2. Academic Validation
  3. Transcriptional synergy in human aortic endothelial cells is vulnerable to combination p300/CBP and BET bromodomain inhibition

Transcriptional synergy in human aortic endothelial cells is vulnerable to combination p300/CBP and BET bromodomain inhibition

  • iScience. 2024 May 16;27(6):110011. doi: 10.1016/j.isci.2024.110011.
Ronan C Bracken 1,  Lindsay M Davison 2,  Dennis P Buehler 2,  Maci E Fulton 2,  Emily E Carson 2,  Quanhu Sheng 3 4,  Lindsey K Stolze 3 4,  Christelle Guillermier 5 6 7,  Matthew L Steinhauser 8,  Jonathan D Brown 2
Affiliations

Affiliations

  • 1 Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 2 Division of Cardiovascular Medicine, Vanderbilt University Medical Center, Nashville, TN 37232, USA.
  • 3 Department of Biostatistics, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
  • 4 Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN 3723, USA.
  • 5 Harvard Medical School, Boston, MA 02115, USA.
  • 6 Center for NanoImaging, Cambridge MA 02115, USA.
  • 7 Department of Medicine, Division of Genetics, Brigham and Women's Hospital, Boston, MA 02115, USA.
  • 8 Aging Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA 15261, USA.
PMID: 38868181 DOI: 10.1016/j.isci.2024.110011
Abstract

Combinatorial signaling by proinflammatory cytokines synergizes to exacerbate toxicity to cells and tissue injury during acute infections. To explore synergism at the gene-regulatory level, we investigated the dynamics of transcription and chromatin signaling in response to dual cytokines by integrating nascent RNA imaging mass spectrometry, RNA Sequencing, amplification-independent mRNA quantification, assay for transposase-accessible chromatin using Sequencing (ATAC-seq), and transcription factor profiling. Costimulation with interferon-gamma (IFNγ) and tumor necrosis factor alpha (TNFα) synergistically induced a small subset of genes, including the chemokines CXCL9, -10, and -11. Gene induction coincided with increased chromatin accessibility at non-coding regions enriched for p65 and STAT1 binding sites. To discover coactivator dependencies, we conducted a targeted chemogenomic screen of transcriptional inhibitors followed by modeling of inhibitor dose-response curves. These results identified high efficacy of either p300/CREB-binding protein (CBP) or bromodomain and extra-terminal (BET) bromodomain inhibitors to disrupt induction of synergy genes. Combination p300/CBP and BET bromodomain inhibition at half-maximal inhibitory concentrations (subIC50) synergistically abrogated IFNγ/TNFα-induced chemokine gene and protein levels.

Keywords

Cell biology; Chemogenomics; Components of the immune system; Genomics; Systems biology; Transcriptomics.

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