9 research outputs found
Analysis of an insulin gene transcription control element Positive and negative regulation appears to be mediated by different element sequences
AbstractPancreatic β-cell-type-specific transcription of the insulin gene is controlled by cis-acting sequence elements lying within its enhancer region. An essential element required for expression is the insulin control element (ICE). The activity of this element is regulated by both positive- and negative-acting transcription factors. In this study, we have identified the nucleotide sequences within the ICE that are required for repression in noninsulin producing cells. Our results indicate that the cis-acting sequences involved in negative control are distinct from those required in activating expression in β cells
Isolation and characterization of bovine lipoproteins: incubation with hepatic lipase and isolated adrenal zona fasciculata cells
The CD46-Jagged1 interaction is critical for human T(H)1 immunity
CD46 is a complement regulator with important roles related to the immune response. CD46 functions as a pathogen receptor and is a potent costimulator for the induction of interferon-γ (IFN-γ)-secreting effector T helper type 1 (TH1) cells and their subsequent switch into interleukin 10 (IL-10)-producing regulatory T cells. Here we identified the Notch family member Jagged1 as a physiological ligand for CD46. Furthermore, we found that CD46 regulated the expression of Notch receptors and ligands during T cell activation and that disturbance of the CD46-Notch crosstalk impeded induction of IFN-γ and switching to IL-10. Notably, CD4+ T cells from CD46-deficient patients and patients with hypomorphic mutations in the gene encoding Jagged1 (Alagille syndrome) failed to mount appropriate T H 1 responses in vitro and in vivo, which suggested that CD46-Jagged1 crosstalk is responsible for the recurrent infections in subpopulations of these patients. © 2012 Nature America, Inc. All rights reserved
Mapping the dynamic genetic regulatory architecture of HLA genes at single-cell resolution
The human leukocyte antigen (HLA) locus plays a critical role in complex traits spanning autoimmune and infectious diseases, transplantation and cancer. While coding variation in HLA genes has been extensively documented, regulatory genetic variation modulating HLA expression levels has not been comprehensively investigated. Here we mapped expression quantitative trait loci (eQTLs) for classical HLA genes across 1,073 individuals and 1,131,414 single cells from three tissues. To mitigate technical confounding, we developed scHLApers, a pipeline to accurately quantify single-cell HLA expression using personalized reference genomes. We identified cell-type-specific cis-eQTLs for every classical HLA gene. Modeling eQTLs at single-cell resolution revealed that many eQTL effects are dynamic across cell states even within a cell type. HLA-DQ genes exhibit particularly cell-state-dependent effects within myeloid, B and T cells. For example, a T cell HLA-DQA1 eQTL ( rs3104371 ) is strongest in cytotoxic cells. Dynamic HLA regulation may underlie important interindividual variability in immune responses.</p