Influence of Pkm2-->1 isoform switching on the cardiac fibroblasts transcriptome
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ABSTRACT:
PROVIDER: PRJNA1236283 | ENA |
REPOSITORIES: ENA
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Project description:Cardiac fibroblasts (CFs) are essential for maintaining tissue integrity and the balance of the extracellular matrix (ECM), both of which are critical for normal heart function. Changes in metabolism can influence CF behavior, with activated fibroblasts often exhibiting distinct metabolic shifts. Pyruvate kinase, a key metabolic enzyme, has two isoforms—Pkm1 and Pkm2—produced through alternative splicing. CFs primarily express the Pkm2 variant rather than Pkm1. While Pkm2 is known to regulate gene transcription in various cell types, its role in CF gene expression is not well understood. In this study, we examined how pyruvate kinase splice variants influence CF gene transcription under baseline conditions and following activation by TGF-β or IL-1β. Our results indicate that switching from the Pkm2 to the Pkm1 variant had no significant effect on CF transcriptional regulation, regardless of ligand-induced activation.
2025-08-20 | GSE291984 | GEO
Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism. RNA was isolated from flash frozen ground whole liver tissue of 35 week old PKM2 KO and WT mice. Three independent mice from each condition were used as biological replicates.
2016-03-25 | E-GEOD-79535 | biostudies-arrayexpress
Project description:Transcriptomic Regulation Driven by TCF12 Isoform Switching
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Project description:To investigate the genome-wide isoform switching events in the small intestinal epithelium, we compared duodenal BMP 24h treated duodenal crypt organoids vs untreated duodenal crypt organoids.
2026-07-04 | GSE232589 | GEO
Project description:Pyruvate kinase M isoform 2 (PKM2) is preferentially expressed in nearly all cancers. It primarily functions as the last enzyme in glycolysis, but has other reported non-canonical functions, including recruiting transcription factors to oncogenes, and phosphorylating proteins. We previously described antisense oligonucleotides that disrupt alternative splicing of PKM pre-mRNA (PKM-ASOs), resulting in PKM2-to-PKM1 isoform switching in hepatocellular carcinoma (HCC), which reduces HCC growth. PKM1 has higher enzymatic activity than PKM2, which potentially drives metabolism away from macromolecule synthesis, and may explain decreased HCC growth upon PKM-ASO treatment. As PKM-ASOs also reduce PKM2 levels, how PKM splice-switching inhibits HCC cell proliferation was unclear. Here, we characterized the individual consequences of altering PKM1 or PKM2 protein levels in HCC, and observed that reducing PKM2 alone was sufficient to decrease HCC cell proliferation, whereas overexpressing PKM1 had no effect. Moreover, increasing PK activity via a small-molecule PKM2 activator had no effect on HCC cell proliferation, suggesting that PKM-ASOs affect PKM2’s non-metabolic functions. Transcriptomic and RT-qPCR analyses of HCC cells treated with PKM-ASO or PKM2-siRNA revealed upregulation of dual-specificity phosphatase 2 (DUSP2) and other related DUSPs, which act directly on ERK1/2 in the MAPK signaling pathway. Luciferase reporter assays demonstrated that PKM-ASO treatment activated the DUSP2 promoter, which correlated with decreased ERK1/2 phosphorylation. Lenvatinib is a second-line HCC therapy that indirectly reduces ERK1/2 phosphorylation, and combined treatment with PKM-ASOs inhibited proliferation of HCC cells more than either treatment alone. In summary, our results reveal a mechanism by which PKM-ASOs affect PKM2 dependency in HCC.
2025-08-09 | GSE274520 | GEO
Project description:We profiled global gene expression for two separate lines of mouse embryonic fibroblasts and find that deletion of PKM2 and expression of PKM1 does not alter global gene expression profiles. We used microarrays to futher characterize the effects of PKM1 expression compared to PKM2 expression on global gene expression in mouse embryonic fibroblasts. Primary mouse embryonic fibroblast cells were used for RNA extraction and hybridization on Affymetrix microarrays. Intensity files were RMA normalized using Affymetrix expression console.
2015-05-01 | E-GEOD-60499 | biostudies-arrayexpress
Project description:Global isoform switching in esophageal adenocarcinoma (EAC) has not been previously characterized. This form of alternative splicing has recently been recognized as highly prevalent in multiple other cancers. In this study, isoform switch analysis was performed using next generation sequencing of RNA isolated from patient tissues across a continuum of histopathologies, ranging from low risk Barrett’s esophagus (BE) to BE with dysplasia and EAC. Patients were stratified based on histopathology.
2022-08-17 | GSE193946 | GEO
Project description:Alternative splicing of the Pkm gene product generates the PKM1 and PKM2 isoforms of pyruvate kinase, and PKM2 expression is closely linked to embryogenesis, tissue regeneration, and cancer. To interrogate the functional requirement for PKM2 during development and tissue homeostasis, we generated germline PKM2 null mice (Pkm2-/-). Unexpectedly, despite being the primary isoform expressed in most wild-type adult tissues, we found that Pkm2-/- mice are viable and fertile. Thus, PKM2 is not required for embryonic or postnatal development. Loss of PKM2 leads to compensatory expression of PKM1 in the tissues that normally express PKM2. Strikingly, PKM2 loss leads to spontaneous development of hepatocellular carcinoma (HCC) with high penetrance that is accompanied by progressive changes in systemic metabolism characterized by altered systemic glucose homeostasis, inflammation, and hepatic steatosis. Therefore, in addition to its role in cancer metabolism, PKM2 plays a role in controlling systemic metabolic homeostasis and inflammation, thereby preventing HCC by a non-cell-autonomous mechanism.
2016-03-25 | GSE79535 | GEO
Project description:Circular RNAs (circRNAs) are covalently closed transcripts involved in the regulation of different cellular processes, and their dysregulation has been frequently observed in cancer. In this study, we investigated the role of circCDYL, a circRNA generated from the CDYL gene, in modulating alternative splicing (AS) and isoform switching in breast cancer cells. Analysis of circRNA profiles in breast cancer cells showed that circCDYL expression increased in estrogen receptor alpha (ERα)-downregulated cells, suggesting a potential link between circCDYL-mediated regulation and ERα signaling pathways. RNA-Sequencing analysis following circCDYL knock-down in MCF-7 cells revealed significant alterations in the splicing pattern, with over 2,900 splicing events significantly affected. Through RNA immunoprecipitation and RNA pull-down assays, we found evidence of an association between circCDYL and the splicing factor hnRNPL. To explore the consequences of this association, we performed AS and isoform switching analysis after circCDYL and hnRNPL silencing, revealing significant effects on AS and a weaker modulation of isoform switching events. Furthermore, we observed that circCDYL and hnRNPL modulated CDYL isoform expression, as confirmed by isoform-specific qRT-PCR analysis. Chromatin immunoprecipitation assays also indicated changes in chromatin marks at the CDYL locus upon knock-down of circCDYL and hnRNPL. These results suggested a possible association between circCDYL and hnRNPL, which contributed to the regulation of alternative splicing in breast cancer cells and may be involved in the modulation of isoform expression and chromatin dynamics of CDYL gene.
2025-04-18 | GSE295065 | GEO
Project description:Characterization of splice isoform switching during human kidney development
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