“Transcriptional regulatory network construction in intestinal innate lymphoid cells and other rare, in vivo cell populations”

Innate lymphoid cells (ILCs) are an immune cell lineage discovered relatively recently. In the last decade, ILCs have been shown to promote tissue homeostasis and immune defense but also contribute to inflammatory diseases. Like many “new” and relatively rare cell types, the transcriptional regulatory networks (TRNs) controlling ILC function are largely unknown. Here we integrate gene expression and chromatin accessibility data to infer regulatory interactions between transcription factors (TFs) and genes within intestinal type 1, 2, and 3 ILCs, using a generalizable, benchmarked framework. We predict the “core” TFs driving ILC subsets and alternative-lineage-gene repression, a mechanism that may contribute to reported plasticity between ILC subsets. We experimentally validate new roles for c-MAF and BCL6 as regulators affecting type 1 and type 3 ILC lineages. By connecting TFs to genes, the TRNs suggest means to selectively regulate ILC effector functions, while our network approach is broadly applicable to identifying regulators in other in vivo cell populations. Finally, we describe design and benchmarking of a new TRN inference method for single-cell RNA-seq – expanding opportunities for TRN inference in rare and poorly characterized cell types in vivo.

 

Emily Miraldi

Cincinnati Children’s Hospital