Newly Identified Enzyme Orchestrates Access to Genes for Transcription

At any given time, most of the roughly 30,000 genes that constitute the human genome are inactive, or repressed, closed to the cellular machinery that transcribes genes into the proteins of the body. In an average cell, only about one in ten genes is active, or expressed, at any given moment, with its DNA open to the cell’s transcriptional machinery.

A dynamic cast of gatekeeper enzymes controls this access to the DNA, adding and removing particular molecules to open or close the genome to transcription as needed. Fully explicating the complex interplay among these enzymes and the molecules they manage has been a primary goal for scientists seeking to understand the mechanisms governing gene control. These mechanisms are vital for health – when they go wrong, diseases like cancer can result.

In study published February 22 in Cell, researchers at the Wistar Institute, Philadelphia (USA) identifiy an important new player in this gene-control system, an enzyme responsible for removing certain molecules, or marks, involved in opening or closing chromatin, the material that makes up chromosomes. The activity of this enzyme thought to be widespread in the genome, likely affecting many genes.

“This enzyme removes methyl groups on lysine 4 of histone H3 which is required to open the chromatin for gene expression, and therefore this enzyme maintains a repressed state of gene expression,” says Ramin Shiekhattar, Ph.D., professor at The Wistar Institute and senior author on the Cell study. Currently, Shiekhattar is also an ICREA professor at the Centre for Genomic Regulation in Barcelona, Spain. “When the enzyme is not present, however, the marks remain in place, and the chromatin is open for transcription.”

The enzyme, called JARID1d, is the first identified member of a new family of enzymes that removes trimethylation at histone H3 lysine 4, a critical components of open chromatin. In mammalian genomes, trimethyl groups at this location have been known to be associated with gene activation. Shiekhattar and his team hypothesized the existence of an enzyme that would remove these trimethyl groups.

“We and others had wondered whether there might not be an enzyme able to remove these trimethyl marks,” says Shiekhattar. “Such an enzyme would have the effect of setting the genes back to their original repressed state.”

An important aspect of Shiekattar’s and colleagues’ work is their demonstration of the intimate connection of JARID1d and Ring6a, a polycomb-like protein. Indeed, they show that Ring6a has the ability to regulate the enzymatic activity of the histone demethylase in vitro as well as in vivo. These results extend the role of transcriptional inhibitory polycomb complexes through their physical and functional link with histone demethylase enzymes.

The research was supported by grants from the National Institutes of Health and the Commonwealth Universal Research Enhancement Program of the Pennsylvania Department of Health.