An international consortium led by the Josep Carreras Leukemia Research Institute, based in Barcelona, and Mass General Brigham in Boston (United States), has demonstrated the ability of the SIRT7 protein to safeguard the X chromosome and preserve genome stability. This breakthrough allows for a better understanding of the biological differences between men and women in aspects of health and aging.
The work, published in the journal 'Nature', is "especially relevant" in women, who have two X chromosomes, while men only have one, as detailed by the Josep Carreras Leukemia Research Institute in a note about the study. The Universitat Autònoma de Barcelona, the Centre for Genomic Regulation, and the American institutions Rutgers University and the City University of New York also participated in the research.
Under normal conditions, in female cells, one of the two X chromosomes remains inactive to ensure adequate balance in gene expression. However, the scientific team found in experimental models that, in the absence of SIRT7, this process is compromised: the inactive X chromosome becomes excessively repressed, while the active X chromosome shows an abnormal increase in its activity.
As the researchers verified, this alteration triggers changes in gene expression and makes the chromosome more susceptible to DNA damage and genomic instability processes. In animal models, females were the most affected by the lack of SIRT7, showing higher levels of DNA damage, poorer overall health, and a shorter life expectancy than males.
The data obtained indicate that SIRT7 functions as a genetic defense system that sustains the stability of the active X chromosome and keeps its gene activity regulated. When this protein is absent, the fragile balance on which cells depend to perform their functions correctly is broken.
This discovery opens the door to future strategies for deepening the understanding and treatment of pathologies that affect men and women differently.
Implications in hematological cancer and immunity
From the Josep Carreras Leukemia Research Institute, they emphasize that the findings of the work are "especially relevant" for the function of the immune system, given that precise regulation of the X chromosome is "essential" for preserving immune balance.
Along these lines, alterations in the activity of said chromosome can affect the formation and functioning of blood and defense cells, which could favor processes of immune dysregulation and contribute to understanding why certain diseases impact women and men differently.
This connection is also relevant in hematological cancers, in which the normal development and function of blood cells and the immune system are altered. Recent studies have shown that X chromosome dysregulation is linked to particularly aggressive variants with a worse prognosis of lymphoma in women. In parallel, other research has demonstrated that SIRT7 participates in maintaining the activity of PAX5, a gene crucial for the development of blood cells and which is frequently altered in leukemia.
Overall, the results of these studies indicate that SIRT7 plays a central role in controlling the functions of blood and immune cells and in their malignant transformation, contributing to these cells maintaining adequate functioning and remaining protected against genetic changes that can drive the onset of hematological cancers.
"Our previous studies showed that the SIRT7 protein helps maintain the activity of genes essential for the normal development of blood cells and which are frequently altered in leukemia. By revealing a new function of SIRT7 in protecting chromosomal stability, this work expands our knowledge of how alterations in this protein can affect the regulation of the immune system and contribute to the development of hematological cancers," stated the group leader of the Josep Carreras Leukemia Research Institute, Alejandro Vaquero.