by La Jolla Institute for Immunology

Researchers at La Jolla Institute for Immunology (LJI) have shed light on a process in immune cells that may explain why some people develop cardiovascular diseases.

Their research, published recently in Genome Biology, shows the key role that TET enzymes play in keeping immune cells on a healthy track as they mature. The scientists found that other enzymes do play a role in this process—but TET enzymes do the heavy lifting.

"If we can figure out what's going on with these enzymes, that could be important for controlling cardiovascular disease," says Atsushi Onodera, Ph.D., a postdoctoral researcher at LJI and first author of the new Genome Biology study.

LJI Professor Anjana Rao, Ph.D., co-discovered TET enzymes while working at Harvard University alongside Mamta Tahiliani, Ph.D., and L. Aravind, Ph.D. Their work showed that this family of three enzymes alters how our genes are expressed.

TET enzymes control gene expression by triggering a process called demethylation, where a molecule called a methyl group is removed from where it sits in the genetic code. Demethylation is important because it alters how a cell 'reads' DNA.

Over the last decade, Rao has shown the importance of TET activity in cancer development. Her work has revealed that TET enzymes are key to proper gene expression in immune cells—and they can actually protect against cancerous mutations.

For the new study, Rao and Onodera investigated how immune cell DNA can be altered by either TET enzymes (a process called passive demethylation) or by a DNA repair enzyme called TDG (active demethylation).

The researchers aimed to uncover which demethylation pathway has a bigger role in determining the gene expression—the very fate—of immune cells.

The researchers started with two immune cell models: CD4 'helper' T cells and monocytes. Both cell types must proliferate and mature into more specific cell types to help fight off pathogens. However, once monocytes are differentiated into macrophages and stimulated with a molecule called LPS, they stop proliferating. By taking a close look at these CD4 helper T cells and macrophages the researchers could better understand proliferating and non-proliferating models.