Although letters representing the three billion pairs of molecules
that form the ?rungs? of the helical DNA ?ladder? are routinely called the
human ?genetic code,? the DNA they comprise transmits traits across
generations in a variety of ways, not all of which depend on the sequence of
letters in the code.
In some cases, rather than the sequence of ?letters,? it is the
physical manner in which DNA is spun around protein spools called histones
and tightly packed into chromosomes that determines whether or with what
intensity specific genes are expressed. A team of scientists at Cold Spring
Harbor Laboratory (CSHL) has solved another in a series of mysteries about
this critical mechanism of gene expression, described in a paper in the
April 8 issue of Current Biology.

Inherited Clumping
According to CSHL professor Rob Martienssen, Ph.D., who led the
research team, about a tenth of our DNA stands aloof, spending its time in
tightly packed clumps called heterochromatin, and unwinding only to
replicate when a cell divides. After copying, both of the resulting DNA
molecules ? to the surprise of many ? have been observed to form reclusive
clumps in the same places as the original one did.

This inherited clumping of DNA, which causes genes to be expressed in
distinctive ways, is one of a series of phenomena that scientists call
epigenetic. The same sequence of nucleotides in two people can produce
different patterns of gene expression if the way the DNA is clumped happens
to be different.

Probing Epigenetics in Yeast
?We have not understood epigenetic inheritance very well,? says Dr.
Martienssen, a plant geneticist and one of the pioneers in the study of
epigenetics. To explore this process, he and his team are studying the way
DNA is packed in yeast, and how this packing can be transmitted across
generations. The single-cell yeast organism is easy to study, in part
because it lacks other epigenetic inheritance mechanisms, such as chemical
modifications of DNA, that complicate the study of more complex animals and
plants.

Long DNA molecules almost miraculously cram into cell nuclei that are
almost a million times smaller than they are. They do so by wrapping around
proteins called histones, which array themselves along the length of the DNA
molecule like beads on a string. These DNA-wrapped histones then form larger
arrays. The densely packed mass is then modified chemically by other
proteins to form heterochromatin.

The dense packing of heterochromatin hides the DNA sequence from the
cellular machinery that reads its genetic information, so the DNA in
heterochromatin is ?silenced.? The genes it contains are effectively turned
off.

Surprisingly, the clumping persists even after cells divide, although,
says Dr. Martienssen, ?it?s always been a mystery how modifications of
histones could be inherited.? A few years ago, however, his group and others
solved this mystery. They found that histone modification is controlled by
complicated cellular mechanisms broadly known as RNA interference, or RNAi.

In RNAi, RNA that is copied from particular regions of DNA interacts
with various proteins to modify histones in the same regions. Because the
RNA matches only the section of DNA that produced it, it ?provides the
specificity that you need to make sure that only that part of the chromosome
gets these histone modifications,? Dr. Martienssen says. ?If the whole
chromosome were to get those histone modifications, you?d be dead.?

All in the Timing
These results raised a new puzzle, though: Since genes contained
within heterochromatin are silenced, how can they give rise to the RNA
molecules that help to modify histones? In new research, Martienssen?s team
has now solved this puzzle by tracking the cells through their cycle of
growth and division.

They found that the interfering RNA molecules appear only during the
brief part of the cell cycle when DNA is replicating. This result,
Martienssen says, ?neatly accounts for the paradox about how ?silent?
heterochromatin can be transcribed [into interfering RNA], because it?s
transcribed only in a narrow window of the cell cycle.?

The researchers also found that RNAi varies strongly with temperature.
They speculate that this variation is responsible for inherited traits such
as vernalization, the well-known process by which certain plants must be
exposed to low temperatures before they will flower. Indeed, Martienssen
says, there is ?a whole slew of epigenetic phenomena that are sensitive to
temperature.?

?RNA Interference Guides Histone Modification during the S Phase of
Chromosomal Replication? appears in the April 8, 2008, edition of Current
Biology. The complete citation is as follows: Anna Kloc, Mikel Zaratiegui,
Elphege Nora and Rob Martienssen. The paper is available online at:
[www.current-biology.com].

Cold Spring Harbor Laboratory is a private, nonprofit research and
education institution dedicated to exploring molecular biology and genetics
in order to advance the understanding and ability to diagnose and treat
cancers, neurological diseases and other causes of human suffering.


www.cshl.edu.