Epigenetic factors modulating phenotypic variability in a mouse model for Marfan syndrome

Author(s)

Rayssa de Carvalho Roberto

• Document type: Master's Dissertation
• Press: São Paulo.
• Institution: Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB)
• Defense date: 2024-08-06

Examining board members

Lygia da Veiga Pereira Carramaschi; Gustavo Ribeiro Fernandes; Tathiane Maistro Malta Pereira

• Advisor: Lygia da Veiga Pereira Carramaschi

Abstract

Marfan syndrome (MFS) is an autosomal dominant and highly penetrant condition, caused by pathogenic variants in the FBN1 gene, which encodes the protein fibrillin-1, a major structural component of the extracellular matrix that provides support to connective tissues and elasticity when combined with other proteins. The disease has an approximate prevalence of 1 in 5.000 people, and 25% of individuals with MFS present de novo variants. The most significant manifestations of MFS include ectopia lentis (dislocation of the ocular lens), aortic aneurysms, aortic dissections, and skeletal abnormalities characterized by overgrowth of the long bones, kyphosis and scoliosis. Pulmonary manifestations are also observed and can be influenced by other manifestations, such as skeletal abnormalities. Additionally, MFS exhibits substantial intra and interfamilial clinical variability, suggesting the involvement of modifier genes and other mechanisms responsible for this variation. The MFS mouse model mg&#916suploxPneosup, with a dominant-negative variant in the Fbn1 gene, established in heterozygous and isogenic 129/Sv mice, presents ocular, cardiovascular, pulmonary and skeletal manifestations, as well as the clinical variability observed in humans. Because of these phenotypic differences among heterozygous mice in the isogenic 129/Sv strain, it is suggested that epigenetic alterations may contribute to the observed clinical variability in the disease. The objective of this work was to use this animal model to understand the influence of DNA methylation on gene expression, which could consequently modulate the severity of disease-related phenotypes. RNAseq and methylome data were used, generated from genetic material extracted from the lungs of 11 samples with mild and severe phenotypes, to perform a comparative analysis between these two groups. The comparisons identified several genes potentially involved in phenotype modulation, including those involved in collagen production and the organization and degradation of the extracellular matrix. Relationships between expression and methylation results were established, identifying genes whose expression may be regulated by methylation marks, which have the potential to modulate MFS phenotypes. (AU)

• FAPESP's process: 21/09203-8 - Epigenetic analysis of the phenotypic variability of a mouse model for Marfan syndrome
• Grantee: Rayssa de Carvalho Roberto
• Support Opportunities: Scholarships in Brazil - Master