Man and mouse share genome structures

January 28, 2005

In the most detailed large-scale study to date of the proteins that package DNA, researchers have mapped a family of switches that turn genes on and off. Their findings may help scientists understand regulatory mechanisms underlying cancer and human development.

The research team includes first author Bradley Bernstein, recipient of a Howard Hughes Medical Institute (HHMI) physician postdoctoral fellowship who works in the Harvard University laboratory of HHMI investigator Stuart L. Schreiber. Other co-authors are from the Broad Institute of MIT and Harvard, and Affymetrix. Their findings are published in the January 28, 2005 issue of Cell.

"Now that the human genome has been sequenced, it is vital to learn how the genome is translated to make living cells and organisms, and how we can use that information to improve human health," said Bernstein, who is an instructor of pathology at Brigham & Women's Hospital and Harvard Medical School. "Every one of our cells has the same genome, yet is completely different. Muscle cells are different from neurons. They are different because different genes are on."

Many scientists believe changes in the regulatory scaffolding surrounding the genome may be as important as changes in the genome itself in causing diseases such as cancer.

This regulatory structure, called chromatin, is a key regulator of gene expression in healthy and diseased cells, Bernstein said. Chromatin is composed of DNA spooled around bundles of histone proteins, and resembles a chain of beads which is then compressed into a working chromosome. Chemical tags placed on the histones alter the way chromatin is organized, thus allowing the right combination of genes to be turned on.

In their study, the researchers analyzed the chromatin structure of the two shortest human chromosomes, numbers 21 and 22, containing about two percent of the human genome. They also sampled additional regions in both the human and mouse genomes, finding similar patterns along equivalent chromosomal regions, even where the underlying DNA sequences are different.

Bernstein and Schreiber began to develop the analytical techniques several years earlier, working with the smaller yeast genome. To investigate the much larger human genome, they collaborated with Affymetrix. They isolated the DNA regions with certain major methyl and acetyl tags, and used new microarray technology to identify the underlying genetic sequences associated with the tagged chromatin. Next, they teamed up with Michael Kamal, the co-first author of the paper, Eric Lander, and their Broad Institute colleagues, for the daunting computational analysis required to interpret the resulting data.

In most cases, the mapped tags coincided with the transcription starting points of active genes, as they and others had seen earlier in the yeast. Unexpectedly, they also found tags idling over regions near genes. The researchers think these sites have important regulatory functions, because the methylation patterns are similar in comparable portions of the mouse genome. Until now, they'd been missed by more standard genome analysis tools.

Most exciting to Bernstein is the unusual density of histone tags spread over the regions of genome containing the HOX genes, which are key regulators of development.

"In most of the genome, we see short stretches associated with activated histones," Bernstein said. "However, in the HOX regions, we see huge stretches of genome, many thousands of base pairs in length, that are completely covered by tags." The researchers speculate that these unique chromatin structures could be activating sets of HOX genes for specific developmental programs.

This global activation may have implications for understanding mechanisms behind certain cancers, Bernstein believes. For example, proteins that place methyl groups on histones can, when mutated, cause leukemia. Bernstein hopes to apply the new technology to characterize chromatin structure in leukemic cells and gain insight into the molecular basis of disease.

"The human genome still has many surprises lurking within it," said 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."
-end-


Howard Hughes Medical Institute

Related Cancer Articles from Brightsurf:

New blood cancer treatment works by selectively interfering with cancer cell signalling
University of Alberta scientists have identified the mechanism of action behind a new type of precision cancer drug for blood cancers that is set for human trials, according to research published in Nature Communications.

UCI researchers uncover cancer cell vulnerabilities; may lead to better cancer therapies
A new University of California, Irvine-led study reveals a protein responsible for genetic changes resulting in a variety of cancers, may also be the key to more effective, targeted cancer therapy.

Breast cancer treatment costs highest among young women with metastic cancer
In a fight for their lives, young women, age 18-44, spend double the amount of older women to survive metastatic breast cancer, according to a large statewide study by the University of North Carolina at Chapel Hill.

Cancer mortality continues steady decline, driven by progress against lung cancer
The cancer death rate declined by 29% from 1991 to 2017, including a 2.2% drop from 2016 to 2017, the largest single-year drop in cancer mortality ever reported.

Stress in cervical cancer patients associated with higher risk of cancer-specific mortality
Psychological stress was associated with a higher risk of cancer-specific mortality in women diagnosed with cervical cancer.

Cancer-sniffing dogs 97% accurate in identifying lung cancer, according to study in JAOA
The next step will be to further fractionate the samples based on chemical and physical properties, presenting them back to the dogs until the specific biomarkers for each cancer are identified.

Moffitt Cancer Center researchers identify one way T cell function may fail in cancer
Moffitt Cancer Center researchers have discovered a mechanism by which one type of immune cell, CD8+ T cells, can become dysfunctional, impeding its ability to seek and kill cancer cells.

More cancer survivors, fewer cancer specialists point to challenge in meeting care needs
An aging population, a growing number of cancer survivors, and a projected shortage of cancer care providers will result in a challenge in delivering the care for cancer survivors in the United States if systemic changes are not made.

New cancer vaccine platform a potential tool for efficacious targeted cancer therapy
Researchers at the University of Helsinki have discovered a solution in the form of a cancer vaccine platform for improving the efficacy of oncolytic viruses used in cancer treatment.

American Cancer Society outlines blueprint for cancer control in the 21st century
The American Cancer Society is outlining its vision for cancer control in the decades ahead in a series of articles that forms the basis of a national cancer control plan.

Read More: Cancer News and Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.