory methylation threshold.
- Reduced Dnmt1 activity in CSCs seemed to inhibit both malignant renewal and oncogenic initiation, suggesting Dnmt1 as a potential target in cancer therapeutic development.
These experiments, and their accompanying mouse models, open new doors to exploring the cause-and-effect interplay between DNA methylation and cellular differentiation in development. To decide your own cellular fate, you can check out the article here in Nature Genetics, November 2009.