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

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

PROVIDER: PRJNA562633 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR10034209_1.fastq.gz	Fastqsanger.gz
	SRR10034209_2.fastq.gz	Fastqsanger.gz
	SRR10034210_1.fastq.gz	Fastqsanger.gz
	SRR10034210_2.fastq.gz	Fastqsanger.gz
	SRR10034211_1.fastq.gz	Fastqsanger.gz

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

Project description: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 TGFβ-mediated 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 RNAi-mediated knockdown attenuates fibroblast activation without altering global histone acetylation. Together these results provide novel mechanistic insight into the essential role HDACs play in TGFβ-mediated fibroblast activation via targeted gene repression.

2019-08-29 | GSE136534 | GEO

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

Project description: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 TGFβ-mediated 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 TGFβ-mediated fibroblast activation via targeted gene repression.

| S-EPMC6826010 | biostudies-literature

Rpd3L HDAC links H3K4me3 to transcriptional repression memory

Project description:Transcriptional memory is critical for the faster reactivation of necessary genes upon environmental changes and requires that the genes were previously in an active state. However, whether transcriptional repression also displays “memory” of the prior transcriptionally inactive state remains unknown. In this study, we show that transcriptional repression of approximately 540 genes in yeast occurs much more rapidly if the genes have been previously repressed during carbon source shifts. This novel transcriptional response has been termed transcriptional repression memory(TREM). Interestingly, Rpd3L histone deacetylase (HDAC), targeted to active promoters induces TREM. Mutants for Rpd3L exhibit increased acetylation at active promoters and delay TREM and RNA PolII dissociation significantly. Surprisingly, the interaction between H3K4me3 and Rpd3L via the Pho23 PHD finger is sufficient to induce histone deacetylation and TREM by Rpd3L. Therefore, we propose that an active mark, H3K4me3 enriched at promoters, instructs Rpd3L HDAC to induce histone deacetylation and TREM.

2018-10-23 | E-MTAB-6551 | biostudies-arrayexpress

Non-canonical WNT5A controls the activation of latent TGFβ to drive fibroblast activation and tissue fibrosis

Project description:Transforming growth factor β (TGFβ) signaling is a core pathway of fibrosis, but the molecular regulation of the activation of latent TGFβ remains incompletely understood. Here, we demonstrate a crucial role of WNT5A/JNK/ROCK signaling that rapidly coordinates the activation of latent TGFβ in fibrotic diseases. WNT5A was identified as predominant non-canonical WNT ligand in fibrotic diseases such as systemic sclerosis, sclerodermatous chronic graft-versus-host disease and idiopathic pulmonary fibrosis, stimulating fibroblast-to-myofibroblast transition and tissue fibrosis by activation of latent TGFβ. The activation of latent TGFβ requires rapid JNK- and ROCK-dependent cytoskeletal rearrangements and integrin αV (ITGAV). Conditional Knockout of WNT5A or its downstream targets prevented activation of latent TGFβ, rebalanced TGFβ signaling and ameliorated experimental fibrosis. We thus uncovered a novel mechanism for the aberrant activation of latent TGFβ in fibrotic diseases and provided evidence for targeting WNT5A/JNK/ROCK signaling in fibrotic diseases as a new therapeutic approach.

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2024-04-23 | GSE264288 | GEO

Rpd3L HDAC links H3K4me3 to transcriptional repression memory

Project description:Rpd3L HDAC links H3K4me3 to transcriptional repression memory

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Fibroblast-specific genetic dissection of TGFβ-Smad2/3 signaling in cardiac fibrosis

Project description:Overall goal: To elucidate fibroblast-specific role of TGFβ-Smad2/3 signaling in fibroblast activation and their differentiation to myofibroblasts. Purpose of analysis: To generate transcriptional profile of Smad2/3 and TGFβreceptors1/2-deficient fibroblasts in the context of pathological cardiac fibrosis.

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Next Generation Sequencing Facilitates Quantitative Analysis of Transcriptomes of Murine Fibroblast Fibroproliferative Response with TGFβ

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Transforming growth factor β (TGFβ) and BMP7 regulate glioblastoma stem cells differentiation status

Project description:Glioblastoma stem cells (GSCs) fate is controlled by environmental cues, among which cytokines play a crucial role. The transforming growth factor β (TGFβ) family signaling pathways controls GSCs. On one hand, TGFβ promotes cell proliferation in GBM, it induces the expression of platelet-derived growth factor-B (PDGFB). Moreover, TGFβ, via its signaling mediators Smad2/3, induces the expression of the cytokine leukemia inhibitory factor (LIF) and Sox4, which in turn enhances the expression of the stem cell transcription factor Sox2; this increases the self-renewal capacity of the GSCs and their stemness characteristics, and enhances the GSC tumor-initiating potential. On the other hand, Bone morphogenic proteins (BMPs) are known to promote GSC differentiation towards the astrocytic phenotype. To further understand which genes are regulated by TGFβ and BMP7 in GSCs we performed a microarray in the Affymetrix HTA2 platform in three different glioblastoma cell line, U2987, and two patient-derived glioblastoma stem cells, U3031MG and U3034MG, in the presence or absence of 5 ng/ml of TGFβ or 30 ng/ml BMP7 for 24 h, three biological replicates per condition.

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