The aryl hydrocarbon receptor regulates expression of mucosal trafficking receptor GPR15

Swaminathan, Gayathri; Nguyen, Linh P.; Namkoong, Hong; Pan, Junliang; Haileselassie, Yeneneh; Patel, Akshar; Ji, Allison Ruoheng; Mikhail, David; Dinh, Theresa; Singh, Harpriya; Liao, Bryce; Vazquez‐Montesino, Luis Miguel; Butcher, Eugene C.; Habtezion, Aida

doi:10.1038/s41385-021-00390-x

Cited by 18 publications

(19 citation statements)

References 32 publications

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“… 27 It has been shown that regulatory T cell GPR15 expression in UC patients is increased 28 and, most recently, the dependence of GPR15 transcription on aryl hydrocarbon receptor signalling has been demonstrated. 29 …”

Section: Discussionmentioning

confidence: 99%

Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2

Nowak

Adams

Kalla

et al. 2022

Journal of Crohn's and Colitis

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Aim To assess the pathobiological and translational importance of whole blood transcriptomic analysis in inflammatory bowel disease (IBD). Methods We analyzed whole blood expression profiles from paired-end sequencing in a discovery cohort of 590 Europeans recruited across six countries in the IBD Character initiative (newly diagnosed patients with Crohn’s disease [CD, n = 156], ulcerative colitis [UC, n = 167], and controls [n = 267]), exploring differential expression (DESeq2), co-expression networks (WGCNA), and transcription factor involvement (EPEE, ChEA, DoRothEA). Findings were validated by analysis of an independent replication cohort (99 CD, 100 UC, and 95 controls). In the discovery cohort, we also defined baseline expression correlates of future treatment escalation using cross-validated elastic-net and random forest modelling, along with a pragmatic ratio detection procedure. Results Disease-specific transcriptomes were defined in IBD (8697 transcripts), CD (7152), and UC (8521), with the most highly significant changes in single genes, including CD177 (log2-fold change [LFC] = 4.63, p = 4.05 × 10 -118), MCEMP1 (LFC = 2.45, p = 7.37 × 10 -109), and S100A12 (LFC = 2.31, p = 2.15 × 10 -93). Significantly over-represented pathways included IL-1 (p = 1.58 × 10 -11), IL-4, and IL-13 (p = 8.96 × 10 -9). Highly concordant results were obtained using multiple regulatory activity inference tools applied to the discovery and replication cohorts. These analyses demonstrated central roles in IBD for the transcription factors NFE2, SPI1 (PU.1), CEBPB, and IRF2, all regulators of cytokine signaling, based on a consistent signal across cohorts and transcription factor ranking methods. A number of simple transcriptome-based models were associated with the need for treatment escalation, including the binary CLEC5A/CDH2 expression ratio in UC (hazard ratio = 23.4, 95% CI 5.3–102.0). Conclusion Transcriptomic analysis has allowed for a detailed characterization of IBD pathobiology, with important potential translational implications.

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Section: Discussionmentioning

confidence: 99%

Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2

Nowak

Adams

Kalla

et al. 2022

Journal of Crohn's and Colitis

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“…In a T cell transfer model of colitis, the suppressive effect of Tregs on intestinal inflammation was diminished by the specific depletion of Ahr in Tregs ( 66 ). Whole-body Ahr deficiency acutely attenuates the expression of GPR15 both in effector memory T cells and in Tregs ( 67 ). Like SCFAs, AhR upregulates GPR15 expression together with FOXP3 in Tregs.…”

Section: Microbial Regulation Of Intestinal Tregsmentioning

confidence: 99%

TREGking From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis

et al. 2022

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The human gastrointestinal tract has an enormous and diverse microbial community, termed microbiota, that is necessary for the development of the immune system and tissue homeostasis. In contrast, microbial dysbiosis is associated with various inflammatory and autoimmune diseases as well as neurological disorders in humans by affecting not only the immune system in the gastrointestinal tract but also other distal organs. FOXP3+ regulatory T cells (Tregs) are a subset of CD4+ helper T cell lineages that function as a gatekeeper for immune activation and are essential for peripheral autoimmunity prevention. Tregs are crucial to the maintenance of immunological homeostasis and tolerance at barrier regions. Tregs reside in both lymphoid and non-lymphoid tissues, and tissue-resident Tregs have unique tissue-specific phenotype and distinct function. The gut microbiota has an impact on Tregs development, accumulation, and function in periphery. Tregs, in turn, modulate antigen-specific responses aimed towards gut microbes, which supports the host–microbiota symbiotic interaction in the gut. Recent studies have indicated that Tregs interact with a variety of resident cells in central nervous system (CNS) to limit the progression of neurological illnesses such as ischemic stroke, Alzheimer’s disease, and Parkinson’s disease. The gastrointestinal tract and CNS are functionally connected, and current findings provide insights that Tregs function along the gut-brain axis by interacting with immune, epithelial, and neuronal cells. The purpose of this study is to explain our current knowledge of the biological role of tissue-resident Tregs, as well as the interaction along the gut-brain axis.

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“…Therefore, it remains unclear whether 3-MC promotes GATA3-dependent AhR binding in T-47D cells genome-wide, or only in a subset of AhR-enriched regions. Additionally, synergistic effects of GATA3 and AhR binding on the expression of GPR15 have been reported in human CD4+ T cells (Swaminathan et al, 2021), suggesting that AhR-GATA3 interactions might not be confined to breast cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Predictive Models of Genome-wide Aryl Hydrocarbon Receptor DNA Binding Reveal Tissue Specific Binding Determinants

Filipovic

Kana

et al. 2022

Preprint

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BackgroundThe Aryl Hydrocarbon Receptor (AhR) is an inducible transcription factor (TF) whose ligands include the environmental contaminant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). TCDD-mediated toxicity occurs through activation of AhR and its subsequent binding to the Dioxin Response Element (DRE), comprising the DNA motif 5’-GCGTG-3’. However, AhR binding in human tissues is highly dynamic and tissue specific. Approximately 50% of all experimentally verified AhR binding sites do not contain a DRE. Additionally, most accessible DREs are not bound by AhR. Identification of tissue specific AhR binding determinants is crucial for understanding downstream gene regulation and potential adverse outcomes of AhR activation.ResultsWe applied XGBoost, a supervised machine learning architecture, to predict the genome wide AhR binding status of DREs in open chromatin as a function of DNA sequence flanking the DRE, chromatin accessibility, histone modifications (HM), TF binding, and proximity of the DRE to gene promoters. We trained and validated our models using 5-fold cross validation to predict the binding status of DREs in AhR-activated MCF-7 breast cancer cells, primary human hepatocytes, and lymphoblastoid GM17212 cells, as well as AhR non-activated HepG2 hepatocellular carcinoma cells. Our results demonstrate highly accurate and robust models of AhR binding; and identify patterns of transcription factor binding and histone modifications predictive of AhR binding. These patterns are consistent within tissues but highly variable across tissues, which is suggestive of tissue-specific mechanisms of AhR binding.ConclusionsAhR binding is driven by a complex interplay of tissue-agnostic DNA sequence flanking its binding motif and tissue-specific local chromatin context.

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The aryl hydrocarbon receptor regulates expression of mucosal trafficking receptor GPR15

Cited by 18 publications

References 32 publications

Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2

Characterisation of the Circulating Transcriptomic Landscape in Inflammatory Bowel Disease Provides Evidence for Dysregulation of Multiple Transcription Factors Including NFE2, SPI1, CEBPB, and IRF2

TREGking From Gut to Brain: The Control of Regulatory T Cells Along the Gut-Brain Axis

Predictive Models of Genome-wide Aryl Hydrocarbon Receptor DNA Binding Reveal Tissue Specific Binding Determinants

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