Large DNA stretches, not single genes, shut off as cells mature

January 18, 2009

Experiments at Johns Hopkins have found that the gradual maturing of embryonic cells into cells as varied as brain, liver and immune system cells is apparently due to the shut off of several genes at once rather than in individual smatterings as previous studies have implied.

Working with mouse brain and liver cells, as well as embryonic stem cells, Johns Hopkins University School of Medicine professor Andrew Feinberg, M.D., M.P.H., led an investigation of a kind of epigenetic modification to histones, the molecular "spools" that DNA winds around in the cell nucleus. This modification is a variety of the so-called epigenetic changes that alter the function of cells without directly altering the nuclear DNA in the cells.

Other scientists had previously found that histone modifications appear to silence individual genes in the DNA that coils around affected histones. But when Feinberg and his team compared the activity of thousands of genes in the liver and brain cells, they found that a particular modification — in which two methyl groups clip onto histones — seemed to silence long stretches of DNA containing many genes at once. The findings will publish in Nature Genetics online on Jan. 18.

Since the silenced stretches varied greatly between the different types of cells, Feinberg, postdoctoral fellow Bo Wen, and their colleagues wondered whether these sections — called large organized chromatin K9 modifications, or LOCKS — might be responsible for the transition from the "blank slate" quality of embryonic cells to the specialized functions that mature cells take on. To find out, he and his team looked for LOCKs in mouse embryonic stem cells. Unlike mature, adult liver and brain cells, in which about 40 percent of the genome was silenced by LOCKs, the embryonic stem cells had no LOCKs.

Next, the researchers compared the regions of DNA affected by LOCKs between mouse liver and brain cells and their corresponding human cells. The same cell types in both organisms had remarkably similar regions of DNA silenced by LOCKs, suggesting that the same genes necessary to control cell function are affected in mice and people.

"These results suggest that LOCKs appear gradually during development, refining cells' functions as they differentiate into particular cell types," Wen says. "Our experiments suggest that the whole forest of genes is changing, but people have been looking at the individual trees."

Because epigenetic changes also are known to play a role in abnormal cell growth, the researchers suspected that LOCKs were involved in the development of cancer. When they looked for genes in several common cancer cell lines often used in research, they indeed found significantly fewer LOCKs than in normal liver and brain cells.

"In cancer, some of these LOCKs may become unlocked," says Feinberg. "Sections of DNA that were silenced in a cell type might become active, giving cancer cells characteristics of other cell types that they're not supposed to have."

Feinberg says this "unlocking" might cause cancer cells to revert to a more immature developmental state, explaining some of their unusual behavior, such as extreme proliferation or migration to different areas of the body.

Source: Johns Hopkins Medical Institutions

Explore further: Genetic variant prompts cells to store fat, fueling obesity

Related Stories

Genetic variant prompts cells to store fat, fueling obesity

November 13, 2017
Obesity is often attributed to a simple equation: People are eating too much and exercising too little. But evidence is growing that at least some of the weight gain that plagues modern humans is predetermined. New research ...

Why we still don't understand sleep, and why it matters

October 23, 2017
One of my first jobs was to keep a lookout for lions. There are some occupations that are not suitable for someone with untreated narcolepsy and this is probably one of them. I was 22, a recent zoology graduate studying meerkats ...

The vibrational theory of olfaction for the win

October 31, 2017
(Medical Xpress)—As occurred in the painstaking deciphering of Egyptian hieroglyphs, adherence to outmoded ideas is a lasting impediment to our understanding of how odorants are decoded by the olfactory system. The primary ...

3-D protein structure offers insight into rapid communication by brain cells

September 13, 2017
New HHMI research reveals how three proteins help brain cells synchronize the release of chemical signals. A similar interaction may play a role in how cells secrete insulin and airway mucus, too.

How anesthetics work, and why xenon's perfect

September 11, 2017
Common wisdom maintains that, because of the myriad effects on the brain, how anesthetic drugs work at the molecular level is a mystery.

Study reveals breakthrough in decoding brain function

September 25, 2017
If there's a final frontier in understanding the human body, it's definitely not the pinky. It's the brain.

Recommended for you

New approach to studying chromosomes' centers may reveal link to Down syndrome and more

November 20, 2017
Some scientists call it the "final frontier" of our DNA—even though it lies at the center of every X-shaped chromosome in nearly every one of our cells.

Genome editing enhances T-cells for cancer immunotherapy

November 20, 2017
Researchers at Cardiff University have found a way to boost the cancer-destroying ability of the immune system's T-cells, offering new hope in the fight against a wide range of cancers.

A math concept from the engineering world points to a way of making massive transcriptome studies more efficient

November 17, 2017
To most people, data compression refers to shrinking existing data—say from a song or picture's raw digital recording—by removing some data, but not so much as to render it unrecognizable (think MP3 or JPEG files). Now, ...

Genetic mutation in extended Amish family in Indiana protects against aging and increases longevity (Update)

November 15, 2017
The first genetic mutation that appears to protect against multiple aspects of biological aging in humans has been discovered in an extended family of Old Order Amish living in the vicinity of Berne, Indiana, report Northwestern ...

US scientists try first gene editing in the body

November 15, 2017
Scientists for the first time have tried editing a gene inside the body in a bold attempt to permanently change a person's DNA to try to cure a disease.

Discovering a protein's role in gene expression

November 10, 2017
Northwestern Medicine scientists have discovered that a protein called BRWD2/PHIP binds to histone lysine 4 (H3K4) methylation—a key molecular event that influences gene expression—and demonstrated that it does so via ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.