GoT-Splice Tool Helps Determine How Gene Mutations Lead to Disease

Researchers at Weill Cornell Medicine, in collaboration with the New York Genome Center and the Princess Margaret Cancer Centre in Toronto, integrated genotyping of transcriptomes (GoT) with long-read single-cell transcriptomics and proteogenomics for single-cell profiling of transcriptomes, surface proteins, somatic mutations, and RNA splicing (GoT-Splice) to gain a deeper understanding of how disruptions in RNA splicing contribute to cellular development and behavior.

RNA splicing involves the rearrangement and reassembly of RNA transcripts derived from active genes. This process plays a fundamental role in cells, potentially yielding multiple distinct proteins with nuanced functions from a single gene. The new methodology, GoT-Splice, not only enables in-depth analysis of tissue samples but also fosters the investigation of how mutations in genes governing RNA splicing lead to myelodysplastic syndrome (MDS), a form of blood cancer.

Dan Landau, co-senior author of the paper published in Cell Stem Cell, emphasizes that mutations altering the RNA-splicing process underlie various cancers and disorders. The study opens avenues for tracing the intricate effects of these changes with unprecedented precision.

For the study, Landau's team used single-cell multi-omics techniques, enabling comprehensive information profiling within individual cells. The GoT-Splice approach is capable of capturing four distinct layers of cellular information. This innovation facilitated the investigation of SF3B1 gene mutations associated with MDS, showcasing how stem-like marrow cells' SF3B1 mutation tips the balance towards red blood cell maturation and survival.

Furthermore, the research unveiled links between SF3B1 mutations and disrupted RNA splicing, impacting genes like BAX that mediate apoptosis, a crucial anticancer mechanism. The method uncovered MDS-like changes in bone marrow cells of individuals with clonal hematopoiesis, an asymptomatic condition involving SF3B1 mutations. Dr. Landau and his team intend to further employ GoT-Splice as a versatile tool for unraveling the intricate mechanisms by which gene mutations precipitate disease.