Opposing functions of BRD4 isoforms in breast cancer
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PROVIDER: PRJNA561383 | ENA |
REPOSITORIES: ENA
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Project description:Bromodomain-containing protein 4 (BRD4) is a cancer therapeutic target in many ongoing clinical trials disrupting primarily BRD4-regulated transcription programs. A critical role of BRD4 in cancer development has been reported and attributed mainly to the abundant long isoform (BRD4-L). Here we show, by isoform-specific knockdown and endogenous protein detection along with transgene expression, the less abundant BRD4 short isoform (BRD4-S) is oncogenic while BRD4-L is tumor-suppressive in breast cancer cell proliferation and migration as well as mammary tumor formation and metastasis. Through integrated RNA-seq transcriptome and genome-wide ChIP-seq and CUT&RUN association profiling, we identify Engrailed-1 (EN1) homeobox transcription factor as a key BRD4-S coregulator particularly in triple-negative breast cancer. BRD4-S and EN1 co-modulate the extracellular matrix (ECM)-associated matrisome network, including type II cystatin gene cluster, mucin 5 and cathepsin loci, via enhancer regulation of cancer-associated genes and pathways. Our work highlights the importance of targeted therapy for the oncogenic but not tumor-suppressive activity of BRD4.
2020-05-22 | GSE136151 | GEO
Project description: Not available
| S-EPMC7362310 | biostudies-literature
Project description:In this study, we show that long and short isoform of the epigenetic regulator BRD4 is overexpressed in ERMS patient-derived cell lines and patient tumour specimens. Functionally, knockdown of long isoform of BRD4 reduced proliferation and promotes differentiation. Knockdown of the short isoform on the other hand promotes migration and invasion. The functional observations were confirmed in vitro and in vivo. Through RNA Sequencing analysis, we identified Myostatin (MSTN) and Integrins (ITGs) as important downstream target of long and short isoform of BRD4 respectively. We thus conclude from this study that long isoform functions as an oncogenic driver and can only promote metastasis only when the short isoform that functions as a blocker of tumor spread is removed. The interplay of the isoform identifies the long form as a therapeutic target and the short form as a predictive biomarker for metastasis in ERMS.
2023-12-01 | GSE215393 | GEO
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:Airn isoforms are important for the functions of cardiomyocytes
| PRJNA343927 | ENA
Project description:BRD4 is well known for its role in super-enhancer organization and transcription activation of several prominent oncogenes including c-MYC and BCL2. As such, BRD4 inhibitors have being pursued as promising therapeutics for cancer treatment. However, drug resistance also occurs for BRD4-targeted therapies. Here we report that BRD4, unexpectedly, interacts with the LSD1/NuRD complex and co-localizes with this repressive complex on super-enhancers. Integrative genomic and epigenomic analyses indicate that the BRD4/LSD1/NuRD complex restricts the hyperactivation of a cluster of genes that are functionally linked to drug resistance. Intriguingly, treatment of breast cancer cells with a small molecule inhibitor of BRD4, JQ1, results in no immediate activation of the drug-resistant genes, but long-time treatment or destabilization of LSD1 by PELI1 decommissions the BRD4/LSD1/NuRD complex, leading to resistance to JQ1 as well as to a broad spectrum of therapeutic compounds. Consistently, PELI1 is up-regulated in breast carcinomas, its level is negatively correlated with that of LSD1, and the expression level of the BRD4/LSD1/NuRD complex-restricted genes is strongly correlated with a worse overall survival of breast cancer patients. Together, our study uncovers a functional duality of BRD4 in super-enhancer organization of transcription activation and repression linking to oncogenesis and chemoresistance, respectively, supporting the pursuit of a combined targeting of BRD4 and PELI1 in effective treatment of breast cancer.
2022-02-01 | GSE171908 | GEO
Project description:ChIP-seq was performed using Drosophila Kc167 cells using antibodies against the two isoforms of Fs(1)h, the Brd4 homologue. Differences in binding patterns between the two isoforms are described.
2012-11-15 | GSE42086 | GEO
Project description:Class Switch Recombination (CSR) is a B cell specific genomic alteration induced by activation induced cytidine deaminase (AID)-dependent DNA break, followed by repair and recombination at the immunoglobulin heavy-chain locus. The involvement of several chromatin-associated factors in promoting AID-induced DNA break formation has been reported. However, the involvement of chromatin adaptors at the repair phase of CSR remains unknown. Here, we provide evidence that acetylated histone reader Brd4 is critical to the repair and recombination step of CSR. Brd4 was recruited to the AID-induced DNA break region, and depletion of Brd4 from the S region chromatin by knockdown or a chemical inhibitor JQ1 causes CSR impairment without affecting AID-induced DNA break generation. Such inhibition of Brd4 suppressed the accumulation of 53BP1 and UNG at the cleaved S regions, perturbed switch donor-switch acceptor microhomology length and reduced Igh/c-myc translocation. We conclude that Brd4 serves as a histone-reader platform required for the recruitment of CSR repair components. Brd4 were depleted from the chromatin by either siRNA treatment or JQ1 (40nM) addition in CH12F3-2A cells in the presence of CIT stimulation. RNA from each samples were extracted and relative difference in transcript level were compared with control RNAi- and DMSO-treated, CIT-stimulated samples.
2014-06-20 | E-GEOD-52239 | biostudies-arrayexpress
Project description:ChIP-seq was performed using Drosophila Kc167 cells using antibodies against the two isoforms of Fs(1)h, the Brd4 homologue. Differences in binding patterns between the two isoforms are described. We examined the differences in Fs(1)h isoform binding across the genome and describe the short isoform to be correlated with transcription at enhancers and promoters. The long isoform is found predominately at insulator binding sites where multiple insulators are bound.
2012-11-15 | E-GEOD-42086 | biostudies-arrayexpress
Project description:Estrogen receptor alpha (ER) is involved in cell growth and proliferation and functions as a transcription factor, a transcriptional coregulator, and in cytoplasmic signalling. The diverse roles of the ER include effects on e.g. bone, endometrium, ovaries, and mammary epithelium. The ER is a key biomarker in clinical management of breast cancer, where it is used as a prognostic and treatment-predictive factor, and a therapeutical target. Several functionally distinct ER isoforms have been described, but current transcript annotation in public databases is incomplete and inconsistent. We analysed short- and long-read RNA sequencing data from breast tumours, breast cancer cell lines, and normal tissues to create a comprehensive annotation of ER transcripts and combined it with experimental studies of full-length protein and six alternative isoforms to compare transcription factor activity, subcellular localisation, and response to the ER-targeting drug fulvestrant. Antibodies differ in ability to detect alternative isoforms, which raises concerns for the interpretation of ER-status in routine pathology. Future work should investigate the effects of alternative isoforms on patient survival and therapy response. An accurate annotation of ER isoforms will aid in interpretation of clinical data and inform functional studies to improve our understanding of the ER in health and disease.
2023-09-20 | GSE208238 | GEO