BioProject

Innate lymphoid cells (ILCs) comprise a population of immune cells that promote tissue homeostasis, defense against infections, and inflammatory disease. More...

Innate lymphoid cells (ILCs) comprise a population of immune cells that promote tissue homeostasis, defense against infections, and inflammatory disease. Yet, the transcriptional control of these functions is not well understood. Here, we leverage an experimental-computational approach for transcriptional regulatory network (TRN) inference, recently validated in an in vitro context, to construct genome-scale TRNs for ILCs isolated ex vivo from the intestine of mice. Chromatin accessibility and gene expression are the key data for our TRN inference method. Thus, we generated ATAC-seq and RNA-seq datasets for ILCs of the small and large intestine to integrate with publicly available ILC genomics data. From our ILC TRN, we predict target genes for hundreds of transcription factors (TFs), recovering both known and novel TF regulators of ILC subtype-specific gene expression patterns. The identified TFs include both activators and repressors of lineage-specific genes. Using KO mice, we validated predictions for two such TFs, MAF and BCL6, as previously unknown regulators affecting the balance of ILC3-ILC1. We additionally demonstrate the utility of our ILC TRN to describe gene expression responses to Bcl6 KO in ILC1, NK and ILC3 and predict TF regulators in each subtype. The ILC TRN and “core” ILC subtype networks are publicly available through an interactive Jupyter-notebook web interface. We anticipate that these maps of ILC subtype-specific transcriptional regulation will serve as an important community resource and lead to the development of new strategies for the control of subtype-specific behaviors, especially in the context of disease. Overall design: Chromatin accessibility (ATAC-seq) of ILCs isolated from the small intestine and large intestine at steady state Less...