日時：3月4日（火）　15：00-16：30
場所：理学部3号館412号室及びZoom
演者：神元　健児　准教授（演者所属）大阪大学微生物研究所　付属バイオインフォマティクスセンター
演題：Dissecting cell identity via network inference and in silico gene perturbation

Recent technological advances in single-cell sequencing enable the acquisition of multi-dimensional data in a high-throughput manner. These technologies reveal the existence of heterogeneity and the diversity of cell states and identities. To dissect the regulatory mechanisms underlying such phenomena, many computational methods to infer Gene regulatory Networks (GRNs) have been proposed. However, understanding biological events from a GRN perspective remains difficult. Even if a computational algorithm can infer GRN models, the biological network is so complex that it is challenging to understand how it systematically dictates cell identities. There is significant demand for new methodologies that bridge the gap between cellular phenotypes and the underlying GRN model. Thus, we have developed a new computational method, CellOracle, for the inference and analysis of GRNs. CellOracle first infers sample-specific GRN configurations from single-cell RNA-seq and ATAC-seq data by utilizing machine learning algorithms and genetic information. Our GRN models are designed to be used for the simulation of cell identity changes in response to gene perturbation. This simulation enables network configurations to be interrogated in relation to cell-fate regulation, facilitating their interpretation. We validate the efficacy of CellOracle to recapitulate known outcomes of well-characterized gene perturbations in developmental processes, including mouse and human hematopoiesis. We also apply CellOracle to zebrafish embryogenesis, systematically perturbing transcription factors and experimentally validating key candidates, identifying a novel mechanism that regulates cell identity in axial mesoderm development. Our validation results demonstrate the efficacy of our new approach to infer and interpret the dynamics of GRN configurations, promoting new mechanistic insights into the regulation of cell identity.

東京大学大学院理学系研究科・生物科学専攻・黒田研究室

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