Inhibition of bromodomain extraterminal histone readers alleviates skin fibrosis in experimental models of scleroderma
Sirapa Vichaikul, … , Amr H. Sawalha, Pei-Suen Tsou
Sirapa Vichaikul, … , Amr H. Sawalha, Pei-Suen Tsou
Published March 29, 2022
Citation Information: JCI Insight. 2022;7(9):e150871. https://doi.org/10.1172/jci.insight.150871.
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Research Article

Inhibition of bromodomain extraterminal histone readers alleviates skin fibrosis in experimental models of scleroderma

Abstract

Binding of the bromodomain and extraterminal domain proteins (BETs) to acetylated histone residues is critical for gene transcription. We sought to determine the antifibrotic efficacy and potential mechanisms of BET inhibition in systemic sclerosis (SSc). Blockade of BETs was done using a pan-BET inhibitor, JQ1; BRD2 inhibitor, BIC1; or BRD4 inhibitors AZD5153 or ARV825. BET inhibition, specifically BRD4 blockade, showed antifibrotic effects in an animal model of SSc and in patient-derived diffuse cutaneous SSc (dcSSc) fibroblasts. Transcriptome analysis of JQ1-treated dcSSc fibroblasts revealed differentially expressed genes related to extracellular matrix, cell cycle, and calcium (Ca2+) signaling. The antifibrotic effect of BRD4 inhibition was mediated at least in part by downregulation of Ca2+/calmodulin–dependent protein kinase II α and reduction of intracellular Ca2+ concentrations. On the basis of these results, we propose targeting Ca2+ pathways or BRD4 as potentially novel therapeutic approaches for progressive tissue fibrosis.

Authors

Sirapa Vichaikul, Mikel Gurrea-Rubio, M. Asif Amin, Phillip L. Campbell, Qi Wu, Megan N. Mattichak, William D. Brodie, Pamela J. Palisoc, Mustafa Ali, Sei Muraoka, Jeffrey H. Ruth, Ellen N. Model, Dallas M. Rohraff, Jonatan L. Hervoso, Yang Mao-Draayer, David A. Fox, Dinesh Khanna, Amr H. Sawalha, Pei-Suen Tsou

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Figure 4

BET inhibition affects Ca2+-related pathways and intracellular Ca2+ in dcSSc fibroblasts.

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BET inhibition affects Ca2+-related pathways and intracellular Ca2+ in d...
(A) The Ca2+ signaling pathway (KEGG: 04020) diagram is overlaid with the expression changes of each gene. The legend describes the values on the gradient. Downregulation is shown in blue, while upregulation is in red. For legibility, 1 gene may be presented at multiple boxes in the diagram. In addition, 1 box may represent multiple genes in the same gene family. For each gene family, the color corresponding to the gene with the highest absolute fold change is displayed. For example, the ORAI box depicts significant upregulation of ORAI1 and ORAI3 and downregulation of ORAI2. The ORAI box is shown in red because ORAI1 shows the most significant fold change among the 3. (B) All the differentially expressed genes in Ca2+ signaling pathway (KEGG: 04020) are ranked based on their absolute value of log fold change. Upregulated genes are shown in red, and downregulated genes are shown in blue. n = 6 patient pairs. (C) BET inhibition by JQ1 significantly reduced intracellular Ca2+ levels in dcSSc fibroblasts. n = 5 patients. Results are expressed as mean ± SD and P < 0.05 was considered significant. Significance was determined by paired 2-tailed t test (C). NT, no treatment.