Waves of changes in genome structure in immune response

Researchers find waves of changes in histones in active immunity

A collaborative project by scientists across Japan including Kyoto University report that a series of temporal events in the nucleus occur in an immune cell during the response to an infection.

The findings, which can be read in Genome Biology , suggest that transcription factor binding and histone modifications coordinate in waves to activate an immune response.

DNA must fit inside a space just a few microns long, which is more than 10 times smaller than the width of a single strand of hair. If unwrapped, that same DNA would be more than 2 meters long. For a gene to be activated or deactivated, the DNA must structurally change.

“We know that transcription factors regulate epigenetic changes. The binding of transcription factors induces histone modifications to activate gene expression,” explains first author Alexis Vandenbon from Kyoto University's Institute for Frontier Life and Medical Sciences. “There is still much to learn about the temporal relationship between transcription factor binding, histone modifications, and gene expression.”

Gene expressions are especially important for immune cells, which must react in the presence of a pathogen, but lay dormant in its absence. Abnormal epigenetic changes can result in autoinflammation or other immune diseases.

Vandenbon and his colleagues decided to study epigenetic changes in dendritic cells, a major cell type in the immune system. It is known to respond to stimulation with lipopolysaccharides, or LPS, a large molecule commonly found on the surface of bacteria.

The study shows that three types of histone modifications, H3K9K14ac, H3K4me3, and H3K36me3, appear in sequential waves at specific time points following the stimulation. H3K9K14ac is one type of acetylation of histone proteins, while H3K4me3 and H3K36me3 are methylations.

H3K9K14 was consistently increased between 30 min and 2 hours after the stimulation, H3K4me between 1 and 4 hours, and H3K36me3 between 8 and 24 hours.

“We found the waves of histone modifiers correlated with STAT1 binding,” said Vandenbon.

STAT1 is a transcription factor that has a fundamental role in immunity, and H3K9K14ac and H3K4me3 were increased around DNA sites to which STAT1 bound. Disrupting STAT1 binding in dendritic cells terminated the waves. This suggests that STAT1 is controlling the place and time of the changes in histone modifications.

The findings indicate to Vandenbon that for immune cells to attach a pathogen, a clear order of events at the nuclear level must occur.

“These waves were only seen in genes activated by lipopolysaccharide. It could be that a proper immune response depends on a series of specific molecular events that operate on a strict time scale,” he says.