Evidence map›Paper›PMID 38417378›Full record

ArticleEBioMedicine2024

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

Feng Guo, Li Zhang, Yuzhen Yu, Lu Gong, Shiyue Tao, Rhiannon B Werder, Shreya Mishra, Yihan Zhou, Wardatul Jannat Anamika, Taotao Lao and 12 more

Open access · goldAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in EBioMedicine, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
2.1field-weighted citation impact, top 13% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed, 9 citations in OpenAlex.

  1. HHIP's dynamic role in epithelial wound healing reveals a potential mechanism of COPD susceptibility.Proceedings of the National Academy of Sciences of the United States of America · 2026
    Article
  2. Article
  3. Review
  4. POU5F1 bridges Hedgehog signaling and epithelial remodeling in COPD.Frontiers in cell and developmental biology · 2025
    Article
  5. Review
  6. Review
  7. Article
4 · The record

Corrections and comments

5 · Who and what money

Authors and funding

22 authors at 9 institutions in 2 countries.

Feng GuoChanning 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.
Li ZhangChanning 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.
Yuzhen YuChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Lu GongChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Shiyue TaoDepartment of Biostatistics, School of Public Health, University of Pittsburgh, Pittsburgh, PA 15224, USA.
Rhiannon B WerderCenter 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.
Shreya MishraDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Yihan ZhouChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Wardatul Jannat AnamikaChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Taotao LaoChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Hiroyuki InuzukaDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Yihan ZhangThe Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Betty PhamChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Tao LiuChanning Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Tiffany S TufenkjianDepartment 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.
Bradley W RichmondDepartment 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.
Wenyi WeiDepartment of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02115, USA.
Hongmei MouThe Mucosal Immunology and Biology Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA.
Andrew A WilsonCenter 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.
Ming HuDepartment of Quantitative Health Sciences, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Wei ChenDepartment 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.
Xiaobo ZhouChanning 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.
Brigham and Women's Hospital · USBeth Israel Deaconess Medical Center · USBoston Medical Center · USCleveland Clinic · USMassachusetts General Hospital · USVanderbilt University Medical Center · USChildren's Hospital of Pittsburgh · USUniversity of Pittsburgh · USXuzhou Medical College · CN

Funding

Metabolic Control of Stemness in lung epithelial progenitors by FAM13AR01HL127200 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI ZHOU, ANNY XIAOBO · 2015 to 2024
$4.9M
Integrative Characterization on the function of COPD GWAS gene, HHIPR01HL148667 · NHLBI · BRIGHAM AND WOMEN'S HOSPITAL · PI WEI, WENYI, ZHOU, ANNY XIAOBO · 2020 to 2023
$2.6M
Molecular understanding of the GSDMB-regulated innate immune responseR01HL162783 · NHLBI · UNIVERSITY OF VIRGINIA · PI Anny Xiaobo Zhou · 2023 to 2026
$2.4M
Targeting Chronic Senescence to Restore Tissue Homeostasis in Myhre syndromeR21AR080778 · NIAMS · MASSACHUSETTS GENERAL HOSPITAL · PI LINDSAY, MARK E, MOU, HONGMEI · 2022 to 2023
$386k
Role of p73 in COPD PathogenesisIK2BX003841 · VA · VETERANS HEALTH ADMINISTRATION · PI RICHMOND, BRADLEY WINSTON · 2019 to 2023
–
BLRD VA IK2 BX003841NHLBI NIH HHS R01 HL127200NHLBI NIH HHS R01 HL148667NHLBI NIH HHS R01 HL162783NIAMS NIH HHS R21 AR080778
6 · The paper itself

Abstract

backgroundAn 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.

methodsWe 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.

findingsWe 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.

interpretationA 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.

fundingSupported by NIH grants R01HL127200, R01HL148667 and R01HL162783 (to X. Z).

Indexed as

Hedgehog ProteinsPulmonary Disease, Chronic ObstructiveAdultAnimalsChromatinEpithelial CellsHumansLungMiceTransforming Growth Factor betaChromatinHedgehog ProteinsTransforming Growth Factor betaChronic obstructive pulmonary diseaseDistal enhancerEpigeneticsEpithelial-mesenchymal transitionHi-CTGFβ

Identifiers

PMID38417378
PMCPMC10944180
OpenAlexW4392214069

What OpenQuestion holds

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LicenceCC BY-NC-ND
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Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.