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Depletion of BRD9-mediated R-loop accumulation inhibits leukemia cell growth via transcription-replication conflict

ABSTRACT: Bromodomain-containing protein 9 (BRD9) has emerged as a promising therapeutic target for blood cancers, including acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), and multiple myeloma (MM). PROTAC-based BRD9 degraders effectively hamper the growth and survival of leukemia cells; however, the underlying mechanism of these BRD9 degraders remains unclear. In this study, we demonstrated that depletion of BRD9 triggers DNA damage via R-loop accumulation, leading to conflicts between transcription and replication processes. Replication stress inhibits the proliferation of leukemia cells and promotes their differentiation. Mechanistically, BRD9 plays a pivotal role in recruiting BRD2 and BRD4 to chromatin through direct interactions, which is critical for preventing R-loop formation during transcription. Depletion of BRD9 in leukemia cells reduces the occupancy of BRD2 and BRD4 at R-loop-prone sites, thus promoting R-loop accumulation, transcription-replication collision, excessive DNA damage, and ultimately, the demise of cancer cells. These findings provide valuable insights into the mechanisms by which BRD9 degraders function as effective therapies for leukemia mediated by the pathological accumulation of R-loops.

ORGANISM(S): Homo sapiens

PROVIDER: GSE300622 | GEO | 2025/07/16

REPOSITORIES: GEO

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Depletion of BRD9-mediated R-loop accumulation inhibits leukemia cell growth via transcription-replication conflict

Project description:Depletion of BRD9-mediated R-loop accumulation inhibits leukemia cell growth via transcription-replication conflict

| PRJNA1281562 | ENA

Affinity Purification experiments for 24 human Bromodomain proteins involved in DNA repair and genome integrity (part 2 of 2)

Project description:Bromodomain proteins (BRD) are key chromatin regulators of genome function and stability, as well as therapeutic targets in cancer. In our associated publication (doi:10.1101/gad.331231.119) we systematically delineate the contribution of human BRD proteins for genome stability and DNA double-strand break (DSB) repair using cell-based assays and proteomic interaction network analysis. These AP-MS experiments were performed in order to construct a protein interaction network for the 24 BRDs we identified as promoters of DNA repair and/or genome integrity: BAZ1B, BRD1, BRD2, BRD3, BRD4, BRD8, BRD9, BRPF3, BRWD3, CECR2, EP300, GCN5/KAT2A, PCAF/KAT2B, PHIP, SMARCA2, SP100, SP110, SP140, TAF1, TRIM24, TRIM28, TRIM33, TRIM66, ZMYND8. In combination with cell based assays, we identified a BRD-reader function of PCAF that bound TIP60-mediated histone acetylations at DSBs to recruit a DUB complex to deubiquitylate histone H2BK120, to allow direct acetylation by PCAF and repair of DSBs by homologous recombination. We also discovered the bromo-and-extra-terminal (BET) BRD proteins, BRD2 and BRD4, as negative regulators of transcription-associated RNA-DNA hybrid (R-Loop) as inhibition of BRD2 or BRD4 increased R-loop formation, which generated DSBs. These breaks were reliant on Topoisomerase II and BRD2 directly bound and activated Topoisomerase I, a known restrainer of R-loops. Thus, comprehensive interactome and functional profiling of BRD proteins revealed new homologous recombination and genome stability pathways, providing a strategy to understand genome maintenance by BRD proteins and the effects of their pharmacological inhibition. This accession provides AP-MS experiment files for the following subset of 6 BRDs: BRD9, EP300, GCN5/KAT2A, PCAF/KAT2B, SP140, TRIM28, as well as their associated controls (Input, Mock, and SBP-tagged NLS).

2019-12-12 | PXD016673 | Pride

Affinity Purification experiments for 24 human Bromodomain proteins involved in DNA repair and genome integrity (part 1 of 2).

Project description:Bromodomain proteins (BRD) are key chromatin regulators of genome function and stability, as well as therapeutic targets in cancer. In our associated publication (doi:10.1101/gad.331231.119) we systematically delineate the contribution of human BRD proteins for genome stability and DNA double-strand break (DSB) repair using cell-based assays and proteomic interaction network analysis. These AP-MS experiments were performed in order to construct a protein interaction network for the 24 BRDs we identified as promoters of DNA repair and/or genome integrity: BAZ1B, BRD1, BRD2, BRD3, BRD4, BRD8, BRD9, BRPF3, BRWD3, CECR2, EP300, GCN5/KAT2A, PCAF/KAT2B, PHIP, SMARCA2, SP100, SP110, SP140, TAF1, TRIM24, TRIM28, TRIM33, TRIM66, ZMYND8. In combination with cell based assays, we identified a BRD-reader function of PCAF that bound TIP60-mediated histone acetylations at DSBs to recruit a DUB complex to deubiquitylate histone H2BK120, to allow direct acetylation by PCAF and repair of DSBs by homologous recombination. We also discovered the bromo-and-extra-terminal (BET) BRD proteins, BRD2 and BRD4, as negative regulators of transcription-associated RNA-DNA hybrid (R-Loop) as inhibition of BRD2 or BRD4 increased R-loop formation, which generated DSBs. These breaks were reliant on Topoisomerase II and BRD2 directly bound and activated Topoisomerase I, a known restrainer of R-loops. Thus, comprehensive interactome and functional profiling of BRD proteins revealed new homologous recombination and genome stability pathways, providing a strategy to understand genome maintenance by BRD proteins and the effects of their pharmacological inhibition. This accession provides AP-MS experiment files for the following subset of 18 BRDs: BAZ1B, BRD1, BRD2, BRD3, BRD4, BRD8, BRPF3, BRWD3, CECR2, PHIP, SMARCA2, SP100, SP110, TAF1, TRIM24, TRIM33, TRIM66, ZMYND8, as well as their associated controls (Input, Mock, and SBP-tagged NLS).

2019-12-12 | PXD016700 | Pride

RNA-seq analysis after dBRD9-A treatment in human multiple myeloma cell line OPM2 and H929

Project description:BRD9 is a defining component of the non-canonical SWI/SNF complex, regulating gene expression by controlling chromatin dynamics. We here identified high BRD9 expression as a poor prognostic factor in multiple myeloma (MM), which is positively correlated with activation of ribosome biogenesis. Genetic and pharmacological depletion of BRD9 downregulates expression of ribosome biogenesis genes and disrupts protein synthesis maintenance machinery, thereby inhibiting MM cell growth in both in vitro and in vivo preclinical models. Importantly, BRD9 interacts with BRD4 and MYC to form a transcription initiation complex that promotes transcription of ribosomal biogenesis genes. These results identify and validate BRD9 as a novel therapeutic target in MM which regulates ribosome biogenesis gene transcription, and provide the framework for clinical evaluation of BRD9 degraders to improve patient outcome in MM. This SuperSeries is composed of the SubSeries listed below.

2023-02-08 | GSE197487 | GEO

Chip-seq analysis after dBRD9-A treatment in human multiple myeloma cell line OPM2

2023-02-08 | GSE197486 | GEO

Distinct roles of Brd2 and Brd4 in potentiating the transcriptional program for Th17 cell differentiation

Project description:We analyzed the ChIP-seq data of Brd2 and Brd4 in Th17 cells. We find that Brd2 and Brd4 have distinct genome-wide deposition in Th17 cells, further experiments reveal tht Brd2 faciliates TF-complex formation in enhancers, enhancer-promoter interaction while Brd4 enhances transcriptional elongation.

2017-03-01 | GSE63778 | GEO

Distinct roles of Brd2 and Brd4 in potentiating the transcriptional program for Th17 cell differentiation

Project description:We analyzed the genome wide distributions of Brd2 and Brd4 in Th17 cells. We find that Brd2 and Brd4 have distinct genome-wide localization in Th17 cells, further experiments reveal tht Brd2 faciliates TF-complex formation in enhancers, enhancer-promoter interaction while Brd4 enhances transcriptional elongation.

2017-03-13 | GSE90788 | GEO

Project description:BRD9 degraders as chemosensitizers in acute leukemia and multiple myeloma

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Bromodomain protein 9 (BRD9) regulates interferon-stimulated genes during macrophage activation via cooperation with BET protein BRD4

Project description:Macrophages induce a number of inflammatory response genes in response to stimulation with microbial ligands. In response to endotoxin Lipid A, lineage-defining and stimulation-responsive transcription factors cooperate to induce a gene activation cascade of primary followed by secondary response genes. Epigenetic state is an important regulator of the kinetics, specificity, and mechanism of gene activation of these two classes. In particular, the SWI/SNF chromatin remodeling complex is required for the activation secondary response genes, but not primary response genes, which generally exhibit open chromatin. Here we show that a recently discovered variant of the SWI/SNF complex, the non-canonical BAF complex (ncBAF), regulates secondary response genes in the interferon (IFN) response pathway. Inhibition of bromodomain-containing protein 9 (BRD9), a subunit of the ncBAF complex, with BRD9 bromodomain inhibitors (BRD9i) or a degrader (dBRD9), led to reduction in a number of interferon-stimulated genes (ISGs) following stimulation with endotoxin lipid A. BRD9-dependent genes overlapped highly with a subset of genes differentially regulated by BET protein inhibition with JQ1 following endotoxin stimulation. We find that the BET protein BRD4 is co-bound with BRD9 in unstimulated macrophages and co-recruited upon stimulation to ISG promoters along with STAT1, STAT2, and IRF9, components of the ISGF3 complex activated downstream of IFNAR stimulation. In the presence of BRD9i or dBRD9, STAT1, STAT2, and IRF9 binding is reduced, in some cases with reduced binding of BRD4. These results demonstrate a specific role for BRD9 and the ncBAF complex in ISG activation and identify an activity for BRD9 inhibitors and degraders in dampening endotoxin- and IFN-dependent gene expression.

2021-11-26 | GSE176146 | GEO

Bromodomain and extra-terminal (BET) inhibitors regulate NK cell biology by inhibiting BRD2 mediated NK cytolytic activity and BRD2/BRD4 mediated inflammatory function

Project description:Natural killer cells are innate lymphocytes that play a pivotal role in the immune surveillance and elimination of transformed or virally infected cells. Using a combined chemico-genetic approach, we have identified that BET bromodomains BRD2 and BRD4 are central regulators of NK cell responses. We show that both BRD2 and BRD4 play a key regulatory function in controlling NK cell specific inflammatory responses. However, knockdown of BRD2 but not BRD4 impairs NK cell cytolytic response, highlighting a redundant role for BRD4 in regulating NK cell killing. We further show that the prototypic monovalent BET inhibitor impairs in vitro NK cell mediated killing of cancer target cells, while the bivalent BET bromodomain AZD5153 does not. We ascribe these differences to the preferential affinity of JQ1(+) to BRD2, while AZD5153 has a higher affinity for BRD4. Our work suggests that inhibiting BET bromodomains may be an effective therapeutic strategy for controlling inflammatory function. Given that BRD2 but not BRD4 inhibition can impair NK cell mediated killing, our findings also have clinical significance in light of the ongoing clinical application of BET bromodomains in oncology.

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