Context-specific regulation of surface and soluble IL7R expression by an autoimmune risk allele

Abstract IL-7 is a key factor in T cell immunity and common variants at IL7R, encoding its receptor, are associated with autoimmune disease susceptibility. IL7R mRNA is induced in stimulated monocytes, yet a function for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level in healthy individuals, and find that monocyte surface and soluble IL7R (sIL7R) are markedly induced by lipopolysaccharide. In monocytes, both surface IL7R and sIL7R expression strongly associate with allelic carriage of rs6897932, a disease-associated IL7R polymorphism. Monocytes produce more sIL7R than CD4 + T cells, and the amount is additionally correlated with the expression of DDX39A, encoding a splicing factor. Synovial fluid-derived monocytes from patients with spondyloarthritis are enriched for IL7R+ cells with a unique transcriptional profile that overlaps with IL-7-induced gene sets. Our data thus suggest a previously unappreciated function for monocytes in IL-7 biology and IL7R-associated diseases.

Download Full-text

Context-specific regulation of monocyte surface IL7R expression and soluble receptor secretion by a common autoimmune risk allele

10.1101/262410 ◽

2018 ◽

Cited By ~ 3

Author(s):

Hussein Al-Mossawi ◽

Nicole Yager ◽

Chelsea Taylor ◽

Evelyn Lau ◽

Sara Danielli ◽

...

Keyword(s):

Genetic Regulation ◽

Biliary Cirrhosis ◽

Transcriptional Signature ◽

Cell Immunity ◽

Key Factor ◽

Multiple Cell ◽

Specific Regulation ◽

Context Specific ◽

Genetically Determined

AbstractIL-7 is a key factor in T-cell immunity and IL7R polymorphisms are implicated in autoimmune pathogenesis. IL7R mRNA is induced in stimulated monocytes in a genetically determined manner, yet a role for IL7R in monocyte biology remains unexplored. Here we characterize genetic regulation of IL7R at the protein level across multiple cell subsets and conditions in healthy individuals. We find monocyte surface and soluble IL7R (sIL7R) protein are markedly expressed in response to lipopolysaccharide (LPS). We further demonstrate alleles of rs6897932, a non-synonymous IL7R polymorphism associated with susceptibility to Multiple Sclerosis, Ankylosing Spondylitis and Primary Biliary Cirrhosis, form the key determinant of both surface IL7R and sIL7R in the context of inflammation. No effect of this allele was observed in unstimulated monocytes or across lymphoid subsets. Production of sIL7R by monocytes greatly exceeded that of CD4+ T-cells, and was strongly associated with both rs6897932 genotype and expression of the splicing factor gene DDX39A. Stimulated monocytes were sensitive to exogenous IL-7, which elicits a defined transcriptional signature. Flow cytometry and single-cell sequencing of synovial fluid derived monocytes from patients with spondyloarthritis showed an enlarged subset of IL7R+ monocytes with a unique transcriptional profile that markedly overlaps that induced by IL-7 in-vitro and shows similarity to the previously described ‘Mono4’ subset. These data demonstrate disease-associated genetic variants at IL7R specifically impact monocyte surface IL7R and sIL7R following innate immune stimulation, suggesting a previously unappreciated key role for monocytes in IL-7 pathway biology and IL7R-associated diseases.

Download Full-text

The Naturally Occurring ∆40p53 Isoform Inhibits eRNA Transcription and Enables Context-Specific Regulation During p53 Activation

SSRN Electronic Journal ◽

10.2139/ssrn.3624472 ◽

2020 ◽

Author(s):

Cecilia Blair Levandowski ◽

T. Jones ◽

Margaret Gruca ◽

Sivapriya Ramamoorthy ◽

Robin Dowell ◽

...

Keyword(s):

Naturally Occurring ◽

P53 Activation ◽

Specific Regulation ◽

Context Specific

Download Full-text

Colonization of Durum Wheat (Triticum turgidum L. var. durum) Culms Exhibiting Premature Senescence (Dead Heads) Associated with Fusarium pseudograminearum Crown Rot

Plant Disease ◽

10.1094/pdis-03-17-0415-re ◽

2017 ◽

Vol 101 (10) ◽

pp. 1788-1794 ◽

Cited By ~ 4

Author(s):

Noel L. Knight ◽

Bethany Macdonald ◽

Mark W. Sutherland

Keyword(s):

Durum Wheat ◽

Disease Susceptibility ◽

Triticum Turgidum ◽

Crown Rot ◽

Vascular Bundles ◽

Fusarium Crown Rot ◽

Fusarium Pseudograminearum ◽

Field Samples ◽

Key Factor ◽

Significant Disease

Fusarium crown rot is a significant disease of durum wheat (Triticum turgidum L. var. durum), which exhibits high levels of disease susceptibility. The most extreme symptom of crown rot is a prematurely senescing culm that typically fails to set grain. Individual crown rot-affected durum wheat plants displaying both nonsenescent and prematurely senescent culms were harvested to compare visual discoloration, Fusarium pseudograminearum biomass, and vascular colonization in culm sections sampled at three different heights above the crown. Field samples of EGA Bellaroi were collected at Wellcamp, QLD, in 2011, 2012, 2013, and 2014, and of Hyperno at Narrabri, NSW, in 2014. Prematurely senescent culms exhibited greater visual discoloration, F. pseudograminearum biomass, and vascular colonization than nonsenescent culms in each year they were examined. The extent of these differences varied between environments and timing of collection in each year. Vascular colonization initially occurred in xylem vessels and spread into phloem tissues as disease severity increased. The increased presence of hyphae in vascular bundles of prematurely senescing culms provides strong evidence for the hypothesis that restriction of water and nutrient movement in a diseased culm is a key factor in crown rot severity.

Download Full-text

Context-specific regulation of lysosomal lipolysis through network-level diverting of transcription factor interactions

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.2104832118 ◽

2021 ◽

Vol 118 (41) ◽

pp. e2104832118

Author(s):

Vinod K. Mony ◽

Anna Drangowska-Way ◽

Reka Albert ◽

Emma Harrison ◽

Abbas Ghaddar ◽

...

Keyword(s):

Oxidative Stress ◽

Target Gene ◽

Specific Nature ◽

C Elegans ◽

Functional Interactions ◽

Genetic Epistasis ◽

Specific Regulation ◽

Context Specific ◽

Factor Interactions ◽

Multicellular Organisms

Plasticity in multicellular organisms involves signaling pathways converting contexts—either natural environmental challenges or laboratory perturbations—into context-specific changes in gene expression. Congruently, the interactions between the signaling molecules and transcription factors (TF) regulating these responses are also context specific. However, when a target gene responds across contexts, the upstream TF identified in one context is often inferred to regulate it across contexts. Reconciling these stable TF–target gene pair inferences with the context-specific nature of homeostatic responses is therefore needed. The induction of the Caenorhabditis elegans genes lipl-3 and lipl-4 is observed in many genetic contexts and is essential to survival during fasting. We find DAF-16/FOXO mediating lipl-4 induction in all contexts tested; hence, lipl-4 regulation seems context independent and compatible with across-context inferences. In contrast, DAF-16–mediated regulation of lipl-3 is context specific. DAF-16 reduces the induction of lipl-3 during fasting, yet it promotes it during oxidative stress. Through discrete dynamic modeling and genetic epistasis, we define that DAF-16 represses HLH-30/TFEB—the main TF activating lipl-3 during fasting. Contrastingly, DAF-16 activates the stress-responsive TF HSF-1 during oxidative stress, which promotes C. elegans survival through induction of lipl-3. Furthermore, the TF MXL-3 contributes to the dominance of HSF-1 at the expense of HLH-30 during oxidative stress but not during fasting. This study shows how context-specific diverting of functional interactions within a molecular network allows cells to specifically respond to a large number of contexts with a limited number of molecular players, a mode of transcriptional regulation we name “contextualized transcription.”

Download Full-text

Common Variants in Cholesterol Synthesis– and Transport–Related Genes Associate with Circulating Cholesterol Responses to Intakes of Conventional Dairy Products in Healthy Individuals

Journal of Nutrition ◽

10.3945/jn.115.222208 ◽

2016 ◽

Vol 146 (5) ◽

pp. 1008-1016 ◽

Cited By ~ 5

Author(s):

Mohammad MH Abdullah ◽

Audrey Cyr ◽

Marie-Claude Lépine ◽

Peter K Eck ◽

Patrick Couture ◽

...

Keyword(s):

Dairy Products ◽

Cholesterol Synthesis ◽

Common Variants ◽

Healthy Individuals

Download Full-text

Capturing context-specific regulation in molecular interaction networks

BMC Bioinformatics ◽

10.1186/s12859-018-2513-7 ◽

2018 ◽

Vol 19 (1) ◽

Cited By ~ 4

Author(s):

Stephen T. A. Rush ◽

Dirk Repsilber

Keyword(s):

Molecular Interaction ◽

Interaction Networks ◽

Molecular Interaction Networks ◽

Specific Regulation ◽

Context Specific

Download Full-text

The interleukin 23 receptor gene does not confer risk to systemic sclerosis and is not associated with systemic sclerosis disease phenotype

Annals of the Rheumatic Diseases ◽

10.1136/ard.2008.096719 ◽

2008 ◽

Vol 68 (2) ◽

pp. 253-256 ◽

Cited By ~ 22

Author(s):

B Rueda ◽

J Broen ◽

O Torres ◽

C Simeon ◽

N Ortego-Centeno ◽

...

Keyword(s):

Systemic Sclerosis ◽

Disease Susceptibility ◽

Clinical Phenotype ◽

Meta Analysis ◽

Receptor Gene ◽

Replication Study ◽

Taqman Assay ◽

Nucleotide Polymorphisms ◽

Healthy Individuals ◽

Interleukin 23

Objectives:Multiple studies indicate the role of the interleukin (IL)-17/IL-23 axis in autoimmune diseases, including systemic sclerosis (SSc). The aim of the current study was to investigate the possible implication of the IL23R gene in SSc susceptibility and/or clinical phenotype.Methods:An initial case–control study in 143 Dutch patients with SSc and geographically matched healthy individuals (n = 246) was carried out and followed by a replication study in a cohort of 365 Spanish patients with SSc and 515 healthy individuals. Seven single nucleotide polymorphisms (SNPs) spanning the IL23R gene were selected and genotyped using a Taqman assay.Results:Using a Dutch cohort of patients with SSc and controls we observed an association between two (rs11209032, rs1495965) of the seven tested SNPs and disease susceptibility (allelic p values: p = 0.02 and p = 0.01 respectively). However, a replication study in an independent Spanish cohort did not confirm these findings and reveal no association of any of the IL23R-tested SNP with disease susceptibility or clinical phenotype. Similarly, a meta-analysis considering both populations did not reveal any significant association. In addition, no association was observed between IL23R genetic variants and SSc clinical phenotypes.Conclusions:Our results suggest that the IL23R gene is not associated with SSc susceptibility or clinical phenotype.

Download Full-text