MGPfact XMBD : A Model-Based Factorization Method for scRNA Data Unveils Bifurcating Transcriptional Modules Underlying Cell Fate Determination

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Abstract Manifold-learning is particularly useful to resolve the complex cellular state space from single-cell RNA sequences. While current manifold-learning methods provide insights into cell fate by inferring graph-based trajectory at cell level, challenges remain to retrieve interpretable biology underlying the diverse cellular states. Here, we described MGPfact XMBD , a model-based manifold-learning framework and capable to factorize complex development trajectories into independent bifurcation processes of gene sets, and thus enables trajectory inference based on relevant features. MGPfact XMBD offers more nuanced understanding of the biological processes underlying cellular trajectories with potential determinants. When bench-tested across 239 datasets, MGPfact XMBD showed advantages in major quantity-control metrics, such as branch division accuracy and trajectory topology, outperforming most established methods. In real datasets, MGPfact XMBD recovered the critical pathways and cell types in microglia development with experimentally valid regulons and markers. Furthermore, MGPfact XMBD discovered evolutionary trajectories of tumor-associated CD8 + T cells and yielded new subtypes of CD8 + T cells with gene expression signatures significantly predictive of the responses to immune checkpoint inhibitor in independent cohorts. In summary, MGPfact XMBD offers a manifold-learning framework in scRNA-seq data which enables feature selection for specific biological processes and contributing to advance our understanding of biological determination of cell fate.

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