Summary: New research reveals how small genetic differences affecting the ETS1 protein can influence an individual’s susceptibility to allergies. These small genetic changes can alter the production of ETS1, which plays a vital role in controlling immune cells known as CD4+ T helper cells, crucial orchestrators in allergic reactions.
The findings suggest that disturbances in the balance of these immune cells can lead to allergic inflammation. This breakthrough in understanding may pave the way for new therapeutic interventions in chronic allergic diseases.
Main aspects:
- The ETS1 protein is critical in regulating CD4+ T helper cells, immune cells integral to the body’s response to allergens.
- Small genetic changes can interfere with the production of the ETS1 protein, potentially leading to imbalances in immune cells and causing allergic inflammation.
- This research provides new insights into the complex relationship between our genes and susceptibility to common diseases such as allergies, which may not be traced to a single gene but to a complex interplay of genetic factors.
Source: University of Pennsylvania
New research is strengthening scientific understanding of why some people are more prone to allergies than others.
Researchers at the University of Pennsylvania’s Perelman School of Medicine have identified how genetic differences that alter a specific protein called ETS1 can affect our body’s response to allergies. They found that small changes in ETS1 in an animal model can lead to an increased likelihood of allergic reactions causing inflammation.
The results were recently published inImmunity.
The U.S. Centers for Disease Control and Prevention reports that allergies are the sixth most common cause of chronic disease in the United States, accounting for more than $18 billion annually.
Although previous research has established a strong genetic basis for allergies and identified specific genetic sequence variations that predispose to these chronic diseases, it remains unclear how our DNA might influence our chances of developing an allergy. But understanding this could lead to better research and potential new treatments.
Using modern genomics and imaging techniques, a collaborative team of researchers led by Penns Golnaz Vahedi, PhD, associate professor of genetics, and Jorge Henao-Mejia, MD, PhD, associate professor of pathology and laboratory medicine, found that The ETS1 protein plays a role in controlling a type of immune cell called CD4+ T helper cells, which are important in allergic reactions and help orchestrate the immune response by activating and coordinating other immune cells.
DNA interactions within the genomic segment comprising the ETS1 gene control the amount of ETS1 protein produced.
We found that these interactions work like a dimmer, Vahedi said. When there are DNA changes in this area, it can screw up the dimmer, causing problems with the control of the ETS1 protein. This can lead to imbalances in our immune cells and cause allergic inflammation.”
While there has been progress in understanding genetic traits that follow predictable patterns, such as those passed down from parents, it has been more difficult to understand conditions that involve many different genes and are common in populations. These complex conditions cannot be explained simply by “turning off” a gene.
Instead, they can be caused by small changes in DNA that affect how genes work together. However, researchers still don’t know much about how these changes in DNA relate to how our genes are organized or how they affect how genes are expressed in more complex diseases.
This work demonstrates how small differences in our DNA can disturb the balance between our immune cells, resulting in significant observable characteristics in patients. This phenomenon can occur in other common diseases such as autoimmune disorders, Henao-Mejia said.
Other co-authors of this study include Aditi Chandra, Sora Yoon and Michael Michieletto.
Financing: This research was funded by the National Institutes of Health (R01AI168240, UC4 DK112217, U01 DK112217, R01 HL145754, U01 DK127768, U01 DA052715, R01 HL136572), the Burroughs Welcome Fund, the Chan Zuckerberg Initiative Award, WW Smith Charitable Trust, the S Foundation loan and PEW Charitable Trust.
About this news about genetic research
Author: Matthew Toal
Source: University of Pennsylvania
Contact: Matthew Toal – University of Pennsylvania
Image: The image is credited to Neuroscience News
Original research: Access closed.
“Quantitative control ofets1dosing by a multi-potentiator hub promotes Th1 cell differentiation and protects against allergic inflammation” by Golnaz Vahedi et al. Immunity
Abstract
Quantitative control ofets1dosing by a multi-potentiator hub promotes Th1 cell differentiation and protects against allergic inflammation
Highlights
- ets1locus forms a multi-enhancer hub containing a super-enhancer calledets1-SELF
- ets1-SE is required for Th1 and the differentiationets1gene dosage control
- Cancellation ofets1-SE leads to protection against colitis and a full-blown allergic response
- ets1the assay controls Th1-specific genome topology through CTCF recruitment
Summary
Multi-enhancer hubs are space groups of enhancers found in many development programs.
Here, we investigated the functional relevance of these three-dimensional structures in T-cell biology.
Mathematical modeling has identified a highly connected multi-enhancer hub at theets1locus, comprising a noncoding regulatory element that was a hot spot for sequence variation associated with allergic disease in humans.
Deletion of this regulatory element in mice revealed that multi-enhancer connectivity was dispensable for T cell development but required for CD4+T helper 1 (Th1) differentiation.
These mice were protected from Th1-mediated colitis but displayed overt allergic responses. Mechanically, the multi-potentiator hub controlled the dosage ofets1which was required for CTCF recruitment and Th1-specific genome topology assembly.
Our results establish a paradigm in which multi-enhancer hubs control cellular competence to respond to an inductive signal through quantitative gene dosage control and provide insight into how sequence variation within non-coding elements at the levelets1locus predisposes individuals to allergic responses.
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