CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis

Ligresti, Giovanni; Caporarello, Nunzia; Meridew, Jeffrey A.; Jones, Dakota L.; Tan, Qi; Choi, Kyoung Moo; Haak, Andrew J.; Aravamudhan, Aja; Roden, Anja C.; Prakash, Y. S.; Lomberk, Gwen; Urrutia, Raúl; Tschumperlin, Daniel J.

doi:10.1172/jci.insight.127111

Cited by 55 publications

(38 citation statements)

References 76 publications

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“…The broad program of known and putative anti-fibrotic genes repressed by TGFβ and rescued by pracinostat suggests that there may be widespread redundancy in the pathways that maintain fibroblast in an inactive state. To test whether the inhibitory effects of pracinostat on fibroblast activation were specifically dependent on PGC1α, a strong regulator of fibroblast quiescence (Caporarello et al, 2019;Ligresti et al, 2019), we used siRNA to knockdown PGC1α and then measured anti-fibrotic efficacy of pracinostat on ACTA2 expression. Interestingly, pracinostat maintained its inhibitory effect on ACTA2 transcript levels ( Fig.…”

Section: Tgfβ Signaling Represses Pgc1α Through Histone Deacetylationmentioning

confidence: 99%

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Jones

Haak

Caporarello

et al. 2019

Journal of Cell Science

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Tissue fibrosis is a chronic disease driven by persistent fibroblast activation that has recently been linked to epigenetic modifications. Here, we screened a small library of epigenetic small-molecule modulators to identify compounds capable of inhibiting or reversing TGFβ-mediated fibroblast activation. We identified pracinostat, an HDAC inhibitor, as a potent attenuator of lung fibroblast activation and confirmed its efficacy in patient-derived fibroblasts isolated from fibrotic lung tissue. Mechanistically, we found that HDAC-dependent transcriptional repression was an early and essential event in TGFβmediated fibroblast activation. Treatment of lung fibroblasts with pracinostat broadly attenuated TGFβ-mediated epigenetic repression and promoted fibroblast quiescence. We confirmed a specific role for HDAC-dependent histone deacetylation in the promoter region of the anti-fibrotic gene PPARGC1A (PGC1α) in response to TGFβ stimulation. Finally, we identified HDAC7 as a key factor whose siRNA-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together, these results provide novel mechanistic insight into the essential role HDACs play in TGFβmediated fibroblast activation via targeted gene repression.

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Section: Tgfβ Signaling Represses Pgc1α Through Histone Deacetylationmentioning

confidence: 99%

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Jones

Haak

Caporarello

et al. 2019

Journal of Cell Science

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“…Transcriptional analyses revealed that TGFβ1 requires HDAC function to promote the repression of a broad complement of anti-fibrogenic genes [ 77 ]. We observed that specific anti-fibrogenic genes such as the orphan nuclear receptor 4 A1 ( NR4A1 ) [ 78 ] or the metabolic regulator peroxisome proliferator activated receptor gamma co-activator-1α ( PGC-1α ), recently identified as a key guardian of fibroblasts quiescence [ 79 ], were potently reactivated upon CM414 treatment ( Figure 6 d). Interestingly CM414 did not seem to modulate the canonical TGFβ1 signaling pathway in LX2, as indicated by the unaltered phosphorylation of SMAD3 ( Figure 6 e).…”

Section: Resultsmentioning

confidence: 99%

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

Clavería-Cabello

Colyn

Uriarte

et al. 2020

Cancers

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Liver fibrosis, a common hallmark of chronic liver disease (CLD), is characterized by the accumulation of extracellular matrix secreted by activated hepatic fibroblasts and stellate cells (HSC). Fibrogenesis involves multiple cellular and molecular processes and is intimately linked to chronic hepatic inflammation. Importantly, it has been shown to promote the loss of liver function and liver carcinogenesis. No effective therapies for liver fibrosis are currently available. We examined the anti-fibrogenic potential of a new drug (CM414) that simultaneously inhibits histone deacetylases (HDACs), more precisely HDAC1, 2, and 3 (Class I) and HDAC6 (Class II) and stimulates the cyclic guanosine monophosphate (cGMP)-protein kinase G (PKG) pathway activity through phosphodiesterase 5 (PDE5) inhibition, two mechanisms independently involved in liver fibrosis. To this end, we treated Mdr2-KO mice, a clinically relevant model of liver inflammation and fibrosis, with our dual HDAC/PDE5 inhibitor CM414. We observed a decrease in the expression of fibrogenic markers and collagen deposition, together with a marked reduction in inflammation. No signs of hepatic or systemic toxicity were recorded. Mechanistic studies in cultured human HSC and cholangiocytes (LX2 and H69 cell lines, respectively) demonstrated that CM414 inhibited pro-fibrogenic and inflammatory responses, including those triggered by transforming growth factor β (TGFβ). Our study supports the notion that simultaneous targeting of pro-inflammatory and fibrogenic mechanisms controlled by HDACs and PDE5 with a single molecule, such as CM414, can be a new disease-modifying strategy.

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“…While H3K9 dimethylation is overrepresented in fibrotic regions of both BILF mice and IPF lungs [ 87 ], G9a specifically methylates H3K9, allowing binding of chromobox homolog 5 (CBX5) and a consequent assembly of a transcriptional repressor complex [ 88 ]. Consequent chromatin modifications inhibit transcription of PPARγ coactivator 1α ( PPARGC1A —peroxisome proliferator-activated receptor gamma coactivator 1-alpha) [ 87 ] that encodes peroxysmal protein PGC1α. PGC1α acts as a regulator of mitochondrial biogenesis and fatty acid oxidation [ 89 ], probably playing an important fibrosis-inhibiting role in BILF [ 90 ] and IPF.…”

Section: Epigenetics and Interstitial Lung Diseasesmentioning

confidence: 99%

“…This study was first to identify the roles of the G9a/CBX5 pathway that both directly and via H3K9 methylation depresses PGC1α expression in its gene promoter region and leads to an uncontrolled IPF fibroblast activation. Administration of BIX01294, a G9a inhibitor, prevents PGC1α depression and mitigates profibrotic effects of TGFβ on IPF fibroblasts; knockdown of either CBX5 or G9a reduces the profibrotic ACTA2 gene expression in IPF lung fibroblasts [ 87 ].…”

Section: Epigenetics and Interstitial Lung Diseasesmentioning

confidence: 99%

More than a Genetic Code: Epigenetics of Lung Fibrosis

et al. 2020

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At the end of the last century, genetic studies reported that genetic information is not transmitted solely by DNA, but is also transmitted by other mechanisms, named as epigenetics. The well-described epigenetic mechanisms include DNA methylation, biochemical modifications of histones, and microRNAs. The role of altered epigenetics in the biology of various fibrotic diseases is well-established, and recent advances demonstrate its importance in the pathogenesis of pulmonary fibrosis—predominantly referring to idiopathic pulmonary fibrosis, the most lethal of the interstitial lung diseases. The deficiency in effective medications suggests an urgent need to better understand the underlying pathobiology. This review summarizes the current knowledge concerning epigenetic changes in pulmonary fibrosis and associations of these changes with several cellular pathways of known significance in its pathogenesis. It also designates the most promising substances for further research that may bring us closer to new therapeutic options.

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CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis

Cited by 55 publications

References 76 publications

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

TGFβ-induced fibroblast activation requires persistent and targeted HDAC-mediated gene repression

Dual Pharmacological Targeting of HDACs and PDE5 Inhibits Liver Disease Progression in a Mouse Model of Biliary Inflammation and Fibrosis

More than a Genetic Code: Epigenetics of Lung Fibrosis

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