Genome-wide studies identify the role of PML/RARα phase separation in PML/RARα and BRD4 chromatin occupancy
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ABSTRACT:
PROVIDER: PRJNA1086441 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR28288290_1.fastq.gz | Fastqsanger.gz | |||
| SRR28288290_2.fastq.gz | Fastqsanger.gz | |||
| SRR28288291_1.fastq.gz | Fastqsanger.gz | |||
| SRR28288291_2.fastq.gz | Fastqsanger.gz | |||
| SRR28288292_1.fastq.gz | Fastqsanger.gz |
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Project description:Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosome translocation that generates the promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion gene. However, the global association between PML/RARα and transcriptional co-regulators, and the rules of their association in governing the key processes during the leukemogenesis remain unclear. Here, we performed the genome-wide binding profiling of PML/RARα and BRD4 in NB4, an APL patient-derived cell line. Moreover, we also performed ChIP-seq of PML/RARα and BRD4 upon genetic or pharmacological pertubation of PML/RARα or BRD4 to determine how they target regulatory elements.
2024-12-31 | GSE261292 | GEO
Project description:Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosome translocation that generates the promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion gene. However, the mechanism underlying PML/RARα mediated transcriptional dysregulation remain unclear. Here, we performed the transcription profiling in NB4, an APL patient-derived cell line.
2024-12-31 | GSE261293 | GEO
Project description:Genome-wide studies identify the role of PML/RARα phase separation in PML/RARα-driven transcriptional dysregulation.
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Project description:We defined the RARα interactome in the MDA-MB453 breast cancer cell line genetically engineered to over-express an N-terminally tagged version of the nuclear retinoic acid receptor. Twenty eight nuclear proteins which interact with RARα and whose interaction is stimulated or reduced by the pan-RAR ligand, all-trans retinoic acid (ATRA) were identified. Given the potential significance of the S100A3 calcium-binding protein in the control of tumor progression, we focused our attention on this factor. Using the two models represented by the ATRA-sensitive SKBR3 and MCF7 breast cancer cell lines characterized by constitutive expression of S100A3 and RARα, we demonstrate that the endogenous forms of S100A3 and RARα interact in physiological conditions. The interaction of S100A3 with RARα is cell context independent and it is observed not only in breast cancer but also in acute promyelocytioc leukemia (APL) cells, characterized by expression of the RARα-derived PML-RARα oncogene, which is the product of the t(15:17) chromosomal translocation. S100A3 interacts directly and specifically with RARα and PML-RARα, being unable to bind other members of the RAR/RXR family of retinoid nuclear receptors. The interaction surface maps to the carboxyl-terminal region of the RARα ligand binding domain. Binding of S100A3 to RARα and PML-RARα controls the constitutive and ATRA-dependent degradation of the two receptors. Silencing of the S100A3 gene decreases the amounts of RARα in breast SK-BR-3 and lung A549 cancer cells, rendering them more refractory to the anti-proliferative action of ATRA. In SK-BR-3 cells, this effect is accompanied by a decrease in the lactogenic/differentiating action of ATRA. In APL-derived NB4 cells, S100A3 knock-down reduces the amounts of both RARα and PML-RARα. Contemporaneous down-regulation of the two receptors is associated with an increase in the basal and ATRA-induced expression of many granulocytic differentiation markers. Opposite on RARα and PML-RARα levels as well as ATRA induced differentiation markers are observed upon over-expression of S100A3 in NB4 cells.
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Project description:Acute promyelocytic leukemia (APL) is characterized by a specific t(15;17) chromosome translocation that generates the promyelocytic leukemia/retinoic acid receptor-α (PML/RARα) fusion gene. However, the global association between PML/RARα and transcriptional co-regulators, and the rules of their association in governing the key processes during the leukemogenesis remain obscure. Here, we performed the genome-wide binding profiling of PML/RARα, HDAC1 and P300, in NB4, an APL patient-derived cell line. We found that PML/RARα targets could be classified into two classes. Moreover, we also performed ChIP-seq of H3K27ac to determine super-enhancers in NB4. We identified a novel function of PML/RARα in super-enhancer regulation during the leukemogenesis of APL.
2020-08-26 | GSE126720 | GEO
Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
2026-03-10 | GSE300021 | GEO
Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
2026-03-10 | GSE300020 | GEO
Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
2026-03-10 | GSE300028 | GEO
Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
2026-03-10 | GSE300027 | GEO
Project description:PML directly binds with BRD4 in the nucleus and facilitates BRD4 protein accumulation to amplify pro-inflammatory gene expression through phase separation-dependent SE-activation via PML/BRD4 condensate formation. In the preclinical mouse models, LSEC-specific deletion of PML/BRD4 complex mitigates liver inflammation and fibrosis. Utilizing single-cell RNA-sequencing, we show that epigenetically aberrant LSECs exhibit a reprogramed pro-inflammatory angiocrine landscape in mouse fibrotic livers and establish that TIMP1+ LSECs promote the recruitment of CD63+ monocyte-derived macrophages (MoMFs) during the progression of liver fibrosis. Thereby, we demonstrate that PML/BRD4 in LSECs govern inflammatory immune cell recruitment in liver fibrosis, and that pharmacological BRD4 inhibition or epigenetic repression of PML SE alleviates liver inflammation and fibrosis. In conclusion, we highlight in this study that PML/BRD4-mediated SE activation via phase separation drives pro-inflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.
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