Researchers used a new mapping method to find 21 genes that drive asthma biology, potentially revealing new targets for drug development.
RT’s Three Key Takeaways:
- DANDELION Computational Tool: Researchers developed a new tool that identifies central disease-driving genes by mapping complex gene regulatory networks instead of focusing only on nearby genetic variants.
- Identification of Novel Genes: The mapping process identified 21 genes related to asthma, 19 of which had not been discovered using traditional genome-wide association studies (GWAS).
- New Therapeutic Pathways: Experimental validation showed that two of these genes are involved in fatty acid metabolism, suggesting that protein palmitoylation could be a new target for asthma treatments.
An interdisciplinary team of researchers at UChicago and Columbia University developed a new computational tool to identify genes most directly related to asthma, according to a study published in Cell.
The tool, known as Dandelion, identifies central genes that drive disease biology by focusing on trans-gene regulation, a process where genetic variants change the expression of other genes in a cascading network. Traditional methods like genome-wide association studies (GWAS) often focus on genes in the periphery of these networks that only indirectly affect disease.
“What’s unique about our method is that we believe the disease genes are not just next to the genetic variants,” said Xuanyao Liu, PhD, assistant professor of medicine and human genetics. “They’re embedded in this gene regulatory network, and the actual disease-driving gene is downstream of those associated variants, maybe on different chromosomes.”
Liu analyzed data from the human transcriptome and the UK Biobank, a repository of health and genetic data, to find 21 candidate genes for asthma. Of these, 19 had not been previously discovered by GWAS tools. Marcelo Nobrega, MD, PhD, chair of the department of human genetics at UChicago, used CRISPR gene-editing and mouse models to validate that these genes lead to asthma phenotypes.
“Xuanyao showed me a list of genes, and we didn’t recognize almost any of them,” said Marcelo Nobrega, MD, PhD, chair of the department of human genetics at UChicago. “I thought that either this is going to be really cool and groundbreaking or it’s going to be wrong.”
The validation experiments showed that knocking out a gene called SLC27A3 protected against asthma effects in epithelial and T cells, while knocking out the SCD gene contributed to the disease. Both genes are involved in the same biochemical pathway for fatty acid metabolism and protein palmitoylation, which involves adding fatty acyl groups to proteins to regulate their activity.
“I am still amazed by the finding that disrupting a lipid metabolic protein, SLC27A3, could offer protection in asthma models at least in part via affecting protein palmitoylation,” said Hening Lin, PhD, professor of medicine and chemistry.
The researchers noted that identifying these central protein targets could help overcome historical limitations in drug development. The team plans to apply the Dandelion tool to other complex conditions, including inflammatory bowel disease and type 2 diabetes.
