Feb. 18, 2002 CHAPEL HILL - New research in yeast cells may have pinpointed a key enzyme in the molecular circuitry that silences genes. The new enzyme, Set2, could prove critical for helping regulate gene expression in the ordered cycle of growth and division common to all living cells that have a nucleus. Thus, it may play an important role throughout life, beginning with early development, in gene regulation.
The research could also have consequences for the design of new targeted treatments for human diseases, including cancer, according to Dr. Brian D. Strahl, assistant professor of biochemistry and biophysics at the University of North Carolina at Chapel Hill School of Medicine. Strahl, the report's principal author, conducted the study while a postdoctoral researcher in the University of Virginia laboratory of senior co-author Dr. C. David Allis.
"The findings add to our knowledge of a basic and very important process and could offer new insight as to why certain genes in cancer are inappropriately expressed and how that might be corrected," Strahl said.
The new report is published in the March 2002 edition of the journal Molecular and Cellular Biology and on the journal's Web site (see below).
The process referred to by Strahl involves chromatin, a multifolded, ribbon-like complex of DNA wrapped around histone proteins. This class of proteins is one of the most highly conserved, appearing in all organisms having nucleated cells. While chromatin packaging allows for efficient storage of genetic information, it also impedes access to DNA by transcription factors, proteins that regulate gene expression.
Among the biochemical modification mechanisms that can dynamically change chromatin's structure - its loosening or tightening - is histone methylation. This modification mainly occurs on lysine residues, one of the amino acids that comprise the tail region of histone molecules.
Recent research at UNC and elsewhere has linked gene silencing, or deactivation, to methylation of particular lysines on the amino acid tail of the histone H3 molecule.
"The identity of any enzyme responsible for this modification was unknown until a few years ago when the first lysine 9-specific histone methyltransferase was identified," said Dr. Yi Zhang, a UNC biochemistry colleague of Strahl's. In December 2001, Zhang reported (in Molecular Cell) having identified the enzyme Set7, which modifies lysine 4 on histone H3 in mammalian cells. By methylating H3 at lysine 4, Set7 makes the chromatin structure more open, so other proteins can access the gene.
In the latest study, Strahl and co-authors described the identification and characterization of Set2, a novel histone methyltransferase that is site-specific for lysine 36 of the H3 tail. Set2 is responsible for methylation at this site. However, the researchers noted that in doing so "it helps to represses or silence gene transcription." Thus, according to Strahl, Set2 might be "a co-regulator of transcription" in the sense that it turns genes "off" instead of "on" as in the case of Set7.
"During development, you have different sets of genes that are important for, say, limb formation, and when the limbs are completed, the genes responsible for them must be turned off," Set2 may thus represent an "off switch" for gene regulation in cells.
In addition, Strahl said this modification could be part of an emerging 'molecular code' of histone modifications that ultimately regulate these processes.
"We believe that methylation and other modifications that affect histone proteins (acetylation, phosphorylation) are all dynamically involved and play critical roles in gene activation and deactivation at the appropriate times."
This process, he explains, possibly could work by the ability of these modifications to bring in additional proteins that result in opening or closing of the chromatin molecule. Further work might reveal the partners that interact with this enzyme, some of which may already be well studied, Strahl said. "Lysine 36 is much deeper into the histone tail than the other lysines that have captured so much recent attention. Although it's still not well understood, we now have some molecular insights into what this modification is doing."
This study was supported by grants from the National Institutes of Health.
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