Hallmark features of human embryonic stem cells controlled by protein
modifications that influence gene expression but do not alter DNA
05, Oct 2007
Download this Press Release
A human embryonic stem cell is reined in - prevented from giving up
its unique characteristics of self-renewal and pluripotency - by the
presence of a protein modification that stifles any genes that would
prematurely instruct the cell to develop into heart or other
specialized tissue. But, thanks to the simultaneous presence of
different protein modifications, stem cells are primed and poised,
ready to develop into specialized body tissue, Singapore scientists
reported in last month's issue of the journal Cell Stem Cell.
The molecules central to this balancing act, H3K4me3 and H3K27me3,
are among the so-called epigenetic modifications that influence the
activity patterns of genes in both human embryonic stem (ES) cells
and mature human adult cells.
Determining how ES cell genes are modified by these epigenetic
markers may explain these cells' unique characteristics, said the
scientists, who are based at the Genome Institute of Singapore (GIS)
and the Bioprocessing Technology Institute (BTI), both under the
Agency for Science, Technology and Research (A*STAR), as well as at
the National University of Singapore (NUS).
The scientists also discovered that genes modified only by one of the
epigenetic markers, H3K4me3, contain the DNA recipes for proteins
that enable an ES cell to proliferate, or duplicate itself. In the
Cell Stem Cell paper, the scientists wrote, "The prevalence of these
genes may be related to the self-renewal property of ES cells."
The scientists also found that the genes that do not carry either of
the two epigenetic modifications are completely silenced in ES cells.
These genes, which are crucial to sensory processes, immunity, and
drug metabolism, are active in highly specialized, mature adult cells.
Although epigenetic markers attach themselves to the tightly wound
bundle of protein material called histones that package and compress
the DNA in the nucleus of each human cell, they do not change the
cell's DNA code. Therefore, epigenetic markers are not permanent.
If they were permanent, ES cells would never be able to differentiate
into heart, kidney, brain, bone, skin and the other specialize cells
crucial to normal human functioning.
"This discovery will advance our understanding of stem cell
epigenetics and chromatin structures, provide potential mechanisms on
maintaining the hallmark properties of ES cells, and help researchers
with the rich source of information to better understand some of the
unique features - such as self-renewal and pluripotency - of human
embryonic stem cells," said Ng Huck Hui, Ph.D., senior group leader
at GIS and a member of the Singapore team that conducted this
research.
Such findings, Dr. Ng added, "will ultimately lead to the development
of new therapies and clinical treatments."
His GIS colleague, Wei Chia-Lin, Ph.D., who headed the Singapore
research team, said, "This study demonstrates the power of a whole
genome and robust sequencing technology, when applied in the
epigenetic analysis of ES cells, can reveal features of the genomes
that were not previously appreciated. The new knowledge and target
candidate genes resulted from such unbiased study are ultimately
important for researchers to understand the fundamental nature of
stem cell proliferation and differentiation.
Drs. Wei and Ng and the other researchers used cutting-edge
technologies developed at GIS, to sequence, or decipher, the DNA of
human ES cells. With the sequence data in hand, the scientists were
able to categorize the genes into three groups, each modified by
different combinations of the two epigenetic markers.
The researchers discovered that the majority of the regions in the
genome harbor active histone marks that act as sign posts and allow
cells to quickly find genes "to turn on" or activate them.
Identifying the locations of these genomic signposts will also be
crucial for discovering human genes that are important for different
functions in ES cells.
Of the two epigenetic markers, H3K4me3 was found to be the most
prevalent - the scientists reported and noted that it occurs near the
DNA areas that are promoters of two-thirds of human genes. Of the
17,469 nonredundant unique human genes that the scientists sequenced,
68% contained H3K4me3, and only 10% contained overlapping H3K27me3.
More information about epigenetic modifications:
In living cells, DNA is packaged along with histone proteins, which
are chief protein components that act as spools around which DNA
winds. The histone proteins are decorated with different marks, which
can affect the various activities of the modified DNA such as
transcription, gene silencing, imprinting and replication. Such marks
key roles in the process of cellular differentiation, allowing cells
to maintain different characteristics despite containing the same
genomic material. While different cells can have identical genetic
DNA sequences, their characteristics and differentiation patterns are
influenced by the different marks on the histone proteins. Therefore,
histone marks represent an epigenetic marker or code that can be used
by the cells to expand their plasticity and complexity.
Notes to the Editor:
Research publication:
The research findings described in this press release can be found in
the September 13, 2007 issue of Cell Stem Cell under the title "Whole-
Genome Mapping of Histone H3Lys4 and 27 Trimethylations Reveals
Distinct Genomic Compartments in Human Embryonic Stem Cells".
Authors:
Xiao Dong Zhao,1,7 Xu Han,2,7 Joon Lin Chew,3 Jun Liu,1 Kuo Ping
Chiu,2 Andre Choo,4 Yuriy L. Orlov,2 Wing-Kin Sung,2,5 Atif Shahab,2
Vladimir A. Kuznetsov,2 Guillaume Bourque,2 Steve Oh,4 Yijun Ruan,1
Huck-Hui Ng,3,6 and Chia-Lin Wei1
1Genome Technology and Biology Group
2Information and Mathematical Science Group
3Stem Cell and Developmental Biology Group
Genome Institute of Singapore, 138672, Singapore
4Bioprocessing Technology Institute, 138668, Singapore
5School of Computing
6Department of Biological Sciences
National University of Singapore, 117543, Singapore
7These authors contributed equally to this work.
For enquiries, please contact the following:
Genome Institute of Singapore:
Winnie Serah Lim
Asst Manager, Corporate Communications
Tel: (65) 6478 8013 / (65) 9730 7884
Email: limcp2@gis.a-
Contact for U.S. journalists:
Cathy Yarbrough
U.S. Communications Advisor
A*STAR (Agency for Science, Technology and Research)
Tel.: 858-243-1814
Email: sciencematter@
About the Genome Institute of Singapore:
www.gis.a-star.
The Genome Institute of Singapore (GIS) is a member of the Agency for
Science, Technology and Research (A*STAR). Established in 2001, the
research institute's mission is to be a world-class genomics
institute and a centre for genomic discovery. GIS pursues the
integration of technology, genetics and biology towards the goal of
individualized medicine. The genomics infrastructure at GIS is
utilized to train new scientific talent, to act as a bridge between
academic and industrial research, and explore scientific questions of
high impact.
About the Bioprocessing Technology Institute:
www.bti.a-star.
The Bioprocessing Technology Institute (BTI) is a member of the Agency
for Science, Technology and Research (A*STAR). Established in 1990 as
the Bioprocessing Technology Unit, it was renamed the Bioprocessing
Technology Institute (BTI) in 2003. The research institute's mission
is to
develop manpower capabilities and establish cutting-edge technologies
relevant to the bioprocessing community. Some of the key research
areas
include expression engineering, animal cell technology, stem cell
research,
microbial fermentation, downstream purification and analytics.
http://www.a-
star.edu.sg/
id=0e5e5bfdf9lc
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StemCells subscribers may also be interested in these sites:
Children's Neurobiological Solutions
http://www.CNSfoundation.org/
Cord Blood Registry
http://www.CordBlood.com/at.cgi?a=150123
The CNS Healing Group
http://groups.yahoo.com/group/CNS_Healing
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