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The subtype-specific transcriptional regulatory networks of intestinal innate lymphoid cells (ATAC-seq)

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE116091 | GEO | 2019/05/21

REPOSITORIES: GEO

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The subtype-specific transcriptional regulatory networks of intestinal innate lymphoid cells (RNA-seq)

Project description: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.

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Project description:Innate lymphoid cells (ILCs) are highly plastic and predominantly mucosal tissue-resident cells that contribute to both homeostasis and inflammation depending on the microenvironment. The recent discovery of naïve-like tissue-resident ILCs suggests an ILC differentiation process that is akin to naïve T cell differentiation. Delineating the naïve-like ILC heterogeneity and the transcriptional, epigenetic and functional mechanisms that underlie ILC differentiation in tissues is crucial for understanding ILC biology in health and disease. Here we show that CD62L distinguishes two subsets of naïve-like CD45RA+ ILCs in tonsil tissue. While both subsets contain uni- and multipotent precursors of ILC1/NK cells and ILC3, CD62L+ ILCs resemble bona fide naïve ILCs with metabolism reminiscent of naïve T cells, lacking transcriptional and epigenetic signatures of mature ILCs. CD62L- ILCs are epigenetically similar to, but transcriptionally distinct from CD62L+ naïve-like ILCs including transcripts of cytokine signaling and metabolic pathways related to mature ILCs. A similar population of CD62L- quiescent ILCs with preferential differentiation capacity towards IL-22-producing ILC3 accumulate in the inflamed mucosa of patients with inflammatory bowel disease (IBD). These data suggest that naïve-like and quiescent ILCs are imprinted by their tissue microenvironment that poises their differentiation potential. Our findings identify restoration of homeostatic IL-22-producing ILC3 from CD62L- quiescent ILCs as a potential approach to improve tissue healing in IBD.

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Project description:We identified that synergistic and inducible expression of Runx1 and Hoxa9 in pluripotent stem cells gave rise to engraftable iHPC capable of developing into mature ILCs in the Rag2-/-Il2rg-/- recipients. We performed single-cell RNA-seq on the entire regenerative CD45.2+GFP+Lin-CD127+ R9-ILC population from the intestine of Rag2-/-Il2rg-/- recipient mice and the CD45.2+Lin-CD127+ WT-ILC population from the intestine of wild type mice (C57BL/6, CD45.2). Single-cell transcriptome illustrated the transcriptome landscape of the R9-ILCs and wild type ILCs including ILC1, ILC2 and ILC3.

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Project description:The development of innate lymphoid cell (ILC) transcription factor reporter mice has shown a previously unexpected complexity in ILC haematopoiesis. Using novel polychromic mice to achieve higher phenotypic resolution we have characterised bone marrow progenitors that are committed to the group 1 ILC lineage. These common ILC1/NK progenitors, which we call ‘aceNKPs’, are defined as lineage–Id2+IL-7Ra+CD25–a4b7–NKG2A/C/E+Bcl11b–. In vitro, aceNKPs differentiate into group 1 ILCs, including NK-like cells that express Eomes without the requirement for IL-15, and produce IFN-g and perforin upon IL-15 stimulation. Following reconstitution of Rag2–/–Il2rg–/– hosts, aceNKPs give rise to a spectrum of mature ILC1/NK cells (regardless of their tissue location) that cannot be clearly segregated into the traditional ILC1 and NK subsets, suggesting that group 1 ILCs constitute a dynamic continuum of ILCs that can develop from a common progenitor. In addition, aceNKP-derived ILC1/NK cells effectively ameliorate tumour burden in a model of lung metastasis where they acquired a cytotoxic NK cell phenotype. Our results identify the primary ILC1/NK progenitor that lacks ILC2 or ILC3 potential and is strictly committed to ILC1/NK cell production irrespective of tissue homing.

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