In mice, DAXX keeps virus-like DNA repeats silenced in microglia, the brain’s immune cells; removing it causes inflammation and signs of cellular senescence

In mice, DAXX keeps virus-like DNA repeats silenced in microglia, the brain’s immune cells; removing it causes inflammation and signs of cellular senescence

On August 17, Nature Neuroscience published a study in which the authors conditionally deleted the Daxx gene in adult mice and tracked the resulting cellular changes. They examined how this deletion affected DNA packaging and the state of microglia.

Mammalian DNA contains repetitive fragments derived from ancient retroviruses. Cells normally keep these fragments silenced by packaging the DNA tightly. In microglia, this process depends on DAXX, a protein that suppresses these virus-like repeats. In mice, DAXX levels declined with age both in the brain and in isolated microglia. In human blood, higher DAXX gene activity was associated with lower activity in nearly every type of retroelement examined.

To establish the sequence of events, the researchers deleted Daxx in young adult mice. LTR retroelements, one type of virus-like DNA repeat, became active within the first few days. Some of these regions lost H3K9me3, a chemical mark that helps maintain tightly packaged DNA. The microglia then activated the interferon program, a set of genes that cells turn on in response to a viral threat, along with other inflammatory genes. The cells lost features of their resting state, and damage appeared in their DNA.

Later, the number of microglial cells declined, and some of the remaining cells showed signs of senescence, a state in which a cell undergoes lasting changes in its activity. The authors separately tested the role of PML, a protein that helps maintain this state. When both Daxx and Pml were deleted, fewer cells tested positive for senescence in a laboratory assay by the eighth week, and more microglial cells remained. Measures of synapses, the connections between nerve cells, declined during the first few weeks, and behavioral tests detected changes in the mice by the eighth week.

In this mouse model, loss of DAXX initiates a sequence of changes. Retrotransposons are released from tightly packaged DNA, microglia enter an interferon state, and DNA damage and PML-dependent signs of senescence subsequently appear. The study links the age-related decline in DAXX to a specific sequence of changes in the brain’s immune cells.