Featured Research

from universities, journals, and other organizations

Even In Our Genome, Good Fences Make Good Neighbors

Date:
May 15, 2009
Source:
Salk Institute
Summary:
Our genome is a patchwork of neighborhoods that couldn't be more different: Some areas are hustling and bustling with gene activity, while others are sparsely populated and in perpetual lock-down. Breaking down just a few of the molecular fences that separate them blurs the lines and leads to the inactivation of at least two tumor suppressor genes, according to researchers.

CTCF and Tumor Suppressor Gene Silencing.
Credit: Courtesy of Michael Witcher, Salk Institute for Biological Studies

Our genome is a patchwork of neighborhoods that couldn't be more different: Some areas are hustling and bustling with gene activity, while others are sparsely populated and in perpetual lock-down. Breaking down just a few of the molecular fences that separate them blurs the lines and leads to the inactivation of at least two tumor suppressor genes, according to researchers at the Salk Institute for Biological Studies.

Their findings, published in the May 15, 2009 issue of Molecular Cell, explain how a single event can put a cell well ahead on the road to becoming a tumor cell. "Selectively removing a couple of fence posts jumpstarts a cascade of global changes all over the genome that may eventually lead to cancer," says Beverly Emerson, Ph.D., a professor in the Regulatory Biology Laboratory, who led the study.

Normally, a complex network of accelerators (growth factors) and brakes (tumor suppressors) keeps a tight lid on cell proliferation. Tumors result when changes in the genome activate cancer-causing genes or inactivate tumor suppressor genes that tip this delicate balance in favor of uncontrolled cell growth.

"For a really long time people have been trying to understand how tumor suppressor genes get silenced in cancer," says postdoctoral researcher and first author Michael Witcher. "Now that we have figured out one of the key events that leads to their inactivation, we might be able to exploit this mechanism to develop novel therapies."

If stretched out, the DNA of a single human cell would form a very thin thread about 6 feet in length. To fit such a long molecule inside a cell's nucleus and keep everything neatly organized, the DNA is threaded around histone proteins and coiled up in a highly condensed structure called heterochromatin. In areas of gene activity, the tightly packed chromatin is unfurled just enough to make the DNA accessible to regulatory proteins.

In many different types of cancers, however, including breast, lung, liver, and pancreatic tumors, as well as multiple myeloma and lymphoma, the tumor suppressor p16 gets buried deep inside heterochromatin. As a result, it cannot be read by the transcription machinery and is unable keep watch over cell growth.

Researchers had known for a long time that sometimes p16 is silenced long before a cell turns cancerous, yet why that particular stretch of DNA was flagged with chemical marks and became wound up so tightly that it became inaccessible had remained a mystery.

Most people looked for clues within the immediate vicinity of the gene but came up empty-handed. When Witcher extended his search further upstream, however, he discovered a binding site for CTCF, short for CCCTC-binding factor, which forms the centerpiece of the molecular fence posts that separate heterochromatin from the rest of the genome. "We found that the binding of this protein is lost from several binding sites in numerous types of cancer cells, leading to the collapse of the molecular boundary," he says. "Once the boundary was gone, the adjacent heterochromatin encroached and silenced the nearest gene."

Further experiments revealed that CTCF was missing because it lacked a chemical modification known as "PARlation," lab lingo for poly(ADP-ribosyl)ation, which allows the protein to bind to select sites in the genome. "Without PARlation, CTCF fails to form the complex necessary to regulate p16 and the tumor suppressor RASSF1A and possibly others, explaining why breast cancer cells always contain both silenced p16 and silenced RASSF1A," says Witcher.

"We believe that destabilization of specific chromosomal boundaries or loss of molecular fences through aberrant CTCF function may be a general mechanism to inactivate tumor suppressor genes and initiate tumorigenesis in numerous forms of human cancers," says Emerson.

This work was supported by the Samuel Waxman Cancer Research Foundation and the Canadian Institute of Health Research.


Story Source:

The above story is based on materials provided by Salk Institute. Note: Materials may be edited for content and length.


Journal Reference:

  1. Michael Witcher, Beverly M. Emerson. Epigenetic Silencing of the p16INK4a Tumor Suppressor Is Associated with Loss of CTCF Binding and a Chromatin Boundary. Molecular Cell, 2009; 34 (3): 271-284 DOI: 10.1016/j.molcel.2009.04.001

Cite This Page:

Salk Institute. "Even In Our Genome, Good Fences Make Good Neighbors." ScienceDaily. ScienceDaily, 15 May 2009. <www.sciencedaily.com/releases/2009/05/090514125146.htm>.
Salk Institute. (2009, May 15). Even In Our Genome, Good Fences Make Good Neighbors. ScienceDaily. Retrieved October 22, 2014 from www.sciencedaily.com/releases/2009/05/090514125146.htm
Salk Institute. "Even In Our Genome, Good Fences Make Good Neighbors." ScienceDaily. www.sciencedaily.com/releases/2009/05/090514125146.htm (accessed October 22, 2014).

Share This



More Health & Medicine News

Wednesday, October 22, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

CDC Revamps Ebola Guidelines After Criticism

CDC Revamps Ebola Guidelines After Criticism

Newsy (Oct. 21, 2014) The Centers for Disease Control and Prevention have issued new protocols for healthcare workers interacting with Ebola patients. Video provided by Newsy
Powered by NewsLook.com
WHO: Ebola Vaccine Trials to Start a in January

WHO: Ebola Vaccine Trials to Start a in January

AP (Oct. 21, 2014) Tens of thousands of doses of experimental Ebola vaccines could be available for "real-world" testing in West Africa as soon as January as long as they are deemed safe in soon to start trials, the World Health Organization said Tuesday. (Oct. 21) Video provided by AP
Powered by NewsLook.com
First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

First-Of-Its-Kind Treatment Gives Man Ability To Walk Again

Newsy (Oct. 21, 2014) A medical team has for the first time given a man the ability to walk again after transplanting cells from his brain onto his severed spinal cord. Video provided by Newsy
Powered by NewsLook.com
CDC Issues New Ebola Guidelines for Health Workers

CDC Issues New Ebola Guidelines for Health Workers

Reuters - US Online Video (Oct. 21, 2014) The U.S. Centers for Disease Control and Prevention has set up new guidelines for health workers taking care of patients infected with Ebola. Linda So reports. Video provided by Reuters
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:

Breaking News:

Strange & Offbeat Stories


Health & Medicine

Mind & Brain

Living & Well

In Other News

... from NewsDaily.com

Science News

Health News

Environment News

Technology News



Save/Print:
Share:

Free Subscriptions


Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

Get Social & Mobile


Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

Have Feedback?


Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
Mobile: iPhone Android Web
Follow: Facebook Twitter Google+
Subscribe: RSS Feeds Email Newsletters
Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins