Ontology highlight
ABSTRACT:
PROVIDER: PRJNA887833 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR22006852_1.fastq.gz | Fastqsanger.gz | |||
| SRR22006852_2.fastq.gz | Fastqsanger.gz | |||
| SRR22006853_1.fastq.gz | Fastqsanger.gz | |||
| SRR22006853_2.fastq.gz | Fastqsanger.gz | |||
| SRR22006854_1.fastq.gz | Fastqsanger.gz |
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Project description:Pancreatic cancer (PC) remains one of the most aggressive and life-threatening malignancies known for its notorious resistance to chemotherapy. This is increasingly ascribed to the subpopulation of undifferentiated cells, known as pancreatic cancer stem cells (PCSCs), which are evolutionary fitter than other tumor cells to evade the cytotoxic effects of chemotherapy. Those cells are crucial for tumor relapse as they possess ‘stem cell-like’ features of self-renewal and differentiation. However, what molecular mechanisms maintain the unique characteristics of PCSCs are poorly understood. Here, we identified an RNA polymerase II-associated PHF5A-PHF14-HMG20A-RAI1-KMT2A transcriptional subcomplex, which regulates the stemness characteristics and tumorigenicity of PCSCs through epigenetic control of gene expression. Targeting the protein subcomplex with a KMT2A-WDR5 inhibitor attenuated the self-renewal and in vivo tumorigenicity of PCSCs, thus offering a novel anti-PCSCs targeting strategy for enhancing the efficiency of chemotherapy which is likely to translate into durable clinical responses in PC patients.
2023-08-23 | PXD038378 | Pride
Project description:Targeting an RNA polymerase II-associated PHF5A transcriptional subcomplex with a KMT2A-WDR5 inhibitor impairs self-renewal and tumorigenicity of pancreatic cancer stem cells
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Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. However, it remains unclear whether components of these networks functionally interact and if so, what factors mediate such interactions. Here we show that WD-repeat protein-5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a novel regulator of ES cell self-renewal. We demonstrate that Wdr5, an ‘effector’ of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. In concordance, genome-wide ChIP-Seq and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. We show that the Oct4-Sox2-Nanog circuitry cooperates with trxG for transcriptional activation of key self-renewal regulators. Furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. Collectively, these findings implicate an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming. 7 Samples
2011-04-08 | E-GEOD-22934 | biostudies-arrayexpress
Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. However, it remains unclear whether components of these networks functionally interact and if so, what factors mediate such interactions. Here we show that WD-repeat protein-5 (Wdr5), a core member of the mammalian Trithorax (trxG) complex, positively correlates with the undifferentiated state and is a novel regulator of ES cell self-renewal. We demonstrate that Wdr5, an ‘effector’ of H3K4 methylation, interacts with the pluripotency transcription factor Oct4. In concordance, genome-wide ChIP-Seq and transcriptome analyses demonstrate overlapping gene regulatory functions between Oct4 and Wdr5. We show that the Oct4-Sox2-Nanog circuitry cooperates with trxG for transcriptional activation of key self-renewal regulators. Furthermore, Wdr5 expression is required for the efficient formation of induced pluripotent stem (iPS) cells. Collectively, these findings implicate an integrated model of transcriptional and epigenetic control, mediated by select trxG members, for the maintenance of ES cell self-renewal and somatic cell reprogramming.
2011-04-08 | GSE22934 | GEO
Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed nascent RNA profiling using global run-on sequncing in mouse ESCs under conditions of self-renewal, differentiation and Phf5a knockdown. These results revealed that genes positively regulated by Paf1 in ESCs exibit RNA elongation pausing on their promoters. We used conditions of self-renewal, differentiation, Phf5a knockdown and Paf1 knockdown to monitor nascent transcript expression changes during Phf5a depletion using global run-on RNA sequencing (GRO-seq). These results revealed that Phf5a through the control of Paf1 complex regulates pause release and elongation of pluripoency-associated genes in embryonic stem cells.
2016-08-31 | GSE73441 | GEO
Project description:Developing small-molecule splicing modulators represents a promising therapeutic approach for various diseases. Natural products such as pladienolide, herboxidiene, and spliceostatin have been identified as potent splicing modulators that target SF3B1 in the SF3b subcomplex. Using integrated chemogenomic, structural and biochemical approaches, we show that PHF5A, another core component of the SF3b complex, is also targeted by these compounds. Mutations in PHF5A-Y36, SF3B1-K1071, SF3B1-R1074, and SF3B1-V1078 confer resistance to these modulators, suggesting a common site of interaction. Whole-transcriptome RNA-seq analysis reveals that PHF5A-Y36C has minimal effect on basal splicing but alters the action of splicing modulators from inducing intron-retention to exon-skipping. Relative intron strength to splicing inhibition correlates with the differential in GC content between adjacent introns and exons, leading to this differential global splicing pattern. We determine the crystal structure of human PHF5A and find that Y36 is located on the surface in a region of high sequence conservation. Structural analysis of the cryo-EM spliceosome Bact complex shows that these mutations cluster in a well-defined pocket surrounding the branch point adenosine suggesting a possible competitive mode of action for these splicing modulators, which interact with the aromatic side-chain of PHF5A-Y36. Collectively, we propose that PHF5A-SF3B1 forms a central node for binding to these small-molecule splicing modulators, offering insights to modulate splicing.
2017-05-25 | GSE96917 | GEO
Project description:Phf5a regulates transcription elongation in mouse embryonic stem cells (ESCs), through regulation of the Paf1 complex. In this study we assayed gene expression profiling using RNA-sequncing in mouse ESCs under conditions of self-renewal, Phf5a knockdown and Paf1 knockdown. These results revealed that Phf5a and Paf1 regulate similar gene expression signatures in mouse ESCs.
2016-08-31 | GSE86248 | GEO
Project description:The tumor-initiating cells (TIC) are cell population that can initiate tumor, mediate drug resistance, and give rise to metastasis. FOXD3 is a forkhead box (Fox) transcription factor family that regulates the pluripotency of embryonic stem cell and tumorigenicity. However, it is unclear whether FOXD3 play any role in TIC and tumor metastasis. Here, we report that FOXD3 is down-regulated in tumor initiating cells and negatively correlated with higher histologic grades and positive lymph node metastasis. FOXD3 repress TIC expansion, cell migration, drug resistance and osteogenesis in vitro and in vivo. Mechanically, we found that FOXD3 repress a cohort of genes including SET and WDR5 and to regulate several TIC related signaling pathway. Moreover, SET and WDR5 was positively correlated with the CSC abundance and tumor progression. Besides, patients with high expression of SET and WDR5 presented a poorer overall survival. Collectively, our work defined that FOXD3-WDR5-SET axis that repress TIC accumulation and lung cancer progression.
2017-01-10 | GSE93323 | GEO
Project description:The highly conserved WD40-repeat protein WDR5 is part of multiple functional complexes both inside and outside the nucleus, interacting with the MLL/SET1 histone methyltransferases that catalyze histone H3 lysine 4 (H3K4) di- and tri-methylation (me2,3), and KIF2A, a member of the Kinesin-13 family of microtubule depolymerase. It is currently unclear whether, and how, the distribution of WDR5 between complexes is regulated. Here, we show that an unannotated microprotein dually encoded in the human SCRIB gene regulates the association of WDR5 with epigenetic and KIF2A complexes. We propose to name this alt-protein EMBOW, or microprotein that is the epigenetic to mitotic binder of WDR5. Loss of EMBOW decreases WDR5 interaction with KIF2A, displaces WDR5 from the spindle pole during G2/M phase, and shortens the spindle length, hence prolonging G2/M phase and delaying cell proliferation. On the other hand, loss of EMBOW increases WDR5 interaction with epigenetic complexes, including KMT2A/MLL1, and promotes WDR5 association with chromatin and binding to the target genes, hence increasing H3K4me3 levels of target genes. Together, these results implicate EMBOW as a regulator of WDR5 that switches it between epigenetic and mitotic regulatory roles during cell cycle, explaining how mammalian cells can temporally control the multifunctionality of WDR5.
2023-09-19 | PXD036699 | Pride
Project description:The embryonic stem (ES) cell transcriptional and epigenetic networks are critical for the maintenance of ES cell self-renewal. It remains unclear whether interactions. Here we show that a core member of the Set/MLL complex, WDrepeat protein-5 (Wdr5), is a novel regulator of self-renewal and partners with Oct4 to maintain an intact transcriptional network and for efficient formation of induced pluripotent stem (iPS) cells. Moreover, we provide evidence that Oct4 interacts with chromatin components and is indispensible for epigenetic regulation. These findings suggest an integrated transcriptional and epigenetic model, mediated through Wdr5, for the maintenance of ES cell self-renewal and somatic cell reprogramming. Differential gene expressions upon down-regulation of Wdr5 was analysed by comparing Wdr5R4 –dox (triplicate) and LucR +dox (duplicate) RNA samples Gene expression changes upon down-regulation of Oct4 was analysed by comparing Oct4 shRNA (duplicate) and GFP shRNA (duplicate) after 4day transfection Wdr5: 5 samples are analyzed: Luciferase (Luc, 2 replicates) and Wdr5 with no dox (minusDox, 3 replicates) Oct4-GFP: 4 samples are analyzed: Oct4 shRNA (Oct4, 2 replicates) and GFP shRNA (GFP, 2 replicates)
2011-04-08 | E-GEOD-19588 | biostudies-arrayexpress