Systems-level identification of key transcription factors in immune cell specification

Transcription factors (TFs) are crucial for regulating cell differentiation during the development of the immune system. However, the key TFs for orchestrating the specification of distinct immune cells are not fully understood. Here, we integrated the transcriptomic and epigenomic measurements in 73 mouse and 61 human primary cell types, respectively, that span the immune cell differentiation pathways. We constructed the cell-type-specific transcriptional regulatory network and assessed the global importance of TFs based on the Taiji framework, which is a method we have previously developed that can infer the global impact of TFs using integrated transcriptomic and epigenetic data. Integrative analysis across cell types revealed putative driver TFs in cell lineage-specific differentiation in both mouse and human systems. We have also identified TF combinations that play important roles in specific developmental stages. Furthermore, we validated the functions of predicted novel TFs in murine CD8+ T cell differentiation and showed the importance of Elf1 and Prdm9 in the effector versus memory T cell fate specification and Kdm2b and Tet3 in promoting differentiation of CD8+ tissue resident memory (Trm) cells, validating the approach. Thus, we have developed a bioinformatic approach that provides a global picture of the regulatory mechanisms that govern cellular differentiation in the immune system and aids the discovery of novel mechanisms in cell fate decisions.Author summary: The immune system protects the human body from invading pathogens and tumors. Enormous efforts have been devoted to developing preventative and therapeutic treatments based on exploitation of diverse immune cell types. Recent technological advances have made it possible to study the regulatory mechanisms at the systems level. However, the noise in the genomic measurements and the complexity of integrating multiple omics assays are still challenging. To tackle the challenges, we constructed the cell-type-specific transcriptional regulatory network for 73 mouse and 61 human immune cell types and assessed the global importance of transcription factors (TFs) using a systems biology approach called Taiji framework. We revealed driver TFs in cell lineage-specific differentiation. Furthermore, we validated the functions of predicted novel TFs in CD8+ T cell differentiation and showed the importance of Elf1 and Prdm9 in the effector versus memory T cell fate specification and Kdm2b and Tet3 in promoting differentiation of CD8+ tissue resident memory (Trm) cells, validating the approach. Our study provides a comprehensive identification of driver regulators directing immune cell development, provides a global picture of the regulatory mechanisms that govern cellular differentiation in the immune system and aids the discovery of novel mechanisms in cell fate decisions.