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Cracking the code of gene regulation
BELFAST, U.K.—Within the vast genetic landscape of the human body, only certain DNA elements are chosen to regulate gene expression. Researchers at Queen’s University Belfast looked into the “how and why” of this in part to better understand how this process predisposes people for certain conditions. They believe they have made a breakthrough discovery that ould open the door for better and earlier diagnostics, possibly before symptoms of disease arise.
As described in the summary of the paper titled “Deciphering the Gene Regulatory Landscape Encoded in DNA Biophysical Features” and published in the interdisciplinary journal iScience, “Gene regulation in higher organisms involves a sophisticated interplay between genetic and epigenetic mechanisms. Despite advances, the logic in selective usage of certain genomic regions as regulatory elements remains unclear. Here we show that the inherent biophysical properties of the DNA encode epigenetic state and the underlying regulatory potential. We find that the propeller twist (ProT) level is indicative of genomic location of the regulatory elements, their strength, the affinity landscape of transcription factors, and distribution in the nuclear 3D space.”
The Queens University team notes that diseases often are the result of things going wrong within a cell or set of cells within the body, and previous research has determined that many of these diseases result from mutations on a certain part of the DNA strand, known as an “enhancer.” In essence, the enhancers serve as a switch to turn on in gene expression and activate the promoter region of a particular gene.
And here is where the ProT aspect comes in. ProT levels represent the angle of twisting of two neighboring DNA bases along the DNA axis, much like the propeller blades of an airplane. The Queens University researchers reportedly are the first to discover that because of high ProT levels, the surface of these enhancer sections on the DNA strands are more physically accessible and flexible than its counterparts, thus allowing easier access for DNA binding regulatory proteins. The same properties potentially make these enhancer regions more prone to be affected by mutagenic agents to harm cells and cause certain diseases, such as cancer.
“These findings answer many fundamental biological questions around the function of DNA in health and disease,” said Dr. Vijay Tiwari of the Wellcome-Wolfson Institute for Experimental Medicine at Queen’s University Belfast and lead author on the paper. “It is important to understand how a healthy cell develops to be able to decode what goes wrong in diseases. Our study is the first of its kind to provide insight into the role physical DNA features play in proper development of specific cell-types of the body and how their malfunctions may underlie diseases.”
The researchers also discovered that as cells become abnormal, they switch to using low ProT regions as enhancer elements. These observations open novel avenues to understand the aetiology of human diseases and potentially develop an early diagnosis.
This could mean we could look at the enhancer section of DNA in any cell of a healthy person and predict their chance of developing disease long before signs and symptoms appear,” noted Tiwari. “This could result in many lives being saved as we can use this tool to make earlier and better disease predictions, reduce disease progression and improve patient outcomes.”
As noted by the authors in the paper, “Several laboratories have attempted to employ computational approaches to predict enhancers based on sequence information. Although these methods were able to predict enhancers to a certain degree, they were unable to decipher the underlying code that drives enhancer selection and strength ... We discover that the ProT levels can reveal the location of enhancers, their strength, the affinity landscape of transcription factors, and distribution in the nuclear 3D space with high accuracy. Using experimental assays including single-molecule AFM imaging measurements, we show that indeed high ProT levels cause increased DNA flexibility and surface accessibility and may potentially explain their usage as regulatory elements. Furthermore, ProT levels also determine the effectivity landscape of the genome to tolerate mutations. Altogether, this work reveals the gene regulatory landscape encoded in the basic genetic sequence features and provides a significant advance in unfolding the mysteries of genetic code.”
According to Queens University Belfast, the classical methods to identify enhancers have been cumbersome. But these new findings argue that identifying high ProT levels is a deterministic feature of enhancers; thus, the researchers hope this discovery will also save resources and time for scientists across the globe in identifying these gene regulatory elements critical in normal as well as diseased states.