genes and their regulatory elements by analyz- ing the changes in gene expression and regu- latory element activity in response to various perturbations, such as drug treatments. Unlike traditional methods, DegCre can de- tect long-range regulatory relationships, where regulatory elements can be located far from the genes they control. This capability is essential for understanding complex genetic networks and identifying drug targets. By providing a more comprehensive and accurate view of gene regulation, DegCre has the potential to accelerate drug discovery and personalized medicine. “With DegCre , we can test potential treat- ments in cells to assess their ability to correct abnormal gene activity and gain insights into their mechanisms of action,” said Roberts. Moving forward, DegCre will make it possible to analyze large datasets from single-cell exper- iments, linking the loss of specific gene func- tions to disease states and identifying potential new treatments. ALLELE-SPECIFIC BINDING IN THE BRAIN Genetic variations within transcription factor binding sites can disrupt the delicate balance of gene expression. These changes, such as single nucleotide polymorphisms (SNPs), can impact transcription factors’ ability to bind DNA, alter- ing gene expression levels. These alterations in gene expression can have a wide range of effects on cellular processes and contribute to individual differences in traits and susceptibility to diseases.
Sometimes, transcription factors preferentially bind to one version (allele) of a genetic variant over the other. This phenomenon, known as allele-specific binding, can significantly influence gene expression. Researchers in the Myers lab and the Greg Cooper lab at HudsonAlpha investigated the impact of genet- ic variation on transcription factor binding in human brain tissue, focusing on allele-specific binding 2 . By analyzing more than 90 transcription factors across nine brain regions, the researchers identified thousands of variants that influenced transcription factor binding. They found that rare genetic variations are more likely to disrupt binding, while common variations have a more balanced effect. Moreover, the study revealed a strong correlation between allele-specific binding and gene expression, highlight- ing a direct link between transcription factor binding and gene regulation. This research provides valuable insights into the mechanisms underlying genetic variation’s impact on gene expression in the human brain. By identifying specific variants that influence transcription factor binding, the study contributes to a larger under- standing of how genetic differences can contribute to individual variation in brain function and susceptibility to neurological disorders. The dataset published in the study also serves as a valuable resource of allele- biased variants validated to impact transcription factor binding in brain cells. ■
RESEARCH REPORT 2023-2024
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