Identification of a distal enhancer regulating hedgehog interacting protein gene in human lung epithelial cells.

Autor:	Guo F; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Jiangsu Key Laboratory of Immunity and Metabolism, Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, Jiangsu 221004, China. Electronic address: Feng.Guo@xzhmu.edu.cn., Zhang L; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA; Department of Integrated Traditional Chinese and Western Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China., Yu Y; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Gong L; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Tao S; Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15224, USA., Werder RB; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Mishra S; Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Zhou Y; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Anamika WJ; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Lao T; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Inuzuka H; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Zhang Y; The Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA., Pham B; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Liu T; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA., Tufenkjian TS; Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Richmond BW; Department of Veterans Affairs Medical Center, Nashville, TN 37232, USA; Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA., Wei W; Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA., Mou H; The Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA., Wilson AA; Center for Regenerative Medicine of Boston University and Boston Medical Center, Boston, MA 02118, USA; The Pulmonary Center and Department of Medicine, Boston University School of Medicine, Boston, MA 02118, USA., Hu M; Department of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA., Chen W; Department of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15224, USA; Division of Pediatric Pulmonary Medicine, UPMC Children's Hospital of Pittsburgh, University of Pittsburgh, Pittsburgh, PA 15224, USA., Zhou X; Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA. Electronic address: Xiaobo.Zhou@channing.harvard.edu.
Jazyk:	angličtina
Zdroj:	EBioMedicine [EBioMedicine] 2024 Mar; Vol. 101, pp. 105026. Date of Electronic Publication: 2024 Feb 27.
DOI:	10.1016/j.ebiom.2024.105026
Abstrakt:	Background: An intergenic region at chromosome 4q31 is one of the most significant regions associated with COPD susceptibility and lung function in GWAS. In this region, the implicated causal gene HHIP has a unique epithelial expression pattern in adult human lungs, in contrast to dominant expression in fibroblasts in murine lungs. However, the mechanism underlying the species-dependent cell type-specific regulation of HHIP remains largely unknown. Methods: We employed snATAC-seq analysis to identify open chromatin regions within the COPD GWAS region in various human lung cell types. ChIP-quantitative PCR, reporter assays, chromatin conformation capture assays and Hi-C assays were conducted to characterize the regulatory element in this region. CRISPR/Cas9-editing was performed in BEAS-2B cells to generate single colonies with stable knockout of the regulatory element. RT-PCR and Western blot assays were used to evaluate expression of HHIP and epithelial-mesenchymal transition (EMT)-related marker genes. Findings: We identified a distal enhancer within the COPD 4q31 GWAS locus that regulates HHIP transcription at baseline and after TGFβ treatment in a SMAD3-dependent, but Hedgehog-independent manner in human bronchial epithelial cells. The distal enhancer also maintains chromatin topological domains near 4q31 locus and HHIP gene. Reduced HHIP expression led to increased EMT induced by TGFβ in human bronchial epithelial cells. Interpretation: A distal enhancer regulates HHIP expression both under homeostatic condition and upon TGFβ treatment in human bronchial epithelial cells. The interaction between HHIP and TGFβ signalling possibly contributes to COPD pathogenesis. Funding: Supported by NIH grants R01HL127200, R01HL148667 and R01HL162783 (to X. Z). Competing Interests: Declaration of interests All authors have read and confirmed the manuscript and accepted the responsibility to submit it for publication. No potential conflicts of interest for all authors listed in the manuscript. (Copyright © 2024 The Author(s). Published by Elsevier B.V. All rights reserved.)
Databáze:	MEDLINE
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