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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.

2019-05-21 | GSE116092 | GEO

Cell autonomous expression of Bcl6 is required to maintain lineage identity of mouse CCR6+ ILC3s [16s rDNA]

Project description:Innate lymphoid cells (ILC) are similar to T helper (Th) cells in expression of cytokines and transcription factors. For example, RORγt is the lineage-specific transcription factor for both ILC3 and Th17 cells. However, the ILC counterpart for BCL6-expressing T follicular helper (Tfh) cells has not been defined. Here, we report that in the ILC compartment, BCL6 is selectively co-expressed with not only CXCR5, but also RORγt and CCR6 in ILC3 from multiple tissues. BCL6-deficient ILC3 produce enhanced levels of IL-17A and IL-22. More importantly, phenotypic and single-cell ATAC-seq analysis show that absence of BCL6 in mature ILC3 increases the numbers of ILC1 and transitional cells co-expressing ILC3 and ILC1 marker genes. A lineage-tracing experiment further reveals BCL6+ ILC3 to ILC1 trans-differentiation under steady state. Lastly, microbiota promote BCL6 expression in colonic CCR6+ ILC3, and thus reinforce their stability. Collectively, our data have demonstrated that CCR6+ ILC3 have both Th17 and Tfh programs and that BCL6 expression in these cells functions to maintain their lineage identity.

2022-12-29 | GSE220437 | GEO

Cell autonomous expression of Bcl6 is required to maintain lineage identity of mouse CCR6+ ILC3s [RNA-seq in vivo]

2022-12-29 | GSE220434 | GEO

Cell autonomous expression of Bcl6 is required to maintain lineage identity of mouse CCR6+ ILC3s

2022-12-27 | GSE221341 | GEO

Gene expression analysis of CD4+ and CD4- ILC1 subsets by RNAseq

Project description:Innate lymphoid cell (ILC) subsets that mirror helper T cells in their effector cytokine profiles have recently emerged as central players in both homeostatic and inflammatory conditions. Like their Th1, Th2 and Th17/Th22 helper T cell counterparts, ILC subsets are categorized based on their expression of specific transcription factors and effector cytokines: group 1 ILC (ILC1) express T-bet and IFN-Î³; group 2 ILC (ILC2) express GATA-3 and type 2 effector cytokines such as IL-13 and IL-5; and group 3 ILC (ILC3) express RORgt and the cytokines IL-22 and/or IL-17. Under this nomenclature, natural killer (NK) cells and lymphoid tissue inducers (LTi) are considered ILC1 and ILC3, respectively. ILC1 contain both CD4+ and CD4- populations, but whether this phenotypic characteristic reflects functional differences between these two populations is unknown. These studies examine the gene expression profiles of CD4+ vs CD4- ILC1 in a cohort of healthy control subjects. ILC subsets were isolated from the peripheral blood of healthy control subjects. cDNA was isolated and amplified from sorted populations, and gene expression was analyzed by RNAseq

2015-12-31 | E-GEOD-69596 | biostudies-arrayexpress

Comprehensive protein-expression map of ILC2 and ILC3 subsets in healthy human skin

Project description:Innate lymphoid cells (ILCs) have emerged as essential players in the skin-associated immune system in health and inflammatory skin diseases. Their low numbers and lack of specific markers hampered extensive characterization and consequently resulted in limited knowledge of their protein expression. Here, we combined flow cytometry and state-of-the-art proteomics to comprehensively describe the proteins constitutively expressed by ILC2 and ILC3 subsets derived from healthy human skin and peripheral blood. We quantified 6666 proteins from skin ILC and identified 608 differentially expressed proteins in the investigated subsets. In addition to the current analyses, highlighting new functions of ILC, the ILC proteomic libraries and the proteomes of the ILC2 and ILC3 subsets will serve as valuable resources for future analyses of ILC function and are available at http://skin.science.

2023-10-10 | PXD037817 | Pride

CD45RA+CD62L- ILCs represent a quiescent local reservoir for the generation of mature ILC in human tissues

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.

2022-02-17 | GSE176367 | GEO

Identification and characterization of regenerative innate lymphoid cells from pluripotent stem cells [WT_ILC/R9_iILC_SmartSeq2]

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.

2022-09-30 | GSE186777 | GEO

Identification of aceNKPs, a committed common progenitor of the ILC1 and NK cell continuum

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.

2022-11-02 | GSE213814 | GEO

Distinct Gene Regulatory Pathways for Human Innate Versus Adaptive Lymphoid Cells [gene expression]

Project description:Innate lymphoid cells (ILCs) serve as sentinels in mucosal tissues, sensing release of soluble inflammatory mediators, rapidly communicating danger via cytokine secretion, and functioning as guardians of tissue homeostasis. Although ILCs have been studied extensively in model organisms, little is known about these âfirst respondersâ in humans, especially their lineage and functional kinships to cytokine-secreting T helper cell (Th) counterparts. Here, we report gene regulatory circuitries for four human ILCâTh counterparts derived from mucosal environments, revealing that each ILC subset diverges as a distinct lineage from Th and circulating natural killer cells, but shares circuitry devoted to functional polarization with their Th counterparts. Super-enhancers demarcate cohorts of cell identity genes in each lineage, uncovering new modes of regulation for signature cytokines, novel molecules that likely impart important functions to ILCs, and potential mechanisms for autoimmune disease SNP associations within ILCâTh subsets. RNA was isolated from two to five replicates of ILC1, ILC3, Th1, Th2 and NK cells. Gene expression levels were determined using Affymetrix Human Gene 1.0 ST arrays.

2016-05-13 | E-GEOD-78896 | biostudies-arrayexpress

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