vollum institute may unlock human genome
From: zipzip (mcpucho_at_hotmail.com)
Date: 12/30/04
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Date: 30 Dec 2004 00:26:47 -0800
http://www.ohsu.edu/news/2004/122804genome.html
VOLLUM INSTITUTE DISCOVERY MAY UNLOCK HUMAN GENOME
Goodman laboratory devises technique to explain patterns of gene
regulation
Take a look at the Genome Study Home Page for more information on this
story
PORTLAND, Ore. -- An Oregon Health & Science University-led development
of a technique for identifying control elements that drive the
expression of genes in brain cells could unleash the disease-fighting
potential of the much-hailed human genome.
Scientists at the OHSU Vollum Institute, which headed the
multidisciplinary study appearing in the Dec. 29 edition of the journal
Cell, are calling the approach a significant advance in understanding
the genome.
The Vollum's director, Richard Goodman, M.D., Ph.D., professor of
cell and developmental biology, and biochemistry and molecular biology,
OHSU School of Medicine, said the technique could give a critical boost
to the new era of genomic discovery set forth when the Human Genome
Project was completed early last year.
"The question was how to understand the enormous amount of genomic
information that has been generated," Goodman said. "Our approach
will help unlock the regulatory control of the genome."
The approach could heighten understanding of the pathways behind
genetic aberrations that cause diabetes, Parkinson's disease, heart
disease, cancer and other diseases, he said.
The Vollum team's technique, developed in collaboration with
scientists at Brookhaven National Laboratory in Upton, N.Y., and State
University of New York, Stony Brook, resulted from an effort by Soren
Impey, Ph.D., in Goodman's laboratory to characterize a family of
genes regulated by the "cAMP response element binding" protein, or
CREB. This well-characterized molecule is among a group of proteins
called transcription factors that interact with regulatory elements in
DNA that are responsible for increasing or decreasing the level of gene
expression in cells.
The technique involves linking DNA from a cell with the transcription
factor protein, then isolating the complex through a process called
immunoprecipitation. Strips of 21-nucleotide-long DNA are then released
from the immunoprecipitated DNA to create "genomic signature tags,"
which are then identified in the international genome database. The
method uncovered about 6,300 regulatory regions that mapped to distinct
sites on the genome.
"A subset of these regions highlight novel genes," said Impey,
assistant professor of neurology, OHSU School of Medicine, and the
study's lead author.
Goodman calls the process "the most comprehensive analysis to date in
a metazoan system - that is, a multicellular system - of where
transcription factors bind to their genomic targets." It gives
scientists a system for mining the entire genome for all the regulatory
sites involving a given transcription factor protein.
"You can start to put together a transcriptional map of pathways that
are involved in cellular function," he said. "In the past, it's
only been possible to look at a very small part of the genome, but now
we can look at the whole thing. It's a big step forward."
David Ginty, Ph.D., professor of neuroscience at The Johns Hopkins
University School of Medicine in Baltimore, studies molecular control
of growth and survival of neurons in the developing vertebrate nervous
system as a Howard Hughes Medical Institute investigator. He said the
challenge to exploiting the human genome has been to uncover the
relationships between identified genes and to understand how complex
patterns of gene expression take place.
But the Goodman lab's discovery, Ginty said, will help scientists
understand how transcription factors coordinate complex genetic
patterns and, therefore, how different cells are made and how they
function.
"The study establishes a beautifully simple approach to identifying
mechanisms of complex genomic control," he said. "The method should
prove useful for establishing how sets of genes are turned on or off in
any given cell type, and how cellular and functional diversity is
achieved."
Exploration of the humane genome has been frenzied since the
International Human Genome Sequencing Consortium, led in the United
States by the National Human Genome Research Institute and the
Department of Energy, and The Institute for Genomic Research (TIGR), a
private genome sequencing company, announced the completion of the
Human Genome Project more than two years ahead of schedule in April
2003. Between 20,000 and 25,000 genes coding for proteins that perform
most life functions were found. But there was a problem.
"That's not very many genes," Goodman said. "And so, in a
sense, declaring the genome solved was somewhat arbitrary because
it's solved when you really understand it. If you look at the genome,
or the database that the genome provided, what you have is a bunch of
letters and it has to be decoded to understand what those letters
mean."
Goodman compared the genome to a phone book in which the names were
interspersed "with a lot of nonsense letters," and the names
themselves were broken into pieces. "And rather than having 26
letters, there are only four, and they're all mixed up," he said.
"It's hard to know where the genes start and stop."
Said Impey: "Although the Human Genome Project identified about
25,000 protein-coding genes, the instruction set that regulates these
genes is, for the most part, unknown. This is important because what
makes a cancerous cell different from a noncancerous cell is the set of
genes that are turned on or off. These instructions or regulatory
regions are believed to be far more numerous than genes, but it was not
clear how to identify them.
"We developed a novel technique that is able to isolate a
comprehensive set of regulatory regions and map them to the entire
genome. Our work will help unravel the genomic instruction set that
governs how genes are regulated in a given cell type. If one views the
genome as a multidimensional puzzle, our method helps make the puzzle a
little simpler."
The discovery already has demonstrated its implications for human
diseases. Goodman's lab is working with the OHSU Cancer Institute on
a cancer-causing oncogene that arises when a rearrangement of
chromosomes generates an abnormal transcription factor. "If you had a
technique that would allow you to take that factor and identify what
its targets are, you would understand why that oncogene causes
cancer," Goodman said.
Another project is examining a transcription factor involved in the
differentiation of dopamine-producing cells. By identifying the targets
of the transcription factor, stem cells differentiated as dopamine
cells could be developed to treat Parkinson's disease.
And a project with Markus Grompe, M.D., of the OHSU Oregon Stem Cell
Center is studying the transcription factor involved in pancreatic beta
cell differentiation.
"This is a factor that drives the expression of insulin, but also
other differentiated properties of a beta cell, so if we can identify
all those targets, we'll understand something about the nature of the
development of a beta cell," Goodman said.
Ginty, of The Johns Hopkins University, said the future could even hold
answers to such questions as how a neuron in the brain stores
information that forms the basis of memory.
"The future of genome exploration will bring an understanding of how
the genome is controlled to yield different cell types of the body and
their various functions," he said.
In addition to Goodman and Impey, study collaborators included: Hyunjoo
Cha-Molstad, Jami Dwyer and Gregory Yochum, Vollum Institute; Sean
McCorkle and John Dunn, Brookhaven National Laboratory; Jeremy Boss,
Emery School of Medicine; Shannon McWeeney, OHSU; and Gail Mandel,
State University of New York,
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