Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Making and breaking heterochromatin

26.09.2012
To fit the two-meter long DNA molecule into a cell nucleus that is only a few thousandths of a millimetre in size, long sections of the DNA must be strongly compacted. Epigenetic marks maintain these sections, known as heterochromatin.

Scientists of the Max Planck Institute of Immunobiology and Epigenetics in Freiburg have now discovered two further mechanisms necessary for the formation of heterochromatin. The research group, led by Thomas Jenuwein, describes two novel enzymes, Prdm3 and Prdm16, which attach a methyl group to a particular packaging protein of the DNA.


Methylation of histones within heterochromatin: The enzymes Prdm3 and Prdm16 attach a methyl group to histone H3. In the cell nucleus, Suv39h attaches two further methyl groups. The cell appears to require this triple methylation for heterochromatin to be stable.
© Art For Science


In euchromatin and heterochromatin, the binding locations for transcription factors are distributed differently. In euchromatin they are concentrated at specific locations, in heterochromatin they are distributed more randomly.
© Art For Science

These epigenetic marks assure that heterochromatin, and with it the structure of the cell nucleus, remain intact. Moreover, in an additional study they have determined that transcription factors bind within heterochromatin and repress the output of non-coding RNA. In contrast to less densely compacted regions known as euchromatin, in which the transcription factors accumulate at specific sites, the binding sites of transcription factors in heterochromatin are much more randomly distributed.

Chromatin consists of the DNA molecule and numerous proteins, including histones, which act as packaging proteins. In contrast to the easily accessible euchromatin, which contains the majority of genes, the densely compacted heterochromatin is mostly made of up of repetitive sequences that are able to form non-coding RNA-molecules. Heterochromatic sections are found at centromeres and at chromosome ends, the telomeres. Chemical modifications of histones can alter the degree to which chromatin is compacted. For example, methyltransferases add methyl groups to proteins at various positions. These epigenetic alterations regulate the formation and maintenance of heterochromatin.

Ines Pinheiro, a doctoral student in Thomas Jenuwein’s department, has now discovered that Prdm3 and Prdm16 function as methyltransferases and attach a methyl group to histone H3 at the lysine 9 (H3K9) position. Until now, both proteins were thought to be just transcription factors, regulating the activity of various genes. Experiments in which the Freiburg-based researchers switch off both enzymes demonstrate how important Prdm3 and Prdm16 are. Heterochromatin breaks down and the heterochromatin regions can be read. “Our experiments show that Prdm3 and Prdm16 attach a methyl group at H3K9. This single-methylated H3 (H3K9me1) is then transported into the cell nucleus and inserted into heterochromatin. Only then heterochromatin remains intact,” explains Thomas Jenuwein, Director at the Max Planck Institute of Immunobiology and Epigenetics. Other methyltransferases, such as Suv39h, can add another two methyl groups (H3K9me3) to the single-methylated histone and thus further increase heterochromatin stability.

Moreover, the researchers in Freiburg observed that the lamina of the cell nucleus is impaired without Prdm3 and Prdm16. Heterochromatin must be associated with this layer of lamina proteins at the inner nuclear membrane. “The cell apparently requires methylation at H3K9 and a yet-unknown chromatin or lamina protein by Prdm3 and Prdm16 for heterochromatin to be stable. As with other methyltransferases, we assume that both enzymes can methylate other molecules besides histones. However, we do not know whether the destruction of the lamina is triggered by the loss of heterochromatin or by the absence of methylation at a lamina protein,” says Jenuwein.

However, it is not just methylation of histones that is necessary to maintain heterochromatic regions. In a further study, doctoral students Aydan Karslioglu and Valentina Perrera examined the role of transcription factors, i.e. proteins that bind to DNA and control gene activity – in the case of heterochromatin, the repression of non-coding RNA molecules. This study showed that two transcription factors are essential for intact heterochromatin: Pax3 and Pax9. Only when both factors and their binding sites are present in the repetitive DNA heterochromatin remains intact. The researchers assume, however, that additional transcription factors can also bind to repetitive sequences in heterochromatin.
Transcription factors thus control gene activity in euchromatin, as well as in heterochromatin. Despite this, there are differences between the two. In heterochromatin, the binding locations are distributed comparatively at random over the DNA strand, whereas euchromatin is concentrated at the locations important for gene regulation. “In our data, the distribution within heterochromatin looks like the Aigulles Droites in the Mont Blanc massif: a lot of small peaks without deep valleys in between. Euchromatin looks more like the Matterhorn: one high peak without secondary peaks,” as Thomas Jenuwein describes the results.

For the researchers, an important difference between heterochromatin and euchromatin lies in the control of gene activity and the formation of RNA. “In heterochromatin, the binding sites for transcription factors are distributed more randomly, so that they cannot reinforce or intensify one another's effect. The DNA therefore cannot be read in such a precise and coordinated manner at these locations. Inhibiting influences that largely turn off heterochromatin dominate in the end,” says Jenuwein. With euchromatin, in contrast, the transcription factors bind to DNA in such a way that they enhance each other's function. This permits precise control over the gene activity.

Contact

Prof. Dr. Thomas Jenuwein
Max Planck Institute of Immunobiology and Epigenetics, Freiburg
Phone: +49 761 5108-785
Fax: +49 761 5108-790
Email: jenuwein@­immunbio.mpg.de
Dr. Monika Lachner
Max Planck Institute of Immunobiology and Epigenetics, Freiburg
Phone: +49 761 5108-786
Email: lachner@­immunbio.mpg.de
Original publications
Inês Pinheiro, Raphaël Margueron, Nicholas Shukeir, Michael Eisold, Christoph Fritzsch, Florian M. Richter, Gerhard Mittler, Christel Genoud, Susumu Goyama, Mineo Kurokawa, Jinsook Son, Danny Reinberg, Monika Lachner & Thomas Jenuwein
Prdm3 and Prdm16 are H3K9me1 Methyltransferases Required for Mammalian Heterochromatin Integrity

Cell - 31 August 2012 (Vol. 150, Issue 5, pp. 948-960)

Aydan Bulut-Karslioglu, Valentina Perrera, Manuela Scaranaro, Inti Alberto de la Rosa-Velazquez, Suzanne van de Nobelen, Nicholas Shukeir, Johannes Popow, Borbala Gerle, Susanne Opravil, Michaela Pagani, Simone Meidhof, Thomas Brabletz, Thomas Manke, Monika Lachner & Thomas Jenuwein
A transcription factor–based mechanism for mouse heterochromatin formation
Nature Structural & Molecular Biology (2012) Advance Online Publication, 16 September 2012 doi:10.1038/nsmb.2382

Prof. Dr. Thomas Jenuwein | Max-Planck-Institute
Further information:
http://www.mpg.de/6366051/heterochromatin-formation

More articles from Life Sciences:

nachricht Researchers develop eco-friendly, 4-in-1 catalyst
25.04.2017 | Brown University

nachricht Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017
25.04.2017 | Laser Zentrum Hannover e.V.

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Making lightweight construction suitable for series production

More and more automobile companies are focusing on body parts made of carbon fiber reinforced plastics (CFRP). However, manufacturing and repair costs must be further reduced in order to make CFRP more economical in use. Together with the Volkswagen AG and five other partners in the project HolQueSt 3D, the Laser Zentrum Hannover e.V. (LZH) has developed laser processes for the automatic trimming, drilling and repair of three-dimensional components.

Automated manufacturing processes are the basis for ultimately establishing the series production of CFRP components. In the project HolQueSt 3D, the LZH has...

Im Focus: Wonder material? Novel nanotube structure strengthens thin films for flexible electronics

Reflecting the structure of composites found in nature and the ancient world, researchers at the University of Illinois at Urbana-Champaign have synthesized thin carbon nanotube (CNT) textiles that exhibit both high electrical conductivity and a level of toughness that is about fifty times higher than copper films, currently used in electronics.

"The structural robustness of thin metal films has significant importance for the reliable operation of smart skin and flexible electronics including...

Im Focus: Deep inside Galaxy M87

The nearby, giant radio galaxy M87 hosts a supermassive black hole (BH) and is well-known for its bright jet dominating the spectrum over ten orders of magnitude in frequency. Due to its proximity, jet prominence, and the large black hole mass, M87 is the best laboratory for investigating the formation, acceleration, and collimation of relativistic jets. A research team led by Silke Britzen from the Max Planck Institute for Radio Astronomy in Bonn, Germany, has found strong indication for turbulent processes connecting the accretion disk and the jet of that galaxy providing insights into the longstanding problem of the origin of astrophysical jets.

Supermassive black holes form some of the most enigmatic phenomena in astrophysics. Their enormous energy output is supposed to be generated by the...

Im Focus: A Quantum Low Pass for Photons

Physicists in Garching observe novel quantum effect that limits the number of emitted photons.

The probability to find a certain number of photons inside a laser pulse usually corresponds to a classical distribution of independent events, the so-called...

Im Focus: Microprocessors based on a layer of just three atoms

Microprocessors based on atomically thin materials hold the promise of the evolution of traditional processors as well as new applications in the field of flexible electronics. Now, a TU Wien research team led by Thomas Müller has made a breakthrough in this field as part of an ongoing research project.

Two-dimensional materials, or 2D materials for short, are extremely versatile, although – or often more precisely because – they are made up of just one or a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

Expert meeting “Health Business Connect” will connect international medical technology companies

20.04.2017 | Event News

Wenn der Computer das Gehirn austrickst

18.04.2017 | Event News

7th International Conference on Crystalline Silicon Photovoltaics in Freiburg on April 3-5, 2017

03.04.2017 | Event News

 
Latest News

NASA's Fermi catches gamma-ray flashes from tropical storms

25.04.2017 | Physics and Astronomy

Researchers invent process to make sustainable rubber, plastics

25.04.2017 | Materials Sciences

Transfecting cells gently – the LZH presents a GNOME prototype at the Labvolution 2017

25.04.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>