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Mapping the foundation of human
development
CAMBRIDGE, Mass. (April 20, 2006) — Embryonic
stem cells may one day provide a means to treat disease,
but according to two new reports, they are already revealing
remarkable insights into the mysteries of human biology.
How humans manage to develop from a single fertilized
egg into the trillions of cells that make up a mature
adult remains a poorly understood process. Now, using
both human and mouse embryonic stem cells, researchers
in the Whitehead Institute labs of Richard
Young and Rudolf
Jaenisch, in collaboration with Harvard University's
Douglas Melton and MIT's David Gifford, have mapped
how a key developmental ingredient controls the genome.
The mouse results were published in the April 20 issue
of Nature, and the human results were published
in the April 21 issue of Cell.
"These papers are a major step forward in our
efforts to map the regulatory circuitry of embryonic
stem cells—which constitutes the founding circuitry
of human beings," says Young.
Both papers focus on a set of proteins collectively
called Polycomb group proteins. Previous studies showed
that the Polycomb proteins are essential for early development.
If the genes that code for Polycomb proteins are lost
in embryonic stem cells, the cells begin to develop
in an uncontrolled fashion and lose their unique properties.
Knowing that Polycomb is key to an embryonic stem cell's
identity, Young and Jaenisch realized that catching
it in action as it interacts with all its target genes
would provide an unprecedented look into how stem cells
are wired.
"We're continuing to map the regulatory network
that controls stem-cell state and development,"
says Whitehead Member Richard Young. "We
hope to use this map to guide the fate of cells
so that they can be used to replace diseased or
damaged cells." |
However, such a project raises a daunting question:
How do you scan all 3 billion letters of the genome
to identify several hundred protein/DNA interactions?
It's the biological equivalent of poring over satellite
images of North America to find all the power stations
that power the electrical grid.
Young's lab has developed a suite of microarray tools
that can scan entire genomes in order to locate certain
targeted molecules. However, this is the first time
such technology has been used to scan the entire genomes
of embryonic stem cells.
A group of researchers, led by postdoctoral scientists
Laurie Boyer, Matthew Guenther, Richard Jenner, Tony
Lee, Stuart Levine, and Kathrin Plath applied the technology
to human and mouse embryonic stem cells. "It required
tremendous innovation from this group," says Young.
"Careful handling of embryonic stem cells, designing
the microarrays, analyzing the sheer volume of data
from the human genome—these experiments were technical
feats carried out by an exceptionally talented team
in an interdisciplinary environment."
Polycomb, it turns out, represses entire networks of
genes that are essential for later development, the
same genes that begin to turn on as a stem cell starts
to differentiate. That explains why embryonic stem cells
immediately grow into specialized cells when Polycomb
proteins are lost.
"Polycomb is dynamic," says Jaenisch, "working
with other molecules to silence genes and then gradually
allowing them to activate during development. It is
also the founding ingredient for development, so knowing
how it works and which genes it interacts with will
be invaluable for understanding these amazing cells."
"We're continuing to map the regulatory network
that controls stem-cell state and development,"
says Young. "We hope to use this map to guide the
fate of cells so that they can be used to replace diseased
or damaged cells."
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Written by David Cameron.
To receive a copy of this paper, please contact newsroom@wi.mit.edu.
Full citation
Cell, 125, April 21, 2006
"Control of Developmental Regulators by Polycomb
in Human Embryonic Stem Cells"
Authors: Tong Ihn Lee(1,8), Richard G. Jenner(1,8),
Laurie A. Boyer(1,8), Matthew G. Guenther(1,8), Stuart
S. Levine(1,8), Roshan M. Kumar(1), Brett Chevalier(1),
Sarah E. Johnstone(1,2), Megan F. Cole(1,2), Kyo-ichi
Isono(3), Haruhiko Koseki(3), Takuya Fuchikami(4), Kuniya
Abe(4), Heather L. Murray(1), Jacob P. Zucker(6), Bingbing
Yuan(1), George W. Bell(1), Elizabeth Herbolsheimer(1),
Nancy M. Hannett(1), Kaiming Sun(1), Duncan T. Odom(1),
Arie P. Otte(5), Thomas L. Volkert(1), David P. Bartel(1,2),
Douglas A. Melton(6), David K. Gifford(1,7), Rudolf
Jaenisch(1,2), and Richard A. Young(1,2)
(1) Whitehead Institute for Biomedical Research, 9
Cambridge Center, Cambridge, MA
(2) Department of Biology, Massachusetts Institute of
Technology, Cambridge, MA
(3) Developmental Genetics Group, RIKEN Center for Allergy
and Immunology, Kanagawa Japan
(4) Technology and Development Team for Mammalian Cellular
Dynamics, BioResource Center, RIKEN Tsukuba Institute,
Ibaraki Japan
(5) Swammerdam Institute for Life Sciences, University
of Amsterdam, Amsterdam, The Netherlands
(6) Howard Hughes Medical Institute, Department of Molecular
and Cellular Biology, Harvard University, Cambridge,
MA
(7) MIT CSAIL, 32 Vassar Street, Cambridge, MA
(8) These authors contributed equally to this work.
* * * * *
Nature, Volume 440 Number 7087, April 20,
2006
"Polycomb complexes repress developmental regulators
in murine embryonic stem cells"
Authors: Laurie A. Boyer(1*), Kathrin Plath(1*), Julia
Zeitlinger(1), Tobias Brambrink(1), Lea A. Medeiros(1,2),
Tong Ihn Lee(1), Stuart S. Levine(1), Marius Wernig(1),
Adriana Tajonar(2), Mridula K. Ray(2), George W. Bell(1),
Arie P. Otte(3), Miguel Vidal(4), David K. Gifford(5),
Richard A. Young(1,2), Rudolf Jaenisch(1,2)
(1) Whitehead Institute for Biomedical Research, Cambridge,
MA
(2) Department of Biology, Massachusetts Institute of
Technology, Cambridge, MA
(3) Swammerdam Institute for Life Sciences, University
of Amsterdam, Amsterdam, The Netherlands
(4) Developmental and Cell Biology Centro de Investigaciones
Biolo´gicas Madrid, Spain
(5) Computer Science and Artificial Intelligence Laboratories,
Massachusetts Institute of Technology, Cambridge, MA
(*) These authors contributed equally to this work.
Whitehead Institute for Biomedical Research
is a nonprofit, independent research and educational
institution. Wholly independent in its governance, finances
and research programs, Whitehead shares a close affiliation
with the Massachusetts Institute of Technology through
its faculty, who hold joint MIT appointments.
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