Understanding the genetic origins of disease variation

Researchers at the Hebrew University-Hadassah Medical School have discovered mechanisms controlling the activation and suppression of mutation-driven disease genes, particularly in cases like glioblastoma. This may revolutionise disease research and clinical applications, advancing  personalised medicine, diagnostic biomarkers, and patient care.

Currently, 98 percent of individuals hospitalised for genetic diseases face insufficiently understood disease mechanisms, as these diseases often manifest differently between patients. Professor Asaf Hellman and his research team aimed to investigate the possible involvement of gene transcriptional variation in this phenomenon. They generated a DNA methylation-oriented, driver-gene-wide dataset of positive and negative regulatory elements in human glioblastomas, thoroughly analysing their effects on inter-patient gene expression variation.

Methylation-directed regulation revealed the interplay between enhancers and silencers in gene regulatory domains, influenced by DNA methylation. This offered key insights into the dynamic control of gene expression. Also, the high-resolution mapping of DNA methylation’s influence on gene expression within intact genomes enabled the scientists to understand how genes may be modified. This knowledge is crucial for solving the complexities of genetic diseases.

The researchers utilised mathematical modelling to find key methylation sites driving gene expression variations, which allows for the exploration of epigenetics shaping disease progression. Observing methylation in glioblastoma patients’ gene expression profiles permits more accurate diagnostics and targeted therapies.

This research represents an important leap forward in genomics, offering insights for monitoring and comprehending the underlying factors contributing to the many outcomes observed in genetic mutation-driven diseases. DNA methylation has an important role in deciding how genes are used, which helps the understanding of why different people may have varying levels of gene activity. Dr Hellman explained: “The research unveils the existence of complex cis-regulatory networks that determine gene expression by combining the effects of positive and negative transcriptional inputs.”

This study was published in Genome Biology.