The human genome: A complex orchestra

August 20, 2015

A team of Swiss geneticists from the University of Geneva (UNIGE), the École Polytechnique Fédérale de Lausanne (EPFL), and the University of Lausanne (UNIL) discovered that genetic variation has the potential to affect the state of the genome at many, seemingly separated, positions and thus modulate gene activity, much like a conductor directing the performers of a musical ensemble to play in harmony. These unexpected results, published in Cell, reveal the versatility of genome regulation and offer insights into the way it is orchestrated.

Chromatin, a complex of protein and DNA, packages the genome in a cell. It also arranges DNA in a way that it can be "read" by a group of proteins called transcription factors, which activate or repress gene expression. However, DNA sequence varies between individuals and thus it leads to molecular variation between people's chromatin states. This ultimately causes variation in the way humans respond to the environment. Understanding the genetic and molecular processes that govern chromatin variability is one of the great outstanding challenges in life sciences, and would open the door to fully uncover how genetic variation predisposes individuals to a wide range of complex diseases, including cancer, diabetes, and autoimmune diseases.

The scientists' study in Cell reports how genetic variation affected three molecular layers in immune cell lines that were derived from 47 individuals whose genomes had been fully sequenced: transcription factor-DNA interactions, chromatin states, and gene expression levels. "We observed that genetic variation at a single genomic position impacted multiple, separated gene regulatory elements at the same time. This extensive coordination was quite surprising, much like a music conductor (i.e. genetic variant) directing all the performers (i.e. transcription factors, chromatin modifications) of a musical ensemble to change the volume (i.e. gene expression) of the music," explains Professor Bart Deplancke from EPFL. Contrary to the traditional model, which holds that gene regulatory elements impact gene expression in a quasi-independent fashion, researchers identified a much more harmonized and synergistic behavior: far from being linear, gene regulatory elements are actually coordinated in their actions.

The new evidence shows that the genome is not just a linear assembly of elements that interact in a pairwise fashion, but rather that it takes place under a more complex organization where different elements form intricate networks. If one element does not act properly, the whole system in which this element is embedded will be disturbed. "We have discovered basic biology rules of how the genome functions and how regulatory sequences act together to impact the expression of a gene," says Professor Alexandre Reymond from UNIL.

Although the Swiss scientists are still far from medical applications, the mechanistic principles they uncovered shed light on very fundamental aspects of genome biology. "It is still too early to determine if one day we would be able to modulate gene expression in a targeted way, but this study reveals a level of complexity of genome function that was previously unanticipated", concludes Professor Emmanouil Dermitzakis from UNIGE. "Applying our discovery to medicine would mean identifying a single conductor and defining its role among all the other conductors for each musical ensemble - rather than merely listing all the performers playing in our genome orchestra."

Université de Genève

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 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