Histone Modification Regulates Gene Expression

Researchers investigating gene regulation have identified a process called ‘trans-tail' regulation of histone modification, which is based on the ubiquitin protein that operates through concerted histone modifications on distinct histone tails. The study was published June 23, 2002, in the online version of Nature.

Histones are proteins that along with DNA form the structure of chromatin, where additional levels of gene regulation occur outside the DNA itself. Chromatin is modified by the addition or removal of chemical groups from the histones. The four major types of histones each have a long protein "tail” which "wags” outside the surface of the chromatin fiber.

Ubiquitin is a small, 76-residue protein found both as free monomer in eukaryotic cells and covalently attached to itself and other proteins. The C-terminus of ubiquitin forms an isopeptide bond with the amino group of a lysine side chain in a target protein. In this way proteins can be covalently modified by the addition of ubiquitin, which may alter the target protein's function.

In the current study, investigators from the University of Virginia (Charlottesville, USA) showed that the ubiquitin-conjugating enzyme Rad6 (Ubc2) mediates methylation of histone H3 at lysine 4 (Lys 4) through ubiquitination of H2B at Lys 123 in yeast (Saccharomyces cerevisiae). Moreover, H3 (Lys 4) methylation is abolished in the H2B-K123R mutant, whereas H3-K4R retains H2B (Lys 123) ubiquitination.

Discovery of this mechanism, referred to as ‘trans-tail' regulation, indicates that the modification of the tail of one histone unit could affect what occurs on the tail of another.

"It means we have to start looking at how the whole group of these histone proteins functions together as a unit, as well as individually,” said C. David Allis, professor in the department of biochemistry and molecular genetics and co-author. "If the ubiquitin chemical flag seems to govern methylation of lysine at K4, but not elsewhere, there is a selectivity going on, and it is remarkably more complicated than we thought. We would like to find out what it is about ubiquitin that causes such a dramatic influence on histone methylation.”




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