Nav: Home

A three-dimensional map of the genome

March 08, 2017

Cells face a daunting task. They have to neatly pack a several meter-long thread of genetic material into a nucleus that measures only five micrometers across. This origami creates spatial interactions between genes and their switches, which can affect human health and disease. Now, an international team of scientists has devised a powerful new technique that 'maps' this three-dimensional geography of the entire genome. Their paper is published in Nature.

Genes are activated to produce RNA and proteins, then switched off again when the molecules are no longer needed. Both the gene and its switches are DNA sequences, and they may lie far apart on the linear genome. This presents a challenge for the cell, because these regions usually have to be brought into contact to activate the gene.

It also creates a problem for scientists trying to understand one of the central questions in biology: how do cells decide which genes should be activated, and when? The answer will partly depend on matching every gene to its control sequences. But DNA strands are too thin to be tracked under the microscope, and even if that were possible, you'd have the vast amount of DNA in the nucleus to contend with. Imagine examining a tangle of yarn the size of the Earth in hopes of observing an encounter between individual strands.

A new technique called Genome Architecture Mapping, or GAM, now helps to identify these contacts. It involves flash-freezing tissue or cells, then cutting thin slices of individual nuclei. The tiny amount of DNA within each slice of the nucleus is then sequenced, and the team deploys a mathematical model, named SLICE, to identify 'hotspots' of increased interaction between strands. The model looks at the frequency with which different genomic regions appear in the slice to infer information about the relative positions of genes and regions called enhancers that activate them.

"An analogy might be this; if you want to understand how school children interact you might take occasional photographs of where they sit in the canteen or appear together in the playground", explains joint-lead author Ana Pombo, who began the project whilst working at the MRC London Institute of Medical Sciences (LMS) and is now based at the Berlin Institute for Medical Systems Biology, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC) and the Berlin Institute of Health (BIH). "If you do that many times over a month, you will begin to see a pattern in those who often sit next to each other, or who run around together while playing. These random snapshots might tell you about their social interactions."

"This is made possible by filtering out random encounters from real interactions using mathematical methods," says the joint-lead author Mario Nicodemi at the Università di Napoli Federico II, who conceived such mathematical models and, aided by his PhD student Antonio Scialdone, developed them.

Paul Edwards, of the Hutchison/MRC Research Centre and Department of Pathology at the University of Cambridge, and Ana Pombo had the initial idea before the techniques necessary to do the experiment were available. "My research team optimised the approach, and as new technical steps came along we added them to our method," she says.

The study, which appears today in Nature, applies the method to mouse embryonic stem cells and the authors hope it will help shed light on many genes whose activity is disturbed in some very serious diseases. In some diseases, the problem lies within the sequence of a gene, but defects in regulatory regions found elsewhere in the genome can be equally dangerous and much harder to understand. The new data provides a long list of new suspects that can now be scrutinized by researchers.

Whilst previous studies have identified two-way contacts, this information does not reveal how often such contacts take place and by implication how important they might be, Pombo says: "They can spot that you and I are friends, but not how strong this friendship is relative to everyone else."

"People have been measuring two-way contacts for a long time," says Robert Beagrie, joint first author on the paper, who was a PhD student with Ana Pombo at the LMS when he collected the data for the study and is now based at the University of Oxford. "Those studies have often shown that you can have a set of different DNA elements that interact with each other in pairs. With this new approach we are able to generate a genome-wide catalogue of all the regions that we are confident interact in groups." Now, the researchers are able to reliably detect and quantify so-called 'three-way contacts' in regions of the genome that are vigorously expressed.

But perhaps the most notable advance of through GAM is that experiments are based on single cells - whether common or scarce in a tissue - and track their positions relative to each other within the tissue. Existing methods require lots of cells of the same type, which has made it difficult to study the biology and diseases of rare types. "There is huge potential for applying this in human tissue samples to catalogue contacts between regulatory regions and their target genes, and to use that to understand genetic variation and how it might alter aspects of nuclear biology," Pombo says.

Some researchers are starting to show interest in using the technique to explore what happens when retroviruses insert their DNA into the genome of a host. Cancer scientists are also keen to create DNA maps of particular areas of a tumor. "By exploiting the unique nature of GAM data, mathematical models can reliably derive such information, opening the way to identify multiple, group interactions that could play a key role in the regulation of genes," explains Nicodemi. "We can now ask whether a gene is contacted at the same time by all of its enhancers, or by each enhancer one at a time?", Beagrie says. "We know that many genes that are important for early development have multiple enhancers. But how and why they are acting to regulate genes remain unanswered questions."
-end-
Robert A. Beagrie, Antonio Scialdone, et al. (2017): "Complex multi-enhancer contacts captured by Genome Architecture Mapping (GAM)." Nature. doi:10.1038/nature21411

Max Delbrück Center for Molecular Medicine in the Helmholtz Association

Related Dna Articles:

In one direction or the other: That is how DNA is unwound
DNA is like a book, it needs to be opened to be read.
DNA is like everything else: it's not what you have, but how you use it
A new paradigm for reading out genetic information in DNA is described by Dr.
A new spin on DNA
For decades, researchers have chased ways to study biological machines.
From face to DNA: New method aims to improve match between DNA sample and face database
Predicting what someone's face looks like based on a DNA sample remains a hard nut to crack for science.
Self-healing DNA nanostructures
DNA assembled into nanostructures such as tubes and origami-inspired shapes could someday find applications ranging from DNA computers to nanomedicine.
DNA design that anyone can do
Researchers at MIT and Arizona State University have designed a computer program that allows users to translate any free-form drawing into a two-dimensional, nanoscale structure made of DNA.
DNA find
A Queensland University of Technology-led collaboration with University of Adelaide reveals that Australia's pint-sized banded hare-wallaby is the closest living relative of the giant short-faced kangaroos which roamed the continent for millions of years, but died out about 40,000 years ago.
DNA structure impacts rate and accuracy of DNA synthesis
DNA sequences with the potential to form unusual conformations, which are frequently associated with cancer and neurological diseases, can in fact slow down or speed up the DNA synthesis process and cause more or fewer sequencing errors.
Changes in mitochondrial DNA control how nuclear DNA mutations are expressed in cardiomyopathy
Differences in the DNA within the mitochondria, the energy-producing structures within cells, can determine the severity and progression of heart disease caused by a nuclear DNA mutation.
Switching DNA and RNA on and off
DNA and RNA are naturally polarised molecules. Scientists believe that these molecules have an in-built polarity that can be reoriented or reversed fully or in part under an electric field.
More Dna News and Dna Current Events

Top Science Podcasts

We have hand picked the top science podcasts of 2019.
Now Playing: TED Radio Hour

In & Out Of Love
We think of love as a mysterious, unknowable force. Something that happens to us. But what if we could control it? This hour, TED speakers on whether we can decide to fall in — and out of — love. Guests include writer Mandy Len Catron, biological anthropologist Helen Fisher, musician Dessa, One Love CEO Katie Hood, and psychologist Guy Winch.
Now Playing: Science for the People

#541 Wayfinding
These days when we want to know where we are or how to get where we want to go, most of us will pull out a smart phone with a built-in GPS and map app. Some of us old timers might still use an old school paper map from time to time. But we didn't always used to lean so heavily on maps and technology, and in some remote places of the world some people still navigate and wayfind their way without the aid of these tools... and in some cases do better without them. This week, host Rachelle Saunders...
Now Playing: Radiolab

Dolly Parton's America: Neon Moss
Today on Radiolab, we're bringing you the fourth episode of Jad's special series, Dolly Parton's America. In this episode, Jad goes back up the mountain to visit Dolly's actual Tennessee mountain home, where she tells stories about her first trips out of the holler. Back on the mountaintop, standing under the rain by the Little Pigeon River, the trip triggers memories of Jad's first visit to his father's childhood home, and opens the gateway to dizzying stories of music and migration. Support Radiolab today at Radiolab.org/donate.