Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Researchers identify protein modules that "read" distinct gene "silencing codes"

01.08.2003


Since the time when humans first learned to record their thoughts in written form, codes have kept sensitive information from prying eyes. But conveying information through a code requires someone who can read it as well as write it. The same is true for one of nature´s methods for transmitting information that activates or silences a gene: the "histone code."



First formally proposed in 2000 by C. David Allis, Ph.D., and his postdoctoral fellow Brian Strahl, Ph.D., the histone code is a pattern of chemical flags that decorates the "tails" of spool-like proteins called histones. Double-helical DNA, spanning some seven feet in length, wraps around histones to condense and compact itself in the nucleus of all body cells. Together, histones and DNA form a largely protective and highly constrained structure called chromatin.

In the August 1 issue of Genes & Development, Allis, along with Rockefeller University colleagues Wolfgang Fischle, Ph.D., and Yanming Wang, Ph.D., and a team of researchers at University of Virginia led by Sepideh Khorasanizadeh, Ph.D., report that protein modules called chromodomains "read" the histone code responsible for silencing, or switching off, genes.


The discovery of histone code "readers" is a crucial next step in unlocking its secrets.

"Understanding chemical modifications to histones is becoming increasingly important for understanding such diseases as cancer," says Allis, Joy and Jack Fishman Professor and head of the Laboratory of Chromatin Biology at Rockefeller. "Ultimately, determining which proteins read the histone code will enable us to develop improved treatments for cancer in humans."

In addition, many scientists, including Allis, believe these chemical modifications are responsible for passing on inherited traits without changing the sequence of DNA, an emerging field called epigenetics.

The scientists demonstrate that chromodomains guide certain proteins to specific locations on the histone tail. And what´s more, they provide evidence that chromodomains, a form of molecular Velcro, read the histone code by distinguishing between two similar locations on the histone tail, a flexible protein chain that pokes through the tightly folded chromatin complex. Each chromodomain therefore docks to a specific location, but not another.

The research reported in the Genes & Development paper focuses on a chemical reaction called methylation that occurs on histone H3 (histones are made of four subunits called H2A, H2B, H3 and H4). During methylation, an enzyme called HMT (histone methyltransferase) attaches a methyl chemical group to lysine, one of the 20 amino acid building blocks of proteins. Lysine, in fact, is methylated at two similar, but not identical, positions in the tail of histone H3: at position 9 (Lys9) and position 27 (Lys27).

"Histone methyltransferases are one of the enzyme classes in the cell nucleus that `writes´ the histone code," says Allis.

In 2001, Allis´ laboratory at the University of Virginia (he joined Rockefeller in March 2003) showed that a protein called HP1 docks to methylated Lys9. HP1 is a protein associated with heterochromatin, a condensed form of chromatin that silences genes.

Importantly, Allis´s team showed that HP1´s chromodomain was the molecular Velcro that attached to methylated Lys9. A year later Khorasanizadeh and co-workers at University of Virginia used X-ray crystallography to visualize how the HP1 chromodomain recognizes the methylation mark on Lys9.

In the Genes & Development paper, Allis and Khorasanizadeh describe how another silencing protein, called Polycomb, binds to methylated Lys27. Both the HP1 and Polycomb chromodomains, although very similar in structure and composition, differ by a few amino acids. This difference ensures that HP1 only docks to a methylated Lys9, and Polycomb only docks to methylated Lys27.

"The structure tells us that the two chromodomains literally use the amino acids that are different between them," says Allis. "Each chromodmain contains a tiny groove that extends further than the sequence that´s immediately identical, and that´s where the molecular discrimination occurs."

In a crucial experiment, Allis and colleagues swapped the chromodomain on HP1 with the chromodomain on Polycomb. When the altered proteins were added to insect cells, they switched their chromosomal targets: HP1 docked with methylated Lys27 where Polycomb normally resides, and Polycomb docked with methylated Lys9 where HP1 normally resides.

"This shows conclusively that chromodomains act as guides to take these proteins to specific methyl marks on the histone tails," says Allis.

Both HP1 and Polycomb play important roles in silencing certain genes crucial for proper development of embryos in a range of species from fruit flies to humans. Loss of HP1 correlates with metastasis in human breast cancer cells, and mutations in Polycomb proteins have been linked to cancers of the prostate and the immune system.

"Methylated Lys9 and Lys27 are two of the hottest histone modification targets in cancer research," says Allis. "Now that we know how HP1 and Polycomb bind to their respective methyl marks, the next step is try to better understand how these effectors are released at the time during the cell cycle or during development when they are no longer needed to silence genes".

Contact: Joseph Bonner, bonnerj@rockefeller.edu

Joseph Bonner | EurekAlert!
Further information:
http://www.rockefeller.edu

More articles from Life Sciences:

nachricht Complex genetic regulation of flowering time
26.05.2020 | Christian-Albrechts-Universität zu Kiel

nachricht Bristol scientists see through glass frogs' translucent camouflage
26.05.2020 | University of Bristol

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: New double-contrast technique picks up small tumors on MRI

Early detection of tumors is extremely important in treating cancer. A new technique developed by researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from normal tissue. The work is published May 25 in the journal Nature Nanotechnology.

researchers at the University of California, Davis offers a significant advance in using magnetic resonance imaging to pick out even very small tumors from...

Im Focus: I-call - When microimplants communicate with each other / Innovation driver digitization - "Smart Health“

Microelectronics as a key technology enables numerous innovations in the field of intelligent medical technology. The Fraunhofer Institute for Biomedical Engineering IBMT coordinates the BMBF cooperative project "I-call" realizing the first electronic system for ultrasound-based, safe and interference-resistant data transmission between implants in the human body.

When microelectronic systems are used for medical applications, they have to meet high requirements in terms of biocompatibility, reliability, energy...

Im Focus: When predictions of theoretical chemists become reality

Thomas Heine, Professor of Theoretical Chemistry at TU Dresden, together with his team, first predicted a topological 2D polymer in 2019. Only one year later, an international team led by Italian researchers was able to synthesize these materials and experimentally prove their topological properties. For the renowned journal Nature Materials, this was the occasion to invite Thomas Heine to a News and Views article, which was published this week. Under the title "Making 2D Topological Polymers a reality" Prof. Heine describes how his theory became a reality.

Ultrathin materials are extremely interesting as building blocks for next generation nano electronic devices, as it is much easier to make circuits and other...

Im Focus: Rolling into the deep

Scientists took a leukocyte as the blueprint and developed a microrobot that has the size, shape and moving capabilities of a white blood cell. Simulating a blood vessel in a laboratory setting, they succeeded in magnetically navigating the ball-shaped microroller through this dynamic and dense environment. The drug-delivery vehicle withstood the simulated blood flow, pushing the developments in targeted drug delivery a step further: inside the body, there is no better access route to all tissues and organs than the circulatory system. A robot that could actually travel through this finely woven web would revolutionize the minimally-invasive treatment of illnesses.

A team of scientists from the Max Planck Institute for Intelligent Systems (MPI-IS) in Stuttgart invented a tiny microrobot that resembles a white blood cell...

Im Focus: NASA's Curiosity rover finds clues to chilly ancient Mars buried in rocks

By studying the chemical elements on Mars today -- including carbon and oxygen -- scientists can work backwards to piece together the history of a planet that once had the conditions necessary to support life.

Weaving this story, element by element, from roughly 140 million miles (225 million kilometers) away is a painstaking process. But scientists aren't the type...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Dresden Nexus Conference 2020: Same Time, Virtual Format, Registration Opened

19.05.2020 | Event News

Aachen Machine Tool Colloquium AWK'21 will take place on June 10 and 11, 2021

07.04.2020 | Event News

International Coral Reef Symposium in Bremen Postponed by a Year

06.04.2020 | Event News

 
Latest News

NIST researchers boost microwave signal stability a hundredfold

26.05.2020 | Physics and Astronomy

Complex genetic regulation of flowering time

26.05.2020 | Life Sciences

'One-way' electronic devices enter the mainstream

26.05.2020 | Information Technology

VideoLinks
Science & Research
Overview of more VideoLinks >>>