May 08, 2005
Discovery Illuminates Surprising Flexibility of Chromosomes
For the first time, scientists have shown that a genetic element on
one chromosome may direct gene activity on another chromosome. Howard
Hughes Medical Institute (HHMI) researchers report that a multi-tasking
master control region appears to oversee both a set of its own genes
and a related gene on a nearby chromosome.
"In the past, people have thought that chromosomes acted
independently," said senior author Richard Flavell, an HHMI
investigator at the Yale University School of Medicine. "Now it's
possible that regulatory regions on one chromosome can facilitate
expression of genes on another chromosome."
“In the past, people have thought that chromosomes acted independently. Now it's possible that regulatory regions on one chromosome can facilitate expression of genes on another chromosome.”
Richard A. Flavell
The researchers report in an advance online publication on May 8,
2005, in the journal Nature, that evidence of a strong physical
connection between two mouse chromosomes at a key region transforms an
immature immune cell into one that can fight an invading pathogen.
The researchers believe this neighborly association may turn out to
be common among many closely coordinated genes that must work together
in different parts of the body. Occasionally, such chromosomal intimacy
could lead to inadvertent gene swapping, which could explain certain
cancers caused by translocated genes, the researchers speculate.
The discovery came from studies of immune cells that patrol the body
for signs of infection. Naïve T cells circulate through the blood
and lymph nodes until they reach a node where another immune cell is
waiting with a matching antigen. This message calls the T cell to
battle.
The signal triggers genetic activity that converts a naïve T
cell into one of two types of helper cells armed with strategic
molecular weapons for different situations. One type, T-helper-cell 1
(TH1), activates interferon-gamma to help kill cells that have been
taken over by harmful bacteria or viruses. The other, T-helper-cell 2
(TH2), turns on interleukin-4 and other cytokines to destroy germs
roving between cells.
On chromosome 11, the interleukin cytokines made by TH2 are spaced
widely apart, but they are kept primed for action by one master control
region on the same chromosome. Last year, researchers in Flavell's lab
found that the control region and the genes were juxtaposed in the cell
nucleus. Somehow, the chromosome contorted to bring all the genetic
elements together.
Now, first author Charalampos "Babis" Spilianakis, a postdoctoral
fellow in Flavell's laboratory, reports a similarly close connection
between the same TH2 cytokine master control region on chromosome 11
and the start of the interferon-gamma gene on chromosome 10.
"We don't yet know the mechanism of interaction," Spilianakis said.
Certain sections of chromosomes likely to be needed by the cell may
gather together at different spots in the nucleus, ready and waiting
for signals that activate their genes, he suggested.
To pinpoint the proximity of the chromosomes, Spilianakis used a
powerful new technique developed by other researchers called chromosome
conformation capture. He captured a freeze-frame of naïve CD4
cells in a test tube with formaldehyde. Then, he used an enzymatic
scalpel to extract DNA in the immediate vicinity of the cytokine
control region on chromosome 11. Subsequent genetic analysis revealed
its coziness with the interferon gene on chromosome 10.
The team used a fluorescent technique to confirm that the consorting
chromosomes were linking their DNA. "We think the TH2 control region on
one chromosome regulates interferon-gamma on the other chromosome,"
Spilianakis said. The relationship between the chromosomes falls apart
when the T cells have differentiated into helper cells, he said.
The researchers suspect the temporary chromosomal closeness keeps an
essential set of genes on standby for rapid response.
The findings reinforce the growing importance of location for gene
activity within the nucleus, Spilianakis said. Large loops of
chromosomes containing active genes can extend outside of the usual
location of a chromosome in the nucleus, other researchers have found.
Other evidence suggests that regulatory elements may act by
repositioning genes and their control regions to more active
transcription spaces within the nucleus.
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