Until recently, the chemical marks littering the DNA inside our cells like trees dotting a landscape could only be studied one gene at a time. But new high-throughput DNA sequencing technology has enabled researchers at the Salk Institute for Biological Studies to map the precise position of these individual DNA modifications throughout the genome of the plant Arabidopsis thaliana, and chart its effect on the activity of any of Arabidopsis’ roughly 26,000 genes.
“For a long time the prevailing view held that individual modifications are not critical,” says Joseph Ecker, Ph.D., a professor in the Plant Biology laboratory and director of the Salk Institute Genomic Analysis Laboratory. “The genomes of higher eukaryotes are peppered with modifications but unless you can take a detailed look at a large scale there is no way of knowing whether a particular mark is critical or not.”
The Salk study, which appears today in the online issue of Cell, paints a detailed picture of a dynamic and ever-changing, yet highly controlled, epigenome, the layer of genetic control beyond the regulation inherent in the sequence of the genes themselves.
Being able to study the epigenome in great detail and in its entirety will provide researchers with a better understanding of plant productivity and stress resistance, the dynamics of the human genome, stem cells’ capacity to self-renew and how epigenetic factors contribute to the development of tumors and disease.
Discoveries in recent years made it increasingly clear that there is far more to genetics than the sequence of building blocks that make up our genes. Adding molecules such as methyl groups to the backbone of DNA without altering the letters of the DNA alphabet can change how genes interact with the cell’s transcribing machinery and hand cells an additional tool to fine-tune gene expression.
“The goal of our study was to integrate multiple levels of epigenetic information since we still have a very poor understanding of the genome-wide regulation of methylation and its effect on the transcriptome,” explains postdoctoral researcher and co-first author Ryan Lister, Ph.D.
The transcriptome encompasses all RNA copies or transcripts made from DNA. The bulk of transcripts consists of messenger RNAs, or mRNAs, that serve as templates for the manufacture of proteins but also includes regulatory small RNAs, or smRNAs. The latter wield their power over gene expression by literally cutting short the lives of mRNAs or tagging specific sequences in the genome for methylation.
But before Lister could start to unravel the multiple layers of epigenetic regulation that control gene expression, he had to pioneer new technologies that allowed him to look at genome-wide methylation at single-base resolution and to sequence the complete transcriptome within a reasonable timeframe.
Collaborating scientists at the ARC Centre of Excellence in Plant Energy Biology at the University of Western Australia in Perth developed a powerful, web-based genome browser, which played a crucial role in unlocking the information hidden in the massive datasets.
Cells employ a whole army of enzymes that add methyl groups at specific sites, maintain established patterns or remove undesirable methyl groups. When Lister and his colleagues compared normal cells with cells lacking different combination of enzymes they discovered that cells put a lot of effort in keeping certain areas of the genome methylation-free.
On the flipside, the Salk researchers found that when they knocked out a whole class of methylases, a different type of methylase would step into the breach for the missing ones. This finding is relevant for a new class of cancer drugs that work by changing the methylation pattern in tumor cells.
“You might succeed in removing one type of methylation but end up with increasing a different type,” says Ecker. “But very soon we will be able to look and see what kind of compensatory changes are happening and avoid unintended consequences.”
Previous studies had found that a subset of smRNAs could direct methylation enzymes to the region of genomic DNA to which they aligned. Overlaying genome-wide methylome and smRNA datasets confirmed increased methylation precisely within the stretch of DNA that matched the sequence of the smRNA. Conversely, heavily methylated smRNA loci tended to spawn more smRNAs.
“We looked at a plant genome but our method can be applied to any system, including humans,” says Lister. Although the human genome is about 20 times bigger than the genome of Arabidopsis – plant biologists’ favorite model system not least because of its compact genome – Ecker predicts that within a year or so, sequencing technology will have advanced far enough to put the 3 billion base pairs of the human genome and their methyl buddies within reach.
“This really is just the beginning of unmasking the role of these powerful epigenetic regulatory mechanisms in eukaryotes,” says Ecker.
Gina Kirchweger | EurekAlert!
To proliferate or not to proliferate
21.03.2019 | Max-Planck-Institut für molekulare Zellbiologie und Genetik
Discovery of a Primordial Metabolism in Microbes
21.03.2019 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH
Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.
The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...
Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.
Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...
The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.
A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...
Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.
"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...
New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum
For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...
11.03.2019 | Event News
01.03.2019 | Event News
28.02.2019 | Event News
21.03.2019 | Life Sciences
21.03.2019 | Physics and Astronomy
21.03.2019 | HANNOVER MESSE