PHF5A coordinates p300 for epigenetic regulation of lipogenesis to promote hepatocellular carcinoma progression
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA702753 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13736912_1.fastq.gz | Fastqsanger.gz | |||
| SRR13736912_2.fastq.gz | Fastqsanger.gz | |||
| SRR13736913_1.fastq.gz | Fastqsanger.gz | |||
| SRR13736913_2.fastq.gz | Fastqsanger.gz | |||
| SRR13736914_1.fastq.gz | Fastqsanger.gz |
Items per page: 5 1 - 5 of 8 |
Similar Datasets
Project description:PHD-finger protein 5A (PHF5A) is a component of U2snRNP, which plays a critical role in mRNA splicing for recognizing the branch site. However, whether it also plays other functions independent of RNA splicing remains elusive. Here, we find that expression levels of PHF5A are significantly upregulated in hepatocellular carcinoma (HCC). Down-regulation of PHF5A restrains liver cancer cell proliferation in vitro and in vivo. RNA-sequencing analysis reveals that fatty-acid biosynthetic enzymes are major downstream targets of PHF5A in HCC. Through metabolomics analysis, we find that inhibition of PHF5A reduces free fatty acid and phospholipid synthesis, further suppressing plasma membrane function. Mechanistically, PHF5A acts as a transcription co-factor of the p300 acetyltransferase for the H3K27 acetylation (Ac) and promotes H3K27Ac-dependent lipogenic genes expression. Our findings demonstrated a surprising splicing-independent role of PHF5A in transcriptional regulation of lipid metabolism for HCC progression and provided a new strategy for HCC therapy by blocking the interaction of PHF5A and p300.
2021-10-01 | GSE167023 | GEO
Project description:The process utilized by cancer cells for adapting to cellular stress is a key point for carcinogenesis. Alternative pre-mRNA splicing induced post-transcriptional gene expression regulation is one of the pathways for tumors maintaining proliferation rates accompanying the malignant phenotype under stress. However, the protein post-translational modification, especially protein acetylation on pre-mRNA splicing processes under stress is unknown. Here, we uncovered a list of hyperacetylated proteins in the context of acutely reduced Acetyl-CoA levels under nutrient starvation. PHD finger-like domain-containing protein 5A (PHF5A/SF3b14b), a component of U2 snRNPs, can be acetylated at lysine 29 in response to multiple cellular stresses. P300 and HDAC6 regulate PHF5A acetylation levels. PHF5A acetylation strengthens the interaction among U2 snRNPs, and affects global pre-mRNA splicing pattern and extensive gene expression. PHF5A hyperacetylation induced alternative splicing stabilizes KDM3A mRNA and promotes its protein expression. Pathologically, PHF5A K29 hyperacetylation and KDM3A upregulation axis are correlated with poor prognosis of colon cancer patients. Our findings uncovered a novel mechanism of anti-stress pathway that acetylation on PHF5A promotes the cancer cells capacity for stress resistance and consequently contributes to colon carcinogenesis.
2018-11-22 | GSE122761 | GEO
Project description:ChREBP-mediated control of Them1 expression coordinates thermogenesis with glycolysis and lipogenesis
| PRJNA1181773 | ENA
Project description:Dysregulated alternative splicing (AS) plays critical roles in driving cancer progression, and the underlying mechanisms remain largely unknown. Here we demonstrated that PHF5A, a component of U2 snRNPs, was frequently upregulated in colorectal cancer (CRC) samples and associated with poor prognosis. PHF5A promoted proliferation and metastasis of CRC cells in vitro and in vivo. Transcriptomic analysis identified PHF5A-regulated AS targets and pathways. Particularly, PHF5A induced TEAD2 exon 2 inclusion to activate YAP signaling, and interference of TEAD2-L partially reversed the PHF5A-mediated tumor progression. Pharmacological inhibition of PHF5A using pladienolide B had potent antitumor activity. Collectively, these data revealed the oncogenic role of PHF5A in CRC through regulating AS, and established PHF5A as potential therapeutic target.
2021-07-16 | GSE180042 | GEO
Project description:Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1a (HNF1a), were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative RT-PCR, western-blotting and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong dowregulation of L-FABP suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1a-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1a-mutated HCA. In theses tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through SREBP-1 and ChREBP that were repressed. We conclude that steatosis in HNF1a-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1a inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies. Keywords: Disease state analysis
2007-05-01 | GSE7473 | 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: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:Biallelic inactivating mutations of the transcription factor 1 gene (TCF1), encoding hepatocyte nuclear factor 1a (HNF1a), were identified in 50% of hepatocellular adenomas (HCA) phenotypically characterized by a striking steatosis. To understand the molecular basis of this aberrant lipid storage, we performed a microarray transcriptome analysis validated by quantitative RT-PCR, western-blotting and lipid profiling. In mutated HCA, we showed a repression of gluconeogenesis coordinated with an activation of glycolysis, citrate shuttle and fatty acid synthesis predicting elevated rates of lipogenesis. Moreover, the strong dowregulation of L-FABP suggests that impaired fatty acid trafficking may also contribute to the fatty phenotype. In addition, transcriptional profile analysis of the observed deregulated genes in non-HNF1a-mutated HCA as well as in non-tumor livers allowed us to define a specific signature of the HNF1a-mutated HCA. In theses tumors, lipid composition was dramatically modified according to the transcriptional deregulations identified in the fatty acid synthetic pathway. Surprisingly, lipogenesis activation did not operate through SREBP-1 and ChREBP that were repressed. We conclude that steatosis in HNF1a-mutated HCA results mainly from an aberrant promotion of lipogenesis that is linked to HNF1a inactivation and that is independent of both SREBP-1 and ChREBP activation. Finally, our findings have potential clinical implications since lipogenesis can be efficiently inhibited by targeted therapies. Keywords: Disease state analysis In a first experiment, microarray analyses were applied to 8 HNF1-alpha mutated HCA and their corresponding non-tumor livers using cDNA in-house manufactured arrays following a randomized and blinded unbalanced design. RNA labelling, hybridization and analysis of fluorescence was carried out, as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501], considering that uneven numbers of samples were randomly allocated to each of the engineers who were not aware of sample phenotypes. To assess data reproducibility and minimize dye bias effects, each of the samples was measured four times, twice with Cy3 and twice with Cy5. To ensure robustness and flexibility in data analysis, a reference design was used with a universal reference sample (Stratagene, USA) serving as a baseline for the comparisons of tumor samples. Hybridizations were performed onto an 11K human array (11K_VJF-ARRAY, GPL3282), which provides a genome-wide coverage of functional pathways. Raw data were obtained using the ArrayVisionM-bM-^DM-" 7.0 software (Imaging Research Inc., USA); the resulting 3.2x106 hybridization data points collected from 32 arrays were stored in a MIAME-compliant database and pre-processed for normalization and filtering as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501]. In a second experiment, HG-U133A Affymetrix GeneChipTM arrays were used to compare the expression profiles of 5 HNF1-alpha mutated HCA and 4 non related non-tumor livers. RNA labelling, hybridization and analysis were carried out following the manufacturerM-bM-^@M-^Ys instructions(Affymetrix, Santa Clara, CA). Raw data were obtained by using Microarray Suite 5.0 (MAS5) software, embedded in the Affymetrix GeneChip Operating Software (Santa Clara, USA); the resulting raw numerical data (CEL files) - available as supplementary files - collected from 9 Affymetrix GeneChips were pre-processed for normalization and filtering as described in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603]. A platform-dependant statistical comparison was performed considering HNF1 alpha-mutated HCA versus non tumor liver tissues, using multiple testing procedures to evaluate statistical significance for differentially expressed genes, as described in [Graudens et al., Genome Biol 2006, 7: R19; PMID: 16542501] and in the supplemental experimental procedures in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603]. Thus, a combined cross-platform analysis was done considering the UGCluster Identifiants as a common primary key (Unigene Build184-June05). Additional information on the procedures is provided in the supplemental experimental procedures in [Rebouissou et al., J Biol Chem 2007, in press; PMID: 17379603].
2007-05-01 | E-GEOD-7473 | biostudies-arrayexpress
Project description:The SF3B complex, a multiprotein component of the U2 snRNP of the spliceosome, mediates branch point selection and facilitates spliceosome assembly and activation. Several splicing modulators bind the SF3B1 and PHF5A subunits of the SF3B complex and globally inhibit splicing. Engineered mutant variants of SF3B1 and PHF5A conferred tolerance to splicing inhibitors with only minor effects on gene expression and AS.
2021-04-11 | GSE153234 | 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