A poorly understood histone modification has been shown to be a more sensitive predictor of gene expression switches than any other tested modification. The finding, revealed by an A*STAR study, provides a new tool for studying gene regulation and could lay the groundwork for a better understanding of disease.
The two meters of DNA in the nucleus of every human cell is tightly wrapped around proteins called histones. If specific sites on these histones are chemically modified, for instance acetylated, these sites can mark interesting DNA regions, including enhancers that stimulate the expression of genes.
Scientists know of over 35 histone acetylation sites but have mostly focused on only two, called H3K27 and H3K9. Shyam Prabhakar from the A*STAR Genome Institute of Singapore calls this narrow focus a “historical accident”. “Their importance was recognized in some seminal papers, but then most genomics researchers looked no further,” he explains.
Prabhakar was not convinced these sites painted a complete picture for genome-wide expression studies, such as those conducted by the International Human Epigenome Consortium.
In this study, Prabhakar’s team led by Vibhor Kumar performed 140 different assays on human immune cells, each of which tested the activity of a candidate enhancer. “We said: Let’s be unbiased — which chemical modification is really telling us about enhancer activity?” Prabhakar recalls.
The scientists compared how well 40 different histone modifications associated with these active enhancers, as a test for how well they might predict unknown enhancers.
The result surprised Prabhakar’s team: they discovered a previously little-known modification — H2BK20 acetylation — predicted enhancer activity better than any other site.
Prabhakar says this acetylation site could help reveal a new dimension of gene regulation specific to different cell states and could complement the information provided by other modifications. “We will be using it, and we hope others will use it, to find a larger set of enhancers and to identify interesting promoters,” he says.
Prabhakar is also excited about the possibility that H2BK20 may be a more sensitive readout of the cellular processes underlying human disease. His team will now investigate by comparing H2BK20 acetylation profiles of diseased and healthy tissue.
“We really need a mechanistic understanding of how all of these different histone acetylations change in disease and how that can be modulated with drugs to carry therapeutic effects,” says Prabhakar.
As drugs that modulate acetylating enzymes are already used to treat diseases such as cancer, Prabhakar says he is quite confident that this will be a productive direction.
The A*STAR-affiliated researchers contributing to this research are from the Genome Institute of Singapore.