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

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

Research output: Contribution to journalArticle

Abstract

Pulmonary fibrosis is a devastating disease characterized by accumulation of activated fibroblasts and scarring in the lung. While fibroblast activation in physiological wound repair reverses spontaneously, fibroblast activation in fibrosis is aberrantly sustained. Here we identified histone 3 lysine 9 methylation (H3K9me) as a critical epigenetic modification that sustains fibroblast activation by repressing the transcription of genes essential to returning lung fibroblasts to an inactive state. We show that the histone methyltransferase G9a (EHMT2) and chromobox homolog 5 (CBX5, also known as HP1α), which deposit H3K9me marks and assemble an associated repressor complex, respectively, are essential to initiation and maintenance of fibroblast activation specifically through epigenetic repression of peroxisome proliferator- activated receptor ã coactivator 1 α gene (PPARGC1A, encoding PGC1α). Both TGF-β and increased matrix stiffness potently inhibit PGC1α expression in lung fibroblasts through engagement of the CBX5/G9a pathway. Inhibition of the CBX5/G9a pathway in fibroblasts elevates PGC1α, attenuates TGF-β- and matrix stiffness-promoted H3K9 methylation, and reduces collagen accumulation in the lungs following bleomycin injury. Our results demonstrate that epigenetic silencing mediated by H3K9 methylation is essential for both biochemical and biomechanical fibroblast activation and that targeting this epigenetic pathway may provide therapeutic benefit by returning lung fibroblasts to quiescence.

Original languageEnglish (US)
Article numbere127111
JournalJCI Insight
Volume4
Issue number12
DOIs
StatePublished - Jan 1 2019

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Fibrosis
Fibroblasts
Lung
Genes
Epigenomics
Methylation
Epigenetic Repression
Peroxisome Proliferator-Activated Receptors
Pulmonary Fibrosis
Essential Genes
Bleomycin
Wounds and Injuries
Histones
Transcriptional Activation
Lysine
Cicatrix
Collagen
Maintenance

ASJC Scopus subject areas

  • Medicine(all)

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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; Prakash, Y.s.; Lomberk, Gwen; Urrutia, Raul A.; Tschumperlin, Daniel J.

In: JCI Insight, Vol. 4, No. 12, e127111, 01.01.2019.

Research output: Contribution to journalArticle

Ligresti, G, Caporarello, N, Meridew, JA, Jones, DL, Tan, Q, Choi, KM, Haak, AJ, Aravamudhan, A, Roden, A, Prakash, YS, Lomberk, G, Urrutia, RA & Tschumperlin, DJ 2019, 'CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis', JCI Insight, vol. 4, no. 12, e127111. https://doi.org/10.1172/jci.insight.127111
Ligresti G, Caporarello N, Meridew JA, Jones DL, Tan Q, Choi KM et al. CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis. JCI Insight. 2019 Jan 1;4(12). e127111. https://doi.org/10.1172/jci.insight.127111
Ligresti, Giovanni ; Caporarello, Nunzia ; Meridew, Jeffrey A. ; Jones, Dakota L. ; Tan, Qi ; Choi, Kyoung Moo ; Haak, Andrew J. ; Aravamudhan, Aja ; Roden, Anja ; Prakash, Y.s. ; Lomberk, Gwen ; Urrutia, Raul A. ; Tschumperlin, Daniel J. / CBX5/G9a/H3K9me-mediated gene repression is essential to fibroblast activation during lung fibrosis. In: JCI Insight. 2019 ; Vol. 4, No. 12.
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