A revolutionary model known as KATMAP is taking the field of alternative gene splicing research by storm. In Boston, a team at the Massachusetts Institute of Technology (MIT), led by MIT’s David Mintz, conceived and designed KATMAP. These resources offer unprecedented views into splicing factor–specific effects on gene regulation. Along with the accompanying technical advances, this study, published in Nature Biotechnology, represents a huge step forward toward comprehensively unraveling the complex, multi-layered mechanisms of gene expression.
Michael P. McGurk is a postdoctoral researcher in the lab of MIT Professor Christopher Burge. Additionally, he is proud to serve as the first author of the KATMAP study. The model utilizes RNA sequencing data generated from perturbation experiments, which manipulate the expression levels of regulatory factors through overexpression or knockdown. Through this analysis, KATMAP is able to infer splicing factor activity and regulatory targets.
Until now, methodologies only allowed for a global average perspective on gene regulation. These models did not have the resolution required to predict the exact regulation of splicing factors at each exon in specific genes. KATMAP redresses this imbalance by specifically profiling splicing factors to uncover their unique regulatory targets.
Through its innovative approach, KATMAP allows scientists to explore how molecular machinery can edit genetic instructions, creating an array of unique combinations essential for various biological processes. “In our analyses, we identify predicted targets as exons that have binding sites for this particular factor in the regions where this model thinks they need to be to impact regulation,” McGurk stated.
Burge emphasized the model’s adaptability: “We now have a tool that can learn the pattern of activity of a splicing factor from types of data that can be readily generated for any factor of interest.” This versatility lays the ground for future research applications, especially in revealing the regulation of splicing both in diseased and developmental contexts.
When asked what he hopes to see come next for KATMAP, McGurk’s enthusiasm shines through. He envisions taking the model further, to include cooperative regulation between splicing factors that act in networks of great complexity. “One of our goals with KATMAP was to try to make the model general enough that it can learn what it needs to assume for particular factors,” he noted, highlighting the model’s potential to adapt to various regulatory contexts.
McGurk and David McWaters, another postdoc in Burge’s lab, joined forces to put KATMAP to the test. Their hard-fought collective efforts were key in making it a reality. Their research into gene splicing has pioneered new methodologies for understanding how mutations can change gene regulation functions.
