[Paleopsych] Histones exert epigenetic control

[Steve Hovland]

Two Papers Broaden Understanding of Epigenetic Control
 by Jeremy Cherfas

http://www.sciencewatch.com/may-june2003/sw_may-june2003_page8.htm

Genes are controlled in at least two distinct ways. One is the
sequence-specific switches that enable regulatory elements to control
individual genes by interacting with set stretches of DNA associated with
that gene. The other is known as epigenetic regulation, because although it
is heritable, it seems to operate independently of the DNA sequence. Two Hot
Papers offer an insight into the workings of one part of epigenetic
regulation.

      Epigenetic control is exerted through histones, proteins that are
intimately associated with DNA, much of which wraps around histones to form
the chromatin of chromosomes. In 1993 Bryan Turner, professor of
experimental genetics at the University of Birmingham Medical School in the
U.K., put forward the idea that chemical modifications to the tails of the
histone proteins created a code, somewhat like the DNA code, that regulatory
elements could read and act upon. This histone code hypothesis, as it was
named in 2000 by C. David Allis, of the University of Virginia School of
Medicine, Charlottesville , finds confirmation in the papers at #4 and #5.
"Something is writing this code," Allis has said, "and something is reading
this code."

     The papers, from groups led by Tony Kouzarides of the University of
Cambridge and by Thomas Jenuwein of the Research Institute of Molecular
Pathology in Vienna, Austria, focus on methylation. This represents a shift
from earlier work, which looked at the more common phenomenon of histone
acetylation. Shiv Grewal, of the Cold Spring Harbor Laboratory, New York ,
had previously shown that in the budding yeast Saccharomyces pombe, two
proteins are crucially important to epigenetic control. Swi6 is needed both
to silence a stretch of DNA and to maintain the inactivation through cell
divisions. Swi6 also needs Clr3, which de-acetylates histones, to keep
inactive DNA silent. A related protein, Clr4, methylates histones.

     The mammalian equivalent of Swi6 is known as HP1, while the equivalent
of Clr4 is known as SUV39H1. Using almost identical techniques the two
groups showed that HP1 proteins, which have long been implicated in
gene-silencing and the structure of DNA-histone complexes, would bind to
histone H3 if the lysine amino acid at position 9 were methylated, but not
if the nearby lysine-4 is methylated, nor if the lysine-9 is unmethylated.
To prove the functional significance of these events Kouzarides’s group
looked at a mutant of Clr4 in yeast. This mutant lacked the ability to
methylate the lysine-9 of H3. As a result, Swi6 did not bind to the H3, and
as a result of that a normally silent marker gene was expressed. Jenuwein’s
group used mouse cells that lacked SUV39H1 in the same search for proof.
These knockout cells did not form the histone-DNA complexes until they were
given a functional version of the SUV39H1 mouse equivalent gene.

     Both groups agree on the picture that emerges from their data. SUV39H1
comes along and places a marker methyl group on lysine 9 of histone 3. This
marker attracts the attention of HP1. Thus SUV39H1 writes at least this part
of the histone code, and HP1 reads it. But HP1 itself contains a domain that
binds with SUV39H1, which is then in a position to place a methyl marker on
the next H3 histone. Like the structure of the DNA double helix itself,
published exactly 50 years ago at this writing, this arrangement is highly
suggestive. Says Kouzarides, it offers "a mechanism for epigenetic events to
be passed on to the next generation."

     Bryan Turner, originator of the histone code hypothesis, does not
begrudge these two papers their moment in the limelight. "I’m absolutely
delighted," Turner tells Science Watch. But he points out that  they were
"pushing at an open door." By that, Turner means that much of the evidence
was already in the literature, albeit in scattered form and not linked
together. These results were just what everyone wanted, Turner said, himself
included, and "that’s why they are so highly cited." Turner is also
convinced that things are going to prove much more complicated than this
first, "shiny example" of a complete specific sequence of events
underpinning epigenetic control.

     One of the exciting aspects of epigenetic control is that it probably
underlies the long-term differentiation of cells. At the start of
development, genes are switched on and off according roughly to their
position in the developing embryo. As differentiation proceeds, however, a
cell’s pattern of activity becomes fixed and is passed on to daughter cells
in a stable manner. To begin with, a cell might become either liver or
muscle, but thereafter liver cells remain liver cells, while muscle cells
remain muscle cells. The ability to manipulate, and possibly even reverse,
this type of differentiation could be the key to new approaches to disease.