Tet enzymes help determine the fate of stem cells by regulating gene activity. They do so by reshaping methyl groups, the chemical tags on DNA that keep stem-cell genes turned off—thereby determining how neural stem cells differentiate into neurons and glial cells (cells that support and protect neurons). Until now, the three Tet-induced DNA modifications to methyl groups— hydroxymethylation (adding 5hmC), formylation (adding 5fC) and carboxylation (adding 5caC) — were thought to activate the neural stem-cell genes in the same way: via hypomethylation (i.e., removing the methyl groups that keep genes inactive).

In study published online on July 31 in Stem Cell Reports, Meelad Dawlaty, Ph.D., and colleagues have overturned that assumption. They’ve shown that Tet enzymes regulate neural stem-cell differentiation by modifying methyl groups in two distinct ways. After engineering neural stem cells that can modify methyl groups in some ways but not others, the researchers showed that DNA hydroxymethylation (adding 5hmC to DNA) specifically drives the formation of neurons, while DNA formylation (adding 5fC) and carboxylation (adding 5caC) promote the development of glial cells, such as astrocytes and oligodendrocytes. The findings offer insights into how neurodevelopment occurs and may improve strategies for generating neurons and glial cells from pluripotent and neural stem cells; and they could also lead to treatments for autism and the many other neurodevelopmental and neurodegenerative disorders in which Tet enzymes are mutated or dysregulated.

Dr. Dawlaty is an associate professor of genetics and of developmental & molecular biology, and a member of the Ruth L. and David S. Gottesman Institute for Stem Cell Research and Regenerative Medicine at Einstein and of the National Cancer Institute–designated Montefiore Einstein Comprehensive Cancer Center.