Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A little tag with a large effect

05.02.2013
Epigenetic marker 5hmC opens the door to studying its role in developmental disorders and disease

February 4, 2013, New York, NY and Oxford, UK – Nearly every cell in the human body carries a copy of the full human genome. So how is it that the cells that detect light in the human eye are so different from those of, say, the beating heart or the spleen?

The answer, of course, is that each type of cell selectively expresses only a unique suite of genes, actively silencing those that are irrelevant to its function. Scientists have long known that one way in which such gene-silencing occurs is by the chemical modification of cytosine—one of the four bases of DNA that write the genetic code—to create an "epigenetic" marker known as 5-methylcytosine (5mC). Appropriate placement of this marker is essential to many normal biological processes, not least embryonic development. Conversely, its erroneous distribution contributes to the evolution of a broad range of cancers.

But 5mC is not the only epigenetic marker on the genomic block. About three years ago at Rockefeller University, Skirmantas Kriaucionis, currently a Ludwig researcher based at Oxford University, and Nathaniel Heintz, of Rockefeller University, discovered that a second modification of cytosine that converts it into 5-hydroxymethylcytosine (5hmC) seems to play a similarly vital role in the selective expression of the genome. Since then, researchers have scrambled to figure out what precisely that role might be. In a recent issue of the journal Cell, Heintz, Kriaucionis and colleagues report that the 5hmC marker has an effect on gene expression opposite to that of 5mC, and identify how its signal is detected and broadly interpreted in the healthy brain cells of mice. Since changes in the distribution of 5hmC are known to take place in a broad range of tumor cells, these findings could prove to be of great value to cancer research.

To begin, the team mapped where exactly 5hmC is found across the genomes of three types of healthy mouse neural cells. They discovered that it is largely associated with DNA that is loosely looped about its protein scaffolding in the nucleus. The 5mC signal, meanwhile, is predominantly located on more tightly packed, less accessible stretches of DNA. It is on the loosely packed DNA that most gene expression takes place.

In line with that finding, they discovered that the 5hmC marker was scattered over regions of the genome where genes are being expressed at high levels. And in concurrence with other studies, they found that the 5mC signal was mainly located on silent islands of the genome.

When the researchers peered more closely at the DNA sequence, they further discovered that 5hmC is largely planted within gene bodies—the parts of genes that encode proteins—not in intervening sequences that mark where the coding regions begin (promoters) and determine how avidly the genes are expressed (enhancers). This surprised them, as it is in such sequences that one would expect an on switch for a gene to be located. "It's easy to see how a modification of enhancer or promoter regions might affect gene expression," says Kriaucionis, PhD, and an assistant member of the Ludwig Institute at Oxford University.

"Indeed, we know 5hmC is found in those sequences in embryonic stem cells, which give rise to the whole body. But it is much less clear how the placement of this marker on the gene body—which contains the instructions for making a protein, not the sequences that determine when or how much of it is made—could have such a pronounced effect on gene activation."

Kriaucionis and colleagues in Nathaniel Heintz' team also discovered that in places where 5hmC is common, 5mC is found at low levels, and vice versa. Further, the patterns and ratios of the two markers and the genes highly expressed in each of the cells assessed varied dramatically. This implies that preexisting molecular signals that are unique to each kind of cell are vital to determining where exactly the 5hmC marker is placed across the genome. Changes in such signals are likely to play a role in the generation of disease, including cancers.

Next, the researchers sought to determine how the 5hmc signal is read. "We must understand what 5hmC is doing in normal cells," says Kriaucionis. "Understanding that will help us trace the process by which genes are incorrectly expressed in disease." The researchers discovered that a molecule known as methyl-CpG-binding protein (MeCP2), which binds 5mC, also binds 5hmC in the cells they studied. Mutations in this protein are known to contribute to Rett Syndrome, a developmental disorder that varies in severity depending on how precisely MeCP2 has been altered. Most importantly one of those mutant MeCP2 proteins was capable of binding 5mC, but not 5hmC. That mutant is known to cause relatively less severe cognitive and speech deficits in Rett patients.

Finally, investigators show in their paper that MeCP2 binding to 5hmC drives gene expression by making DNA more accessible to the molecular machinery that decodes genetic information—while its association with 5mC has the opposite effect. Though the current study focused on healthy mouse neural tissue, the unraveling of 5hmC's tangled role in genome expression is likely to be of value to cancer research. Other researchers have shown that 5hmC is highly depleted in several cancers, including the blood cancer acute myeloid leukemia and the blood disorder myelodysplastic syndrome, which can progress to cancer. This depletion is accompanied by the disruption of a tumor suppressor gene named TET2, which encodes a protein that creates the 5hmC signal on DNA.

Kriaucionis's lab is now assessing what role 5hmC plays in the development of different types of blood cells, with the aim of deciphering how its loss contributes to the generation of blood cancers.

This work was supported by the Howard Hughes Medical Institute (NH), Simons Foundation Autism Research Initiative and Conte Center PSH MH090963 (NH), the Ludwig Institute for Cancer Research (SK) and Spanish MECD (MM).

About The Ludwig Institute for Cancer Research

The Ludwig Institute for Cancer Research is an international non-profit organization committed to improving the understanding and control of cancer through integrated laboratory and clinical discovery. Leveraging its worldwide network of investigators and the ability to sponsor and conduct its own clinical trials, Ludwig is actively engaged in translating its discoveries into applications for patient benefit. Since its establishment in 1971, the Ludwig Institute has expended more than $1.5 billion on cancer research.

For further information please contact Rachel Steinhardt, rsteinhardt@licr.org or +1-212-450-1582.

Rachel Steinhardt | EurekAlert!
Further information:
http://www.licr.org

More articles from Life Sciences:

nachricht A Map of the Cell’s Power Station
18.08.2017 | Albert-Ludwigs-Universität Freiburg im Breisgau

nachricht On the way to developing a new active ingredient against chronic infections
18.08.2017 | Deutsches Zentrum für Infektionsforschung

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: Fizzy soda water could be key to clean manufacture of flat wonder material: Graphene

Whether you call it effervescent, fizzy, or sparkling, carbonated water is making a comeback as a beverage. Aside from quenching thirst, researchers at the University of Illinois at Urbana-Champaign have discovered a new use for these "bubbly" concoctions that will have major impact on the manufacturer of the world's thinnest, flattest, and one most useful materials -- graphene.

As graphene's popularity grows as an advanced "wonder" material, the speed and quality at which it can be manufactured will be paramount. With that in mind,...

Im Focus: Exotic quantum states made from light: Physicists create optical “wells” for a super-photon

Physicists at the University of Bonn have managed to create optical hollows and more complex patterns into which the light of a Bose-Einstein condensate flows. The creation of such highly low-loss structures for light is a prerequisite for complex light circuits, such as for quantum information processing for a new generation of computers. The researchers are now presenting their results in the journal Nature Photonics.

Light particles (photons) occur as tiny, indivisible portions. Many thousands of these light portions can be merged to form a single super-photon if they are...

Im Focus: Circular RNA linked to brain function

For the first time, scientists have shown that circular RNA is linked to brain function. When a RNA molecule called Cdr1as was deleted from the genome of mice, the animals had problems filtering out unnecessary information – like patients suffering from neuropsychiatric disorders.

While hundreds of circular RNAs (circRNAs) are abundant in mammalian brains, one big question has remained unanswered: What are they actually good for? In the...

Im Focus: RAVAN CubeSat measures Earth's outgoing energy

An experimental small satellite has successfully collected and delivered data on a key measurement for predicting changes in Earth's climate.

The Radiometer Assessment using Vertically Aligned Nanotubes (RAVAN) CubeSat was launched into low-Earth orbit on Nov. 11, 2016, in order to test new...

Im Focus: Scientists shine new light on the “other high temperature superconductor”

A study led by scientists of the Max Planck Institute for the Structure and Dynamics of Matter (MPSD) at the Center for Free-Electron Laser Science in Hamburg presents evidence of the coexistence of superconductivity and “charge-density-waves” in compounds of the poorly-studied family of bismuthates. This observation opens up new perspectives for a deeper understanding of the phenomenon of high-temperature superconductivity, a topic which is at the core of condensed matter research since more than 30 years. The paper by Nicoletti et al has been published in the PNAS.

Since the beginning of the 20th century, superconductivity had been observed in some metals at temperatures only a few degrees above the absolute zero (minus...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Call for Papers – ICNFT 2018, 5th International Conference on New Forming Technology

16.08.2017 | Event News

Sustainability is the business model of tomorrow

04.08.2017 | Event News

Clash of Realities 2017: Registration now open. International Conference at TH Köln

26.07.2017 | Event News

 
Latest News

New gene catalog of ocean microbiome reveals surprises

18.08.2017 | Life Sciences

Astrophysicists explain the mysterious behavior of cosmic rays

18.08.2017 | Physics and Astronomy

AI implications: Engineer's model lays groundwork for machine-learning device

18.08.2017 | Information Technology

VideoLinks
B2B-VideoLinks
More VideoLinks >>>