Cells take risks with their identities
CAMBRIDGE, Mass. (July 12, 2007) — Biologists
have long thought that a simple on/off switch controls
most genes in human cells. Flip the switch and a cell
starts or stops producing a particular protein. But
new evidence suggests that this model is too simple
and that our genes are more ready for action than previously
thought.
Scientists in the lab of Whitehead Member Richard
Young have discovered that many human genes hover between “on” and “off” in
any given cell. According to the study, which appears
online in Cell on July 12, these genes begin
making RNA templates for proteins—a process termed
transcription—but fail to finish. The templates
never materialize, and the proteins never appear.
“Surprisingly, about one-third of our genes, including
all the regulators of cell identity, fall into this new
class,” says Young, who is also an MIT professor
of biology. “It seems awfully risky for an adult
cell to leave genes primed that could change its identity.”
“This is a new model for regulation
of the developmental regulators,” says
Whitehead Member Richard Young. “It
could bring us a step closer to reprogramming
cells in a controlled fashion, which has important
applications for regenerative medicine.” |
The human body comprises more than 200 types of cells.
Each cell contains the same complete set of genes,
but expresses only a unique fraction of them, churning
out proteins that make it a nerve or skin or white
blood cell. Scientists have known for years that a
cell hides the genes it doesn’t need by coiling
the dormant DNA tightly around protein spools called
histones. The new study, however, suggests that DNA
packaging stays loose at the beginning of many inactive
genes, contrary to textbook models.
Whitehead postdoctoral researchers Matthew Guenther
and Stuart Levine screened the entire human genome
for a chemical signature—a landmark—that
corresponds with this looser DNA packaging configuration
and thus with transcription initiation. They worked
with embryonic stem cells, liver cells and white blood
cells.
“We expected to find the landmark on 30 to 40
percent of the genes because that’s how many
are active in each cell,” Guenther says. “We
were shocked when it showed up on more than 75 percent
of the genes in both unspecialized embryonic stem cells
and specialized adult cells.”
Further experiments confirmed that the majority of
inactive genes undergo “transcriptional tryouts.” They
begin making RNA, but never complete the job. Apparently,
most of an inactive gene remains tightly coiled around
histones, which prevent the RNA transcriptional machinery
from progressing along the DNA.
“These genes are like cars revving their engines
before the beginning of a race,” Guenther explains. “They’re
not parked in a garage with their engines off. They’re
at the starting gate, waiting for a flag that says ‘go.’”
These overzealous “cars” include all the
genes responsible for directing cells along particular
developmental paths—master regulators that should
have no reason for gearing up in healthy specialized
cells. Activating such genes might cause a cell to
assume new properties. This vulnerability to metamorphosis
could help to explain why some cells acquire new, unhealthy
states in cancer, autoimmune diseases, diabetes and
other illnesses.
It could also explain why researchers—including
Whitehead Member Rudolf
Jaenisch, who is also an author
on the latest study—were recently able to convert
mouse adult skin cells to embryonic stem cells by simply
introducing four key genes. Given the right signals,
inactive developmental regulators primed for transcription
could roar to life.
“This is a new model for regulation of the developmental
regulators,” Young maintains. “It could
bring us a step closer to reprogramming cells in a
controlled fashion, which has important applications
for regenerative medicine.”
This research is funded by the National Institutes of
Health. |
