Alternative gene regulation in Schinzel-Giedion Syndrome

How might the control of our genes change in a pathological context?

The precise control of when and why our genes are switched on and off in the different cells of our body and during the different stages of our lives is well studied but remains elusive for many aspects.

In a study recently published in the journal Nature Communications, a team of researchers from IRCCS Ospedale San Raffaele, led by Dr. Alessandro Sessa, has studied a rare disorder, called Schinzel-Giedion Syndrome (SGS), in which the molecular alterations help to shed new light on this issue.


The relationship between SETBP1 and human diseases

SGS is an ultra-rare and severe disease that affects children bearing mutations inside the SETBP1 gene. The very same mutations, which induce the accumulation of the relative SETBP1 protein, have been found to be at the basis of severe cases of leukemia. Moreover, even low levels of SETBP1 are damaging, at least for brain function; indeed, an inactivating mutation in one SETBP1 allele is sufficient to cause a neurological condition characterized by intellectual disabilities and behavioral problems.

However, little is known about the pathological mechanisms linked with the alteration of SETBP1 levels; thus, the therapeutic options for the associated pathological conditions are limited.


San Raffaele’s research

In this study, San Raffaele scientists reveal that the cells which carry the genetic defects associated with both SGS and leukemia present an alternative strategy for gene regulation compared to the healthy cells. In other words, the molecular controllers which impose what genes are switched on, for how long and how strong, are different.

“With the aim of understanding the pathological mechanisms at the basis of the diseases associated with SETBP1 accumulation, in the lab we have generated and deeply studied at molecular levels multiple experimental systems based on either induced pluripotent stem cells or genetic murine models. We found that, instead of choosing another subset of genes to achieve the same task, the mutant cells actually utilize the same group of genes as the normal cells to perform specific processes, e.g., neuronal maturation, but are regulated in a different way,” says Alessandro Sessa.

The researchers have tried to interpret the consequences of this defect: “The alternative gene regulation that we discovered is novel – explains Mattia Zaghi, first author of the study. It represents both the aftermath of the mutations in SETBP1 and the attempt of the cell to overcome it, using new regulatory elements”.


The impact of the study

The importance of the study is that the researchers have described for the first time the molecular circuitries that characterize important pathological conditions, both SGS and blood cancers, which may lead to the identification of new therapeutic relevant targets. “The discovery and the confirmation in several experimental models of the molecular rewiring associated with these pathological conditions have revealed new vulnerabilities. We have laid the basis for the identification, in the near future, of new clinical treatments for diseases associated with SETBP1 mutations.” Sessa concludes.