Scientists at The Genome Institute of Singapore (GIS) and The Scripps Research Institute (TSRI) led an international effort to build a map that shows in detail how the human genome is modified during embryonic development.
This detailed mapping is a significant move towards the success of targeted differentiation of stem cells into specific organs, which is a crucial consideration for stem cell therapy.
The study was published in the journal Genome Research on Feb. 4, 2010.
Senior author and Senior Group Leader at the GIS, a biomedical research institute of Singapore's Agency for Science, Technology and Research (A*STAR), Chia-Lin Wei, Ph.D., said, "In this study, we mapped a major component of the epigenome, DNA methylation, for the entire sequence of human DNA, and went further by comparing three types of cells that represented three stages of human development: human embryonic stem cells, human embryonic stem cells that were differentiated into skin-like cells, and cells derived from skin. With these comprehensive DNA methylome maps, scientists now have a blueprint of key epigenetic signatures associated with differentiation."
"The cells in our bodies have the same DNA sequence," said TSRI Professor Jeanne Loring, Ph.D., who is a co-senior author of the paper along with Isidore Rigoutsos of IBM Thomas J. Watson Research Center and Chia-Lin Wei of GIS. "Epigenetics is the process that determines what parts of the genome are active in different cell types, making a nerve cell, for example, different from a muscle cell."
DNA methylation causes specific subunits of DNA to be chemically modified, which controls which areas of the genome are active and which ones are dormant. DNA methylation is critical to the process in which embryonic cells change from "pluripotent stem cells," which have the ability to turn into hundreds of cell types, to "differentiated cells," distinct types of cells that make up different parts of the body, such as the skin, hair, nerves, etc.
In reviewing the data produced by the study -- information on the methylation of three billion base pairs of DNA -- the scientists were able to identify previously unknown patterns of DNA methylation. They identified cases in which DNA methylation appeared to enhance, rather than repress, the activity of the surrounding DNA, and found evidence to suggest a role for DNA methylation in the regulation of mRNA splicing.
"We produced a very large amount of data," said Loring, "but it actually simplifies the picture. We identified patterns of many genes that are methylated or de-methylated during differentiation. This will allow us to better understand the exquisitely choreographed changes that cells undergo as they develop into different cell types."
Louise Laurent of TSRI and the University of California, San Diego, one of the first authors of the study, added, "The data are publicly available, and we are looking forward to learning what other scientists discover from using this information for their own studies on individual genes, embryonic development, and stem cells."
"This is definitely an exciting finding in the field of stem cell research," added co-first author Eleanor Wong, who is a graduate student from the GIS in Dr Wei's lab. "Using this knowledge, scientists can now survey different cell types and developmental pathways, identify the genes affected, and characterize the functions of these genes in the process of differentiation. It's all very exciting!"
Funding for this work was provided by grants from the National Institutes of Health, the California Institute for Regenerative Medicine, A*STAR of Singapore, and The Esther B. O'Keeffe Foundation.
The research findings are published in the Feb. 4, 2010 online issue of Genome Research under the title, "Dynamic changes in the human methylome during differentiation."
Louise Laurent,1,2,8 Eleanor Wong,3,4,8 Guoliang Li,5,9 Tien Huynh,6,9 Aristotelis Tsirigos,6,9 Chin Thing Ong,3 Hwee Meng Low,3 Ken Wing Kin Sung,5,7 Isidore Rigoutsos,6,10 Jeanne Loring,1,10 and Chia-Lin Wei3,4,10
- UCSD Medical Center, Department of Reproductive Medicine, San Diego, California 92103, USA;
- Center for Regenerative Medicine, Department of Chemical Physiology, The Scripps Research Institute, La Jolla, California 92037, USA;
- Genome Technology & Biology Group, Genome Institute of Singapore, Singapore 138672, Singapore;
- Department of Biological Sciences, National University of Singapore, Singapore 119077, Singapore;
- Computational & Mathematical Biology, Genome Institute of Singapore, Singapore 138672, Singapore;
- Bioinformatics & Pattern Discovery Group, IBM Thomas J. Watson Research Center, Yorktown Heights, New York 10598, USA;
- Department of Computer Science, School of Computing, National University of Singapore, Singapore 119077, Singapore.
- These authors contributed equally to this work.
- These authors contributed equally to this work.
- Corresponding authors:
GENOME INSTITUTE OF SINGAPORE:
The Genome Institute of Singapore (GIS) is a member of the Agency for Science, Technology and Research (A*STAR). It is a national initiative with a global vision that seeks to use genomic sciences to improve public health and public prosperity. Established in 2001 as a centre for genomic discovery, the GIS will pursue the integration of technology, genetics and biology towards the goal of individualized medicine. The key research areas at the GIS include Systems Biology, Stem Cell & Developmental Biology, Cancer Biology & Pharmacology, Human Genetics, Infectious Diseases, Genomic Technologies, and Computational & Mathematical Biology. The genomics infrastructure at the GIS is utilized to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact.
THE SCRIPPS RESEARCH INSTITUTE:
The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Scripps Florida is located in Jupiter, Florida.
AGENCY FOR SCIENCE, TECHNOLOGY AND RESEARCH (A*STAR):
The Agency for Science, Technology and Research (A*STAR) is the lead agency for fostering world-class scientific research and talent for a vibrant knowledge-based and innovation-driven Singapore. A*STAR oversees 14 biomedical sciences, and physical sciences and engineering research institutes, and seven consortia & centre, which are located in Biopolis and Fusionopolis, as well as their immediate vicinity.
A*STAR supports Singapore's key economic clusters by providing intellectual, human and industrial capital to its partners in industry. It also supports extramural research in the universities, hospitals, research centres, and with other local and international partners.
FOR MORE INFORMATION:
Genome Institute of Singapore:
Winnie Serah Lim
Tel: (65) 6808 8013
(65) 9730 7884
The Scripps Research Institute: