Researchers develop 'cytological ruler' to build 3D map of human genome

August 28, 2018

It has been almost 20 years since the human genome was first sequenced, but researchers still know little about how the genome is folded up and organized within cells. In a paper to be published August 28 in theJournal of Cell Biology, researchers from the University of Illinois at Urbana-Champaign describe a new technique that can measure the position of every single gene in the nucleus to build a 3D picture of the genome's organization.

The location of genes--whether they are close to the edge or the center of the nucleus, for example--may have significant effects on their activity, and a gene's position may therefore change as a cell develops or becomes diseased. Researchers can examine the position of individual genes using a microscope, but determining the position of every gene at the same time is impossible this way.

Yu Chen, Andrew Belmont, and colleagues from the University of Illinois at Urbana-Champaign have now developed a technique called tyramide signal amplification sequencing (TSA-Seq) that allows the distance of every gene from specific nuclear landmarks to be measured simultaneously. The study was carried out in collaboration with Jian Ma's group at Carnegie Mellon University and with researchers at the Netherlands Cancer Institute and Northwestern University Feinberg School of Medicine.

The TSA-Seq technique involves targeting an enzyme--horseradish peroxidase--to particular nuclear structures, such as the nuclear lamina that surrounds the nucleus or protein-containing granules called nuclear speckles that tend to be found in the center of the nucleus. The horseradish peroxidase then generates a highly reactive molecule called tyramide that can be used to label any DNA in the enzyme's vicinity. The closer a gene is to the enzyme, the more it will be labeled. So, when researchers subsequently sequence the cells' DNA, they can calculate how close each gene was to the nuclear structure tagged with horseradish peroxidase.

"TSA-Seq is the first genome-wide method capable of estimating actual distances of genes from particular nuclear subcompartments," says Chen.

Chen and colleagues tested their approach in leukemia cells and found that genes closer to nuclear speckles tended to be more active than genes closer to the nuclear lamina. Indeed, by examining the position of neighboring genes, the researchers were able to trace whole sections of chromosomes that looped out from the nuclear periphery toward speckles in the center of the nucleus. The function of nuclear speckles is unknown, but the regions of chromosomes close to speckles seem to be "hot zones" of gene activity.

"The logic of this nuclear organization remains to be determined, but our model would suggest that chromosome movements of just a few hundred nanometers could have substantial functional significance," Belmont says. A small shift in a gene's position so that it lies close to a nuclear speckle could be sufficient to dramatically enhance the gene's activity, for example.

The researchers say that the technique still needs to be improved, but they hope to use TSA-Seq to map the positions of genes in other cell types and examine how these positions change as cells develop or become diseased.
-end-
Chen et al., 2018. J. Cell Biol.http://jcb.rupress.org/cgi/doi/10.1083/jcb.201807108?PR

About the Journal of Cell BiologyTheJournal of Cell Biology (JCB)features peer-reviewed research on all aspects of cellular structure and function. All editorial decisions are made by research-active scientists in conjunction with in-house scientific editors. JCBmakes all of its content free online no later than six months after publication. Established in 1955, JCB is published by Rockefeller University Press. For more information, visit jcb.org.

Visit our Newsroom, and sign up for a weekly preview of articles to be published. Embargoed media alerts are for journalists only.

Follow JCB on Twitter at @JCellBiol">@JCellBiol and @RockUPress">@RockUPress.

Rockefeller University Press

Related Genome Articles from Brightsurf:

Genome evolution goes digital
Dr. Alan Herbert from InsideOutBio describes ground-breaking research in a paper published online by Royal Society Open Science.

Breakthrough in genome visualization
Kadir Dede and Dr. Enno Ohlebusch at Ulm University in Germany have devised a method for constructing pan-genome subgraphs at different granularities without having to wait hours and days on end for the software to process the entire genome.

Sturgeon genome sequenced
Sturgeons lived on earth already 300 million years ago and yet their external appearance seems to have undergone very little change.

A sea monster's genome
The giant squid is an elusive giant, but its secrets are about to be revealed.

Deciphering the walnut genome
New research could provide a major boost to the state's growing $1.6 billion walnut industry by making it easier to breed walnut trees better equipped to combat the soil-borne pathogens that now plague many of California's 4,800 growers.

Illuminating the genome
Development of a new molecular visualisation method, RNA-guided endonuclease -- in situ labelling (RGEN-ISL) for the CRISPR/Cas9-mediated labelling of genomic sequences in nuclei and chromosomes.

A genome under influence
References form the basis of our comprehension of the world: they enable us to measure the height of our children or the efficiency of a drug.

How a virus destabilizes the genome
New insights into how Kaposi's sarcoma-associated herpesvirus (KSHV) induces genome instability and promotes cell proliferation could lead to the development of novel antiviral therapies for KSHV-associated cancers, according to a study published Sept.

Better genome editing
Reich Group researchers develop a more efficient and precise method of in-cell genome editing.

Unlocking the genome
A team led by Prof. Stein Aerts (VIB-KU Leuven) uncovers how access to relevant DNA regions is orchestrated in epithelial cells.

Read More: Genome News and Genome Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.