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Structure of Nurf55 bound to the histone H3 tail.











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FMI

May 11 2011

Chromatin environment regulates polycomb repressive complex 2 activity

In a study published in Molecular Cell, scientists from the Friedrich Miescher Institute for Biomedical Research of the Novartis Research Foundation describe how a conserved repressor complex, which helps determine developmental patterns of gene expression, adapts its activity based on the chromatin context it encounters. This new found mechanism ensures that cells retain control over important developmental programs. Loss of cell-type specific patterning of gene expression is a well-documented hallmark of cancer cells.

PRC2, which is short for polycomb repressive complex 2, is a key determinant of cell fate decision processes. PRC2, which is highly conserved from plants to humans, helps silence specific genes and thereby controls developmental programs. Not surprisingly de-regulation of PRC2 is frequently observed in cancer cells. How PRC2 activity is regulated, and how the regulation of developmental programs is passed on to the daughter cells through epigenetic marks, has remained enigmatic.

Scientists from the Friedrich Miescher Institute for Biomedical Research in collaboration with colleagues from the Novartis Institutes for BioMedical Research in Shanghai and Basel, and the Max-Planck Institutes in Munich and Göttingen, have been able to dissect the molecular mechanism of PRC2 regulation. Their results are now available online and will be published in the next issue of the renowned journal Molecular Cell.

The PRC2 complex is composed of four subunits designated E(z), Su(z)12, Nurf55 and Esc. They work together to add methyl groups onto histone tails and thereby influence the transcriptional state of genes. The methylation marks added by PRC2 confer a transcriptionally inactive state. PRC2 can bind to inactivating methyl groups on histones, which in turn stimulates its own methyltransferase activity. Through this positive feed-forward loop long stretches of chromatin can be marked with inactive chromatin signatures. "In our field one of the most intriguing questions is how the different marks on histones correlate with transcriptional activity and how they are maintained to control cell fate," comments Nicolas Thomä, group leader at the FMI and last author of the present study, "Through the structural analysis of Nurf55 and the concomitant functional study of the entire PRC2 complex, we have been able to determine the mechanism of how PRC2 maintains methylation patterns, which then directly affect developmental programs."

In their study, the scientists show that PRC2 distinguishes between different methylation states and that the histone signatures directly control PRC2 activity. While repressed chromatin, methylated at histone H3 lysine 27, activates PRC2, chromatin carrying transcriptionally active signatures (H3 lysine 4 and H3 lysine 36 trimethyl-marks) directly inhibit the complex in an allosteric fashion. This regulatory switch is driven by the Su(z)12 subunit. "We were surprised to see how well PRC2 can actually read the methylation state of chromatin, and that chromatin in fact directly tunes its enzymatic activity. PRC2 is a thightly regulated logic switch that autonomously knows what transcriptional state the chromatin is in, and that is able to respond differentially to these epigenetic signatures. In a developmental context, it is absolutely crucial for PRC2 to know when to stop and not to deactivate stretches of chromatin that should be active. The fact that the PRC2 complex alone can autonomously copy repressive chromatin stretches without overwriting active domains was a rather unexpected finding of the present study. This now gives us a framework to think about how repressive and active chromatin signatures are re-established after replication," comments Thomä. "In the end, this structural description of the PRC2 complex and the mechanistic understanding of PRC2 function should allow us in the future to modulate PRC2 function in cancer cells and beyond."

Publication in Molecular Cell
Schmitges FW, Prusty AB, Faty M, Stützer A, Lingaraju GM, Aiwaian J, Sack R, Hess D, Li L, Zhou S, Bunker RD, Wirth U, Bouwmeester T, Bauer A, Ly-Hartig N, Zhao K, Chan H, Gu J, Gut H, Fischle W, Müller J, Thomä NH. Histone methylation by PRC2 is inhibited by active chromatin marks. Molecular Cell, 42:330-341, May 6, 2011.

More about Nicolas Thomä
Nicolas Thomä is a group leader at the FMI. He is interested in the machinery that controls the integrity of the DNA. He combines X-ray crystallography with biochemical and biophysical studies to better understand large protein complexes involved in crucial cellular functions such as DNA repair, telomere maintenance and epigenetics in health and disease.
» More about Nicolas Thomaä

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