Turning genes on and off in a pathological context

Turning genes on and off in a pathological context

Publication date: 28-08-2023

Updated on: 28-08-2023

Topic: Research

Estimated reading time: 1 min

How genes are turned on and off within the body's cells during different stages of life has always been a subject of study, but little is still known. A team of researchers at IRCCS Ospedale San Raffaele in Milan, coordinated by Dr. Alessandro Sessa of the Stem Cells and Neurogenesis Unit, studying a rare type of disease, Schinzel-Giedion syndrome (SGS), has highlighted how some molecular alterations may help shed new light on this.

SGS is a very rare, very serious disease for which there is currently no cure, affecting infants from birth. Survival beyond childhood is low due to progressive neurodegeneration, increased risk of cancer, recurrent infections, and respiratory failure. The condition is caused by mutations in the SETBP1 gene that cause an accumulation of the related protein and are also responsible for severe forms of leukemia. Unfortunately, the pathological mechanisms are not known, nor are there any effective therapeutic approaches.

Scientific study

In this paper, just published in the scientific journal Nature Communications, researchers at San Raffaele reveal how cells carrying the genetic defect that causes SGS have an alternative gene regulatory program than healthy cells: that is, they found that the molecular controllers that dictate which genes are turned on, for how long and how strongly, are different than in healthy cells.

The next step was to understand on experimental models, both in vitro and in vivo, the consequences of these differences. Specific defects in cell maturation programs, particularly in the nervous system, have been identified that could be key to identifying new pathways for treating SGS.

Study results

“With the goal of delineating the pathological mechanisms underlying the disease, we used both induced human pluripotent stem cells (iPSCs) and mouse models as models. We were thus able to identify that the mutated cells that cause the disease are characterized not so much by having a different set of genes used, but rather by how they are controlled, that is, deregulated,” explains Alessandro Sessa.

The researchers then tried to interpret the consequences of this defect: “The different gene regulation we identified is quite unique in the literature,” says Mattia Zaghi, first author of the study. “It is both a defect given by the genetic mutation and the cell's attempt to overcome it by bringing in new regulatory elements.”


“The impact of this study is that we have described for the first time the molecular circuits characteristic of important pathological mutations in both SGS and blood neoplasms, which could lead to the identification of new therapeutic targets.” Alessandro Sessa explains. 

“Having identified and confirmed in several different experimental systems the molecular rearrangement of these pathological conditions has allowed us to describe possible vulnerabilities, laying the foundation for being able to identify, one day tomorrow, new therapeutic opportunities in pathological conditions due to mutations in the SETBP1 gene.”

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