R-loops break walls of gene silencing

March 2, 2012, UC Davis

(Medical Xpress) -- Researchers at the University of California, Davis, have figured out how the human body keeps essential genes switched “on” and silences the vast stretches of genetic repeats and “junk” DNA.

Frédéric Chédin, associate professor in the Department of Molecular and Cellular Biology, describes the research in a paper published today (March 1) in the journal Molecular Cell. The work could lead to treatments for lupus and other autoimmune diseases, by reversing the process known as cytosine methylation.

“R-loops” are the key, say graduate student Paul Ginno, Chédin and colleagues. The loops emerge in the RNA transcription process in DNA sections that are rich in cytosine and guanine, the C and G in the four-letter DNA code. These C and G stretches serve as “on” switches, or promoters, for about 60 percent of human .

Scientists have known since the 1980s that these so-called CG island promoters are not subject to methylation. But, Chédin said, the mechanism has been a long-standing mystery.

The UC Davis researchers built a catalog of almost 8,000 CG islands in the human genome, studied their DNA sequences and found the CG sequences to be skewed toward having one strand of the double helix rich in guanine, and the complementary strand rich in cytosine.

Then, in RNA transcription, the G-rich RNA remains stably bound to a C-rich DNA strand, forcing the G-rich DNA strand into a loop — which then prevents methylation.

DNA methylation is considered part of the new field of epigenetics, which studies inheritable genetic changes that are not directly coded in the DNA sequence. However, the new work shows that, at least at CG islands, the epigenetic state is determined by the DNA sequence.

Scientists know that reduced methylation of DNA plays a key role in triggering autoimmunity in lupus, Chédin said. However, the molecular events behind this DNA under-methylation have been unclear.

“Our work establishes that excessive R-loop formation may drive under-methylation and autoimmunity,” Chédin said.

Co-authors: Paul Lott, graduate student; Holly Christensen, undergraduate; and Ian Korf, associate professor in the Department of Molecular and Cellular Biology and the Genome Center.

The National Institutes of Health and the Foundation for Prader-Willi Research supported the project.

Explore further: Controlling patterns of DNA methylation

Related Stories

Controlling patterns of DNA methylation

October 28, 2011
A study performed by scientists in Dirk Schübeler's team at the Friedrich Miescher Institute for Biomedical Research in Basel identifies DNA sequences that autonomously determine DNA methylation patterns. Genomic patterns ...

Silence of the genes

July 22, 2011
A molecular mechanism by which gene silencing is regulated at the genome-wide level in plants has been uncovered by a research team led by Motoaki Seki of the RIKEN Plant Science Center, Yokohama, Japan. The researchers ...

Discoveries in mitochondria open new field of cancer research

June 20, 2011
(Medical Xpress) -- Researchers at Virginia Commonwealth University Massey Cancer Center have revealed novel mechanisms in mitochondria that have implications for cancer as well as many other age-related diseases such as ...

Scientists complete first mapping of molecule found in human embryonic stem cells

July 21, 2011
Stem cell researchers at UCLA have generated the first genome-wide mapping of a DNA modification called 5-hydroxymethylcytosine (5hmC) in embryonic stem cells, and discovered that it is predominantly found in genes that are ...

Environment and diet leave their prints on the heart

November 29, 2011
A University of Cambridge study, which set out to investigate DNA methylation in the human heart and the 'missing link' between our lifestyle and our health, has now mapped the link in detail across the entire human genome.

Recommended for you

Peers' genes may help friends stay in school, new study finds

January 18, 2018
While there's scientific evidence to suggest that your genes have something to do with how far you'll go in school, new research by a team from Stanford and elsewhere says the DNA of your classmates also plays a role.

A centuries-old math equation used to solve a modern-day genetics challenge

January 18, 2018
Researchers developed a new mathematical tool to validate and improve methods used by medical professionals to interpret results from clinical genetic tests. The work was published this month in Genetics in Medicine.

Can mice really mirror humans when it comes to cancer?

January 18, 2018
A new Michigan State University study is helping to answer a pressing question among scientists of just how close mice are to people when it comes to researching cancer.

Group recreates DNA of man who died in 1827 despite having no body to work with

January 16, 2018
An international team of researchers led by a group with deCODE Genetics, a biopharmaceutical company in Iceland, has partly recreated the DNA of a man who died in 1827, despite having no body to take tissue samples from. ...

Epigenetics study helps focus search for autism risk factors

January 16, 2018
Scientists have long tried to pin down the causes of autism spectrum disorder. Recent studies have expanded the search for genetic links from identifying genes toward epigenetics, the study of factors that control gene expression ...

The surprising role of gene architecture in cell fate decisions

January 16, 2018
Scientists read the code of life—the genome—as a sequence of letters, but now researchers have also started exploring its three-dimensional organisation. In a paper published in Nature Genetics, an interdisciplinary research ...

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.