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Topic Name: New mechanism of gene control
Category: Genetic Engineering
Research persons: Richard Young,Stuart Levine and Matthew Guenther
Location: Whitehead Institute,9 Cambridge Center,Cambridge, MA 02142, United States
Details
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 MIT biology professor and Whitehead Institute 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. "It seems awfully risky
for an adult cell to leave genes primed that could change its identity."
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 explain why some cells acquire new, unhealthy states in cancer, autoimmune
diseases, diabetes and other illnesses.
It could also explain why researchers--including MIT biology professor and
Whitehead member Rudolf Jaenisch, who is also an author of 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."
About Researchers:
Richard Young-Member, Whitehead Institute
Professor of Biology, MIT
617.258.5218
young@wi.mit.edu
Rudolf Jaenisch, MD
Member, Whitehead Institute
Professor of Biology, MIT
617.258.5186 phone
617.258.6505 fax
kemske@wi.mit.edu
Funded:
This research is funded by the National
Institutes of Health.
In The Images-
Microarrays (such as this one) helped researchers pinpoint the location of important landmarks on the genome &Whitehead postdoctoral students Stuart Levine and Matthew Guenther ,
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