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1.
Front Genet ; 11: 585746, 2020.
Article in English | MEDLINE | ID: mdl-33362848

ABSTRACT

BACKGROUND: Asthma is a chronic airway disease driven by complex genetic-environmental interactions. The role of epigenetic modifications in bronchial epithelial cells (BECs) in asthma is poorly understood. METHODS: We piloted genome-wide profiling of the enhancer-associated histone modification H3K27ac in BECs from people with asthma (n = 4) and healthy controls (n = 3). RESULTS: We identified n = 4,321 (FDR < 0.05) regions exhibiting differential H3K27ac enrichment between asthma and health, clustering at genes associated predominately with epithelial processes (EMT). We identified initial evidence of asthma-associated Super-Enhancers encompassing genes encoding transcription factors (TP63) and enzymes regulating lipid metabolism (PTGS1). We integrated published datasets to identify epithelium-specific transcription factors associated with H3K27ac in asthma (TP73) and identify initial relationships between asthma-associated changes in H3K27ac and transcriptional profiles. Finally, we investigated the potential of CRISPR-based approaches to functionally evaluate H3K27ac-asthma landscape in vitro by identifying guide-RNAs capable of targeting acetylation to asthma DERs and inducing gene expression (TLR3). CONCLUSION: Our small pilot study validates genome-wide approaches for deciphering epigenetic mechanisms underlying asthma pathogenesis in the airways.

2.
J Clin Invest ; 129(8): 3153-3170, 2019 07 02.
Article in English | MEDLINE | ID: mdl-31264977

ABSTRACT

Hedgehog (Hh) proteins regulate development and tissue homeostasis, but their role in atopic dermatitis (AD) remains unknown. We found that on induction of mouse AD, Sonic Hedgehog (Shh) expression in skin, and Hh pathway action in skin T cells were increased. Shh signaling reduced AD pathology and the levels of Shh expression determined disease severity. Hh-mediated transcription in skin T cells in AD-induced mice increased Treg populations and their suppressive function through increased active transforming growth factor-ß (TGF-ß) in Tregs signaling to skin T effector populations to reduce disease progression and pathology. RNA sequencing of skin CD4+ T cells from AD-induced mice demonstrated that Hh signaling increased expression of immunoregulatory genes and reduced expression of inflammatory and chemokine genes. Addition of recombinant Shh to cultures of naive human CD4+ T cells in iTreg culture conditions increased FOXP3 expression. Our findings establish an important role for Shh upregulation in preventing AD, by increased Gli-driven Treg cell-mediated immune suppression, paving the way for a potential new therapeutic strategy.


Subject(s)
Dermatitis, Atopic/immunology , Hedgehog Proteins/immunology , Signal Transduction/immunology , Skin/immunology , T-Lymphocytes, Regulatory/immunology , Zinc Finger Protein Gli2/immunology , Animals , Dermatitis, Atopic/genetics , Dermatitis, Atopic/pathology , Forkhead Transcription Factors/genetics , Forkhead Transcription Factors/immunology , Gene Expression Regulation/immunology , Hedgehog Proteins/genetics , Mice , Mice, Knockout , Signal Transduction/genetics , Skin/pathology , T-Lymphocytes, Regulatory/pathology , Transforming Growth Factor beta/genetics , Transforming Growth Factor beta/immunology , Zinc Finger Protein Gli2/genetics
3.
Mediators Inflamm ; 2015: 347965, 2015.
Article in English | MEDLINE | ID: mdl-25977599

ABSTRACT

Clinical treatment with glucocorticoids (GC) can be complicated by cytokine-induced glucocorticoid low-responsiveness (GC-resistance, GCR), a condition associated with a homogeneous reduction in the expression of GC-receptor- (GR-) driven anti-inflammatory genes. However, GR level and phosphorylation changes modify the expression of individual GR-responsive genes differently. As sustained IL-1ß exposure is key in the pathogenesis of several major diseases with prevalent GCR, we examined GR signaling and the mRNA expression of six GR-driven genes in cells cultured in IL-1ß and afterwards challenged with GC. After a GC challenge, sustained IL-1ß exposure reduced the cytoplasmic GR level, GR(Ser203) and GR(Ser211) phosphorylation, and GR nuclear translocation and led to selective GCR in the expression of the studied genes. Compared to GC alone, in a broad range of GC doses plus sustained IL-1ß, FKBP51 mRNA expression was reduced by 1/3, TTP by 2/3, and IRF8 was completely knocked down. In contrast, high GC doses did not change the expression of GILZ and DUSP1, while IGFBP1 was increased by 5-fold. These effects were cytokine-selective, IL-1ß dose- and IL-1R1-dependent. The integrated gain and loss of gene functions in the "split GCR" model may provide target cells with a survival advantage by conferring resistance to apoptosis, chemotherapy, and GC.


Subject(s)
Glucocorticoids/metabolism , Interleukin-1beta/pharmacology , Receptors, Glucocorticoid/metabolism , Blotting, Western , Cell Line , Fluorescent Antibody Technique , Humans , Insulin-Like Growth Factor Binding Protein 1/genetics , Interferon Regulatory Factors/genetics , Phosphorylation , Reverse Transcriptase Polymerase Chain Reaction , Tacrolimus Binding Proteins/genetics , Tristetraprolin/genetics
4.
Proc Natl Acad Sci U S A ; 107(13): 5925-30, 2010 Mar 30.
Article in English | MEDLINE | ID: mdl-20231472

ABSTRACT

Studies here respond to two long-standing questions: Are human "pre/pro-B" CD34(+)CD10(-)CD19(+) and "common lymphoid progenitor (CLP)/early-B" CD34(+)CD10(+)CD19(-) alternate precursors to "pro-B" CD34(+)CD19(+)CD10(+) cells, and do the pro-B cells that arise from these progenitors belong to the same or distinct B-cell development pathways? Using flow cytometry, gene expression profiling, and Ig V(H)-D-J(H) sequencing, we monitor the initial 10 generations of development of sorted cord blood CD34(high)Lineage(-) pluripotential progenitors growing in bone marrow S17 stroma cocultures. We show that (i) multipotent progenitors (CD34(+)CD45RA(+)CD10(-)CD19(-)) directly generate an initial wave of Pax5(+)TdT(-) "unilineage" pre/pro-B cells and a later wave of "multilineage" CLP/early-B cells and (ii) the cells generated in these successive stages act as precursors for distinct pro-B cells through two independent layered pathways. Studies by others have tracked the origin of B-lineage leukemias in elderly mice to the mouse B-1a pre/pro-B lineage, which lacks the TdT activity that diversifies the V(H)-D-J(H) Ig heavy chain joints found in the early-B or B-2 lineage. Here, we show a similar divergence in human B-cell development pathways between the Pax5(+)TdT(-) pre/pro-B differentiation pathway that gives rise to infant B-lineage leukemias and the early-B pathway.


Subject(s)
Lymphoid Progenitor Cells/cytology , Lymphoid Progenitor Cells/immunology , Lymphopoiesis/immunology , Precursor Cells, B-Lymphoid/cytology , Precursor Cells, B-Lymphoid/immunology , Animals , Antigens, CD19/metabolism , Antigens, CD34/metabolism , B-Lymphocyte Subsets/cytology , B-Lymphocyte Subsets/immunology , Base Sequence , Bone Marrow Cells/cytology , Cell Differentiation/immunology , Cell Proliferation , Coculture Techniques , DNA/genetics , Fetal Blood/cytology , Fetal Blood/immunology , Gene Expression Profiling , Gene Rearrangement, B-Lymphocyte, Heavy Chain , Humans , Infant, Newborn , Leukemia, B-Cell/genetics , Leukemia, B-Cell/immunology , Mice , Models, Immunological , Neprilysin/metabolism , Stromal Cells/cytology
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