Researchers at the Salk Institute for Biological Studies and University of California, San Diego (UCSD) School of Medicine uncovered evidence of the link when studying the roles DNMT3A and TET2 mutations play in the formation of new blood cells. The study linked abnormal inflammatory signaling related to DNMT3A and TET2 deficiency with the development of atherosclerosis, the thickening or hardening of the arteries seen in people with cardiovascular disease.

To understand the mechanistic link between the genes and atherosclerosis, the UCSD researchers collaborated with Gerald Shadel, PhD, director of the Salk Institute's San Diego Nathan Shock Center of Excellence in the Basic Biology of Aging, who had previously looked at the same inflammatory pathway while examining responses to mitochondrial DNA stress. Working with Shadel, the UCSD team showed why DNMT3A and TET2 mutations led to inflammatory responses and ultimately atherosclerosis.

"We found that the genes DNMT3A and TET2, in addition to their normal job of altering chemical tags to regulate DNA, directly activate expression of a gene involved in mitochondrial inflammatory pathways, which hints as a new molecular target for atherosclerosis therapeutics," Shadel said in a statement.

In a study published on August 4 in the journal Immunity, Shadel, UCSD's Dr. Christopher Glass, PhD, professor of cellular and molecular medicine, and their collaborators describe how DNMT3A and TET2 maintain mitochondrial DNA integrity by regulating expression of the TFAM gene. Loss of DNMT3A and TET2 function leads to the release of mitochondrial DNA, activation of cGAS signaling and, in turn, to a type I interferon response.

The work built on Shadel's earlier discovery that mitochondrial DNA is expelled from mitochondria into the cell's interior when TFAM levels are reduced. The presence of mitochondrial DNA in the cell's interior triggers an immune reaction, as would happen in the presence of a pathogen, and an associated inflammatory response. The new study showed DNMT3A and TET2 interact with RBPJ and ZNF143 to regulate the expression of TFAM and, in doing so, prevent the release of mitochondrial DNA.

"We discovered that DNMT3A and TET2 mutations prevent their ability to bind and activate the TFAM gene," said Isidoro Cobo, first author of the study and a postdoctoral scholar in Glass' lab. "Missing or reducing this binding activity leads to mitochondrial DNA release and an overactive mitochondrial inflammation response. We believe this may exacerbate plaque buildup in atherosclerosis."

Based on the findings, the researchers speculated that there may be therapeutic value in targeting the cGAS-type I interferon pathway in patients with DNMT3A or TET2 mutations. Targeting the pathway may reduce the risk of cardiovascular disease.