BRD4 inhibition rewires cardiac macrophages toward a protective phenotype marked by low MHC class II expression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1209896 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31977626.fastq.gz | Fastqsanger.gz | |||
| SRR31977627.fastq.gz | Fastqsanger.gz | |||
| SRR31977628.fastq.gz | Fastqsanger.gz | |||
| SRR31977629.fastq.gz | Fastqsanger.gz | |||
| SRR31977630.fastq.gz | Fastqsanger.gz |
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Project description:Bromodomain and extra-terminal domain (BET) proteins, including BRD4, bind acetylated chromatin and co-activate gene transcription. A BET inhibitor, JQ1, prevents and reverses pathological cardiac remodeling in preclinical models of heart failure. However, the underlying cellular mechanisms by which JQ1 improves cardiac structure and function remain poorly defined. Here, we demonstrate that BRD4 knockdown reduced expression of genes encoding CC chemokines in cardiac fibroblasts, suggesting a role for this epigenetic reader in controlling fibroblast-immune cell crosstalk. Consistent with this, JQ1 dramatically suppressed recruitment of monocytes to the heart in response to stress. Normal mouse hearts were found to have approximately equivalent numbers of major histocompatibility complex (MHC-II)high and MHC-IIlow resident macrophages, while MHC-IIlow macrophages predominated following JQ1 treatment. Single-cell RNA-seq data confirmed that JQ1 treatment or BRD4 knockout in CX3CR1+ cells reduced MHC-II gene expression in cardiac macrophages, and studies with cultured macrophages further illustrated a cell autonomous role for BET proteins in controlling the MHC-II axis. Bulk RNA-seq analysis demonstrated that JQ1 blocked proinflammatory macrophage gene expression through a mechanism that likely involves repression of NF-kB signaling. JQ1 treatment reduced cardiac infarct size in mice subjected to ischemia/reperfusion. Our findings illustrate that BET inhibition affords a powerful pharmacological approach to manipulate monocyte-derived and resident macrophages in the heart. Such an approach has the potential to enhance the reparative phenotype of macrophages to promote wound healing and limit infarct expansion following myocardial ischemia.
2025-01-15 | GSE286548 | GEO
Project description:To investigate the mechanism that drives dramatic mistargeting of active chromatin in NUT midline carcinoma, we have identified protein interactions unique to the BRD4-NUT fusion oncoprotein compared to wild type BRD4. Using crosslinking, affinity purification, and mass spectrometry, we identified the EP300 acetyltransferase as uniquely associated with BRD4 through the NUT fusion in both NMC and non-NMC cell types. We also discovered ZNF532 among a small number of candidates associated with BRD4-NUT in NMC patient cells but not present in 293T cells.
2017-04-05 | PXD005786 | Pride
Project description:Analysis of BRD4 ChIP-seq data of two types of human transformed fibroblasts (WT and HGPS) to identify specific and common binding sites for BRD4. Transformed cell lines were obtained by retroviral introduction of TERT (T), V12-HRAS (R) and SV40 large and small T antigens (S) of primary skin fibroblasts for HGPS patients (TRS-HGPS) and age-matched control wild-type individuals (TRS-WT) Abstract: Advanced age and DNA damage accumulation are strong risk factors for cancer. The premature-aging disorder Hutchinson Gilford Progeria Syndrome (HGPS) provides a unique opportunity to study the interplay between DNA damage and aging-associated tumor mechanisms, since HGPS patients do not develop tumors despite elevated levels of DNA damage. Here, we have used HGPS patient cells to identify a protective mechanism to oncogenesis. We find that HGPS cells are resistant to neo-plastic transformation. This resistance is mediated by the bromodomain protein BRD4, which exhibits altered genome-wide binding patterns in transformation-resistant cells leading to inhibition of oncogenic de-differentiation. BRD4 also in-hibits, albeit to a lower extent, the tumorigenic potential of transformed cells from healthy individuals and BRD4-mediated tumor protection is clinically relevant, since a BRD4 gene signature predicts positive clinical outcome in breast and lung cancer. Our results demonstrate a protective function for BRD4 and suggest tissue-specific functions for BRD4 in tumorigenesis. Examination of BRD4 binding events in TRS-WT and TRS-HGPS fibroblasts (2 independent cell lines in each group)
2014-10-02 | E-GEOD-61325 | biostudies-arrayexpress
Project description:BRD4 Inhibition of spindle cell malignant peripheral nerve sheath tumor (sMPNST) tumor cells Cells were treated with Brd4 shRNA (3 days) or 500 nM JQ1 (2 days) before RNA isolation
2013-09-13 | E-GEOD-50865 | biostudies-arrayexpress
Project description:The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.
2019-04-04 | PXD012715 | Pride
Project description:Midkine expression by stem-like tumor cells drives persistence to mTOR inhibition and rewires the microenvironment toward an immune-suppressive state
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Project description:During heat stress cyto-protective genes including heat shock proteins are transcriptionally up-regulated and post-transcriptional splicing is inhibited. In contrast, co-transcriptional mRNA-splicing is maintained. These factors closely resemble the proteotoxic stress response during tumor development. The bromodomain protein BRD4 has been identified as an integral member of the oxidative stress as well as of the inflammatory response. Furthermore, there is evidence for BRD4's role in splicing regulation; Using RNA-Seq analyses we indeed found a significant increase in splicing inhibition, in particular intron retentions, during heat treatment in BRD4-deficient cells, but not under normal conditions. Subsequent experiments revealed that heat stress leads to the recruitment of BRD4 to nuclear stress bodies, to the interaction with the heat shock factor 1 (HSF1) and to the transcriptional up-regulation of non-coding Sat III RNA transcripts. These findings implicate BRD4 as a central regulator of splicing during heat stress. Since BRD4 is a potent target for anti-cancer therapies, our data linking BRD4 to the splicing machinery and the heat stress response - give additional insight into the mode of action of BRD4 inhibitors. WI38 cells have been treated by heatshock and anti BRD4 siRNA and combination.
2016-09-07 | E-GEOD-73471 | biostudies-arrayexpress
Project description:BRD4 is a key regulatory factor in multiple cancers and cellular stress responses with pleotropic functions. BRD4 regulates chromatin remodeling and transcription through its histone acetyltransferase (HAT) and kinase activities, respectively. The mechanism responsible for switching BRD4 from a chromatin to transcriptional regulator is currently unknown. Here, we report that in response to a broad range of stimuli, this switch is mediated by the JNK kinase which directly interacts with BRD4. JNK specifically phosphorylates human BRD4 at Ser1117, Thr1186 and Thr1212, triggering transient BRD4 release from chromatin. JNK phosphorylation of BRD4 halts its HAT-mediated chromatin regulation and activates its transcription-enhancing kinase function. BRD4 release from chromatin is necessary to toggle between its enzymatic activities: chromatin-bound BRD4 is kinase inactive and RNA Pol II-bound BRD4 does not acetylate chromatin. BRD4 release from chromatin augments its interaction with and phosphorylation of key transcriptional regulators RNA Pol II, PTEFb and c-MYC. The PP4 phosphatase dephosphorylates JNK phosphorylated BRD4 in the nucleoplasm, which promotes its interaction with RNA Pol II at transcriptionally active sites. Accordingly, JNK-mediated release of BRD4 from chromatin leads to significantly elevated transcription of BRD4-regulated immune and inflammatory response genes through enhanced BRD4-Pol II interaction at the promoters of these genes. JNK phosphorylation of BRD4 occurs during T-cell activation and is required for epithelial to mesenchymal transition (EMT) in prostate cancer cells. These findings thus characterize a novel mechanism that triggers the transition of BRD4 from a chromatin regulator to transcriptional activator during stress/immune/inflammatory responses and EMT.
2024-01-16 | MSV000093873 | MassIVE
Project description:Targeted protein degradation is a modality based on small molecules that induce proximity between a protein of interest (POI) and an E3 ubiquitin ligase, thus prompting POI ubiquitination and degradation. To expand the reach of TPD, current research is geared to unlock novel E3s. To that end, the transcriptional co-activator protein BRD4 has emerged as a frequently used POI. Derivatization of known BRD4 ligands with structurally diverse substituents has yielded a suite of potent BRD4 degraders, thus generating the notion that BRD4 is particularly amenable to TPD. Here, we mechanistically characterize two BRD4 degraders via orthogonal CRISPR screens. Despite their structural dissimilarity, both degraders functionally converge on a unifying mechanism of action that involves the CRL4DCAF16 ligase complex. Using recombinant reconstitution, as well as biophysical and structural elucidation, we demonstrate that BRD4 has an intrinsic activity for DCAF16, which is further enhanced by both compounds. We uncover a novel mode of molecular recognition based on multivalent "gluing" of BRD4 onto DCAF16 that requires both bromodomains of BRD4. Our data thus imply a substantial conceptual overlap between PROTACs and molecular glue degraders, and highlight multivalency as a novel concept in the design of proximity-inducing drugs.
2024-01-08 | PXD040570 | Pride