Scientists Find Genome Structure Responsible for Gene Activation

01/27/05 -- The first high-resolution analysis of the key feature that controls the activation of genes on human chromosomes was reported today in the journal Cell, by researchers from the Broad Institute of MIT and Harvard and Affymetrix Inc. (Nasdaq: AFFX). The study is pioneering in its large scale and surprising in its results. It reveals previously unknown domains of gene regulation in human chromosomes and also suggests the existence of many novel functional elements in the human genome.

The research team used Affymetrix GeneChip(R) microarrays, each containing millions of distinct DNA fragments to examine "chromatin," the intricate structure that packages the genome and makes certain genes accessible and others inaccessible to the cell. Using these microarrays, the researchers surveyed two entire human chromosomes (chromosomes 21 and 22) as well as additional regions in both the human and mouse genomes.

Despite rapid progress in identifying human genes based on the completed sequence of the human genome, the genome's complex regulatory network -- the mechanisms that turn genes on and off -- still remains poorly understood. "Chromatin is a key part of the regulatory network that controls how genetic information is translated into a cell or an organism. Understanding chromatin is important because many of its components are implicated in cancer and other diseases," said Dr. Brad Bernstein, a research associate at the Broad Institute and instructor of pathology at Harvard Medical School, who co-led the study.

With the ability to perform genome-wide analysis, it should now become possible to gain very general insight into the structure and function of chromatin, said the researchers. In particular, such studies may be useful for understanding how gene regulation becomes defective in certain diseased tissues and cells, they said.

In the January 28 issue of Cell, the researchers report that:

-- Much of the human genome is organized into small chromatin structures that are remarkably similar to those found in single-celled budding yeast.
-- Striking exceptions are found, however, for certain clusters of genes that control the body plan of the developing embryo. These "Hox" gene clusters are organized into huge active chromatin domains.
-- Both the small and large chromatin structures are nearly identical in humans and mice, indicating that they have important functions that have been preserved over nearly 100 million years of evolution.

The chromatin data "will be an invaluable resource in our effort to define the regulatory network of the genome," said Michael Kamal, co-lead author on the study and a computational biologist at the Broad.

"This project illustrates the power of high-throughput technologies on our understanding of biology," said Stuart Schreiber, who is a member of the Broad Institute, a professor at Harvard University, and an expert on chromatin research.

"These experiments underscore the importance of analyzing the whole genome -- including the parts thought to be unimportant 'junk' DNA -- when looking for functional domains like sites of chromatin methylation," said Thomas Gingeras, Ph.D., Vice President of Biological Sciences, Affymetrix Laboratories. "High-density microarrays allow us to interrogate the genome without making any assumptions of what parts are important and what parts aren't. Using this unbiased investigational approach, we're finding that there may be much less 'junk' DNA in the genome than we thought."

"The human genome still has many surprises lurking within it," said Eric S. Lander, director of the Broad Institute and senior author on the study. "One of the most important is the mystery of how genes are turned on. The ability to take global views of chromatin in human cells holds tremendous promise for unraveling this mystery."

Dr. Bernstein is also affiliated with the Brigham and Women's Hospital and is a postdoctoral researcher in the Howard Hughes Medical Institute lab of Stuart L. Schreiber at the Department of Chemistry and Chemical Biology at Harvard University.

The authors also include:

At the Broad Institute: Kerstin Lindblad-Toh, Dana J. Huebert, Scott McMahon, Elinor K. Karlsson, and Edward J. Kulbokas.

At Affymetrix: Stefan Bekiranov, Dione K. Bailey and Thomas R. Gingeras.

The research was supported by funds from the National Institutes of Health, the Howard Hughes Medical Institute and Affymetrix, Inc.

About Affymetrix:

Affymetrix scientists invented the world's first high-density microarray in 1989 and began selling the first commercial microarray in 1994. Since then, Affymetrix GeneChip(R) technology has become the industry standard in molecular biology research. Affymetrix technology is used by the world's top pharmaceutical, diagnostic and biotechnology companies as well as leading academic, government and not-for-profit research institutes. More than 1,200 systems have been shipped around the world and nearly 3,000 peer-reviewed papers have been published using the technology. Affymetrix' patented photolithographic manufacturing process provides the most information capacity available today on an array, enabling researchers to use a whole-genome approach to analyzing the relationship between genetics and health. Affymetrix is headquartered in Santa Clara, Calif., with manufacturing facilities in Sacramento, Calif., and Bedford, Mass. The company maintains important sales and marketing operations in Europe and Asia and has about 900 employees worldwide.

All statements in this press release that are not historical are "forward-looking statements" within the meaning of Section 21E of the Securities Exchange Act as amended, including statements regarding Affymetrix' "expectations," "beliefs," "hopes," "intentions," "strategies" or the like. Such statements are subject to risks and uncertainties that could cause actual results to differ materially for Affymetrix from those projected, including, but not limited to risks of the Company's ability to achieve and sustain higher levels of revenue, higher gross margins, reduced operating expenses, uncertainties relating to technological approaches, manufacturing, product development, personnel retention, uncertainties related to cost and pricing of Affymetrix products, dependence on collaborative partners (including uncertainties related to the outcome of the collaboration discussed in this press release), uncertainties relating to sole source suppliers, uncertainties relating to FDA and other regulatory approvals, competition, risks relating to intellectual property of others and the uncertainties of patent protection and litigation. These and other risk factors are discussed in Affymetrix' Form 10- K for the year ended December 31, 2003 and other SEC reports, including its Quarterly Reports on Form 10-Q for subsequent quarterly periods. Affymetrix expressly disclaims any obligation or undertaking to release publicly any updates or revisions to any forward-looking statements contained herein to reflect any change in Affymetrix' expectations with regard thereto or any change in events, conditions, or circumstances on which any such statements are based.

NOTE: Affymetrix, the Affymetrix logo, and GeneChip are registered trademarks owned or used by Affymetrix, Inc.

Source: Affymetrix, Inc.