Epigenetics: Finding the right data signals

Skip to Navigation

Ezine

  • Published: Jan 15, 2015
  • Channels: Chemometrics & Informatics
thumbnail image: Epigenetics: Finding the right data signals

Function and form

Epigenetic signals help determine which genes are activated at a given time in a particular cell in the body. Now, researchers in Germany have used a  novel analytical method to enable them to systematically characterize the relevant epigenetic tags and so reveal how the system adapts to the loss of single epigenetic writer and eraser enzymes.

Epigenetic signals help determine which genes are activated at a given time in a particular cell in the body. Now, researchers in Germany have used a novel analytical method to enable them to systematically characterize the relevant epigenetic tags and so reveal how the system adapts to the loss of single epigenetic writer and eraser enzymes.

Every cell, with a few exceptions, carries a copy of an organism's DNA. However, each cell type only expresses a sub-set of all the genes available that it needs for its particular function, whether muscle cell, nerve cell, brain cell etc. The activation of specific genes at specific times is determined by cell-type-specific chemical modification of the proteins that package the genes in the cell nucleus, the histones. In turn, these modifications are controlled by enzymes, writers and erasers, respectively, that attach or remove the various tags themselves controlled by epigenetic signal pathways that respond to changes in the environment in which the cell finds itself.

"Perturbations of these signalling pathways can precipitate the development of diseases, such as cancer or Alzheimer's disease," explains Peter Becker of Ludwig-Maximillians-Universität München. He and doctoral student Christian Feller have now characterized the enzymes involved in signalling pathways associated with attachment of acetyl groups to histones; they provide details in the journal Molecular Cell.

The four histones of the acetyltransferase

The histones, of which there are four main types, form spools around which nuclear DNA is tightly wrapped and thus packed into chromatin within the cell nucleus. Packed up like this makes the DNA inaccessible to the gene-reading enzymes. However, the attachment of those acetyl groups to specific exposed sites weakens the grip the histones have on the DNA and so unmasks the genes at those points allowing them to become activated.

"Although histone acetylation as such has been known for a long time, we know relatively little about the target sites in the histones, how the presence of groups at neighbouring sites gives rise to motifs, and how frequently such motifs appear in the cell nucleus," Becker explains. Researchers have suggested that different acetylation motifs are linked to different epigenetic signalling pathways. Histone acetylation is carried out by acetyltransferases, of which there are many, sixty in humans, some 40 in the fruitfly Drosophila melanogaster, most of which closely resemble their human counterparts. Becker explains that it was not possible technically until now to unravel the contribution of individual acetyltransferases to the formation of acetylation motifs.

Cancer lead

He and his colleagues used mass spectrometry and proteomics to analyse protein fragments and so reliably quantify both single histone modifications and their various combinations. "Our close cooperation with two experts in proteomics, Axel Imhof and Ignasi Fornè, was crucial to our success. It enabled us to develop an optimized procedure for mass spectrometric analysis of histone fragments that can identify many of the acetylation motifs in the cell," explains Feller. The team worked with fruitfly enzymes and blocked each acetyltransferase, and deacetylase, in turn to help them define the contribution of each. The experiments show that adjacent acetyl groups also affect how target sites are recognized by the enzymes.

"Our most surprising finding was that the depletion of single acetyltransferases often leads to the attachment of novel acetylation tags at nearby sites, so that the overall level of acetylation is often very similar to the normal one," adds Feller. Histone acetylation seems to be able to compensate, in the short term, for the loss of individual functional components. This, "illustrates the complexity of the circuitry that links the various epigenetic signalling pathways," Becker adds.

"The knowledge gained through this latest work about the histone modifications patterns and the enzymes that bring it about allows evaluating the action of drugs that affect histone acetylation patterns, several of which are already used in cancer therapy," Becker told SpectroscopyNOW. He adds that, "The methodology we used will allow correlating global histone modification patterns with certain cellular states, including diseased or aging cells. Monitoring how the entire system changes upon treatment of tumour cells with drugs will not only lead to a better understanding of their effects, but also reveal how the system responds to chemotherapy."

Related Links

Molecular Cell 2015, in press: "Global and Specific Responses of the Histone Acetylome to Systematic Perturbation"

Article by David Bradley

The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

Social Links

Share This Links

Bookmark and Share

Microsites

Suppliers Selection
Societies Selection

Banner Ad

Click here to see
all job opportunities

Copyright Information

Interested in separation science? Visit our sister site separationsNOW.com

Copyright © 2017 John Wiley & Sons, Inc. All Rights Reserved