Transcriptomic and Epigenetic Profiling of Fibroblasts in Idiopathic Pulmonary Fibrosis

Hanmandlu, Ankit; Zhu, Lisha; Mertens, Tinne; Collum, Scott D.; Bi, Weizhen; Xiong, Feng; Wang, Ruo–Yu; Amirthalingam, Rajarajan T; Ren, Dewei; Han, Leng; Jyothula, Soma; Li, Wenbo; Zheng, Wenyi; Karmouty‐Quintana, Harry

doi:10.1165/rcmb.2020-0437oc

Cited by 17 publications

(10 citation statements)

References 56 publications

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“…Therefore, we sought to determine if the stiffness-activated pREs may contribute to tissue responses or transformations in IPF. We compared the accessibility of the pREs in diseased IPF versus healthy lung tissue ( 76 ). We found that accessible chromatin regions that overlapped hit pREs identified in the bulk phenotype screens and pREs connected to a gene in the single cell CRISPRi screen were significantly more accessible in IPF lung tissue versus lung tissue from unaffected controls ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness

Cosgrove,

Bounds,

Taylor

et al. 2024

Preprint

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Epigenetic control of cellular transcription and phenotype is influenced by changes in the cellular microenvironment, yet how mechanical cues from these microenvironments precisely influence epigenetic state to regulate transcription remains largely unmapped. Here, we combine genome-wide epigenome profiling, epigenome editing, and phenotypic and single-cell RNA-seq CRISPR screening to identify a new class of genomic enhancers that responds to the mechanical microenvironment. These ‘mechanoenhancers’ could be active on either soft or stiff extracellular matrix contexts, and regulated transcription to influence critical cell functions including apoptosis, mechanotransduction, proliferation, and migration. Epigenetic editing of mechanoenhancers on rigid materials tuned gene expression to levels observed on softer materials, thereby reprogramming the cellular response to the mechanical microenvironment. These editing approaches may enable the precise alteration of mechanically-driven disease states.

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Section: Resultsmentioning

confidence: 99%

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness

Cosgrove,

Bounds,

Taylor

et al. 2024

Preprint

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“…A pseudo-bulk differential expression analysis (DEA) between IPF and HC samples identified a total of 1469 differentially expressed genes (DEGs) ( Fig. 1c (iii) ), including genes associated with fibroblasts, previously reported to be upregulated in IPF ( FNDC1 , COL10A1, THY1 ) 26 , as well as matrix metalloproteinases (MMPs) 27 and genes involved in IPF-associated signalling pathways ( SFRP2 , WNT10A , TGFBI ) 28,29 . Many of the upregulated genes in IPF samples mapped to areas of remodelled tissue.…”

Section: Resultsmentioning

confidence: 99%

Translational mapping of spatially resolved transcriptomes in human and mouse pulmonary fibrosis

Franzén,

Lindvall,

Hühn

et al. 2023

Preprint

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Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. To address these limitations, we generated spatially resolved transcriptome maps of human IPF and bleomycin-induced mouse lung fibrosis. We uncovered distinct fibrotic niches in the IPF lung, characterized by aberrant alveolar epithelial cells in a microenvironment dominated by TGFβ signaling alongside factors such as p53 and ApoE. We also identified a clear divergence between the arrested alveolar regeneration in the IPF fibrotic niches, and the active tissue repair in the acutely fibrotic mouse lung. Our study offers in-depth insights into the IPF transcriptional landscape and proposes alveolar regeneration as a promising therapeutic strategy for IPF.

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“…In the context of IPF, it has been shown that there is hyperacetylation. Consequently, as demonstrated by Hanmandlu et al, alterations in chromatin accessibility led to gene expression of fibrotic-related pathways [ 47 ]. In agreement with these findings, we discovered that IPF fibroblasts display a higher amount of H3K9 acetylation, and inhibiting its activity as a deacetylase in normal lung fibroblasts causes a defect in the H3K9ac/H3K9me2 ratio due to a hyperacetylation.…”

Section: Discussionmentioning

confidence: 99%

Absence of HDAC3 by Matrix Stiffness Promotes Chromatin Remodeling and Fibroblast Activation in Idiopathic Pulmonary Fibrosis

Toscano-Marquez

Romero

Espina-Ordoñez

et al. 2023

Cells

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Idiopathic pulmonary fibrosis (IPF) is a chronic and fatal disease characterized by progressive and irreversible lung scarring associated with persistent activation of fibroblasts. Epigenetics could integrate diverse microenvironmental signals, such as stiffness, to direct persistent fibroblast activation. Histone modifications by deacetylases (HDAC) may play an essential role in the gene expression changes involved in the pathological remodeling of the lung. Particularly, HDAC3 is crucial for maintaining chromatin and regulating gene expression, but little is known about its role in IPF. In the study, control and IPF-derived fibroblasts were used to determine the influence of HDAC3 on chromatin remodeling and gene expression associated with IPF signature. Additionally, the cells were grown on hydrogels to mimic the stiffness of a fibrotic lung. Our results showed a decreased HDAC3 in the nucleus of IPF fibroblasts, which correlates with changes in nucleus size and heterochromatin loss. The inhibition of HDAC3 with a pharmacological inhibitor causes hyperacetylation of H3K9 and provokes an increased expression of Col1A1, ACTA2, and p21. Comparable results were found in hydrogels, where matrix stiffness promotes the loss of nuclear HDAC3 and increases the profibrotic signature. Finally, latrunculin b was used to confirm that changes by stiffness depend on the mechanotransduction signals. Together, these results suggest that HDAC3 could be a link between epigenetic mechanisms and the fibrotic microenvironment.

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Transcriptomic and Epigenetic Profiling of Fibroblasts in Idiopathic Pulmonary Fibrosis

Cited by 17 publications

References 56 publications

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness

Mechanosensitive genomic enhancers potentiate the cellular response to matrix stiffness

Translational mapping of spatially resolved transcriptomes in human and mouse pulmonary fibrosis

Absence of HDAC3 by Matrix Stiffness Promotes Chromatin Remodeling and Fibroblast Activation in Idiopathic Pulmonary Fibrosis

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