The new model enabled the team to predict how gene regulation differs between cell types and how it changes when cells are exposed to stimuli such as specific drugs. Moreover, the model revealed in extreme detail what the architecture of the ‘on and off buttons’ of each gene is. Crucially, the team did not stop at prediction. Every model output was subjected to rigorous experimental testing to make sure that these predictions were indeed correct.
“We can now actually read the language of the gene control system”, says Van Steensel. “Our PARM model allows us to uncover these rules at scale, so we can now understand, and even predict, how regulatory DNA controls gene activity.”
Despite notable progress in the field, the existing AI models were either too heavy to be applied to the vast numbers of mutations that exist or are too generic and do not adequately capture cell type variability. The PARM model changes that. It allows researchers to predict the functional impact of regulatory mutations in specific cell types and under specific conditions, such as drug treatments, opening new paths for cancer diagnostics, patient stratification, and future therapies.
Last week, Google’s Deepmind published in Nature about their model AlphaGenome, aimed at understanding gene regulation as well. “This is a great model”, says Van Steensel. “However, PARM is more flexible and it is experimentally and computationally lightweight. The tool requires around 1000 times less computing power than AlphaGenome, making it far more feasible for academic researchers around the world. With this model you only need one petridish of cells and one day of computing to see in detail how a particular cell type, such as a tumor cell, uses its DNA code to respond to a signal such as a hormone, nutrient or drug.”
The PARM model was developed within the PERICODE project, initiated by Oncode Institute. Seven research groups collaborated within the project: Bas van Steensel (NKI), Jeroen de Ridder (UMCU), Emile Voest (NKI), Michiel Vermeulen (NKI), Lude Franke (UMCG), Sarah Derks (Amsterdam UMC), Wilbert Zwart (NKI). The AVL Foundation financially supported the PERICODE project.
Research at the NKI is financially supported by KWF Dutch Cancer Society.
Photo 1:
Hatice Yücel en Lucía Barbadilla-Martínez van de onderzoeksgroep van Bas van Steensel in het Nederlands Kanker Instituut, waar de lab-techniek ontwikkeld is die ten grondslag ligt aan het nieuwe AI-model PARM.
Photo 2:
This screenshot of the PARM model shows one of the genes described in the Nature paper (APOC2). Several DNA-letters standing upright next to each other usually means that a transcription factor binds there and activates the gene.