Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Identifying super-enhancer-derived signatures with prognostic value through selective inhibitors (Microarray gene expression data)

ABSTRACT: CDK12 and CDK13 promote transcription elongation within the gene body and regulate the processivity of RNAPII. THZ531 inhibits the enzymatic activity of CDK12 and 13 through covalent binding. Gene expression profiling was performed to investigate the THZ531-induced transcription effect, and search the subset of sensitive genes in osteosarcoma cell lines, U2-OS and SJSA-1.

ORGANISM(S): Homo sapiens

PROVIDER: GSE250566 | GEO | 2024/01/31

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors [ChIP-Seq]

Project description:Cyclin-dependent kinases 12 and 13 (CDK12 and CDK13) play critical roles in the regulation of gene transcription. However, the absence of CDK12 and CDK13 inhibitors has hindered the ability to investigate the consequences of their inhibition in healthy cells and cancer cells. Here we describe the rational design of a first-in-class CDK12 and CDK13 covalent inhibitor, THZ531. Co-crystallization of THZ531 with CDK12–cyclin K indicates that THZ531 irreversibly targets a cysteine located outside the kinase domain. THZ531 causes a loss of gene expression with concurrent loss of elongating and hyperphosphorylated RNA polymerase II. In particular, THZ531 substantially decreases the expression of DNA damage response genes and key super-enhancer-associated transcription factor genes. Coincident with transcriptional perturbation, THZ531 dramatically induced apoptotic cell death. Small molecules capable of specifically targeting CDK12 and CDK13 may thus help identify cancer subtypes that are particularly dependent on their kinase activities.

2016-05-19 | GSE72023 | GEO

Covalent targeting of remote cysteine residues to develop CDK12 and CDK13 inhibitors [Affymetrix]

2016-08-29 | GSE72022 | GEO

Quant-seq analysis to determine the effects of CDK12 and CDK13 inhibition by THZ531 in alternative polyadenylation

Project description:We performed 3' Quant-seq on MV4;11 cells after 6 hours treatment of THZ531 to determine whether CDK12 and CDK13 inhibtion cause alternative polyadenlation

2020-04-29 | GSE141368 | GEO

Transcriptome wide alternative splicing analysis to determine the effect of CDK12 and CDK13 inhibition by THZ531 in alternative splicing (Total RNA-Seq)

Project description:We performed Total RNA-seq on MV4;11 cells after 6 hours treatment of THZ531 to determine whether CDK12 and CDK13 inhibtion to cause splicing defects.

2020-04-29 | GSE141372 | GEO

CDK13 cooperates with CDK12 to control global RNA polymerase II processivity

Project description:The RNA polymerase II (POLII) driven transcription cycle is tightly regulated at distinct checkpoints through cyclin dependent kinases (CDKs) and their cognate Cyclins. The molecular events underpinning transcriptional elongation and processivity and CDK-Cyclins involved remain poorly understood. Using CRISPR-CAS9 homology-directed-repair we generated analog-sensitive-kinase variants of CDK12 and CDK13 to probe their individual and shared biological and molecular roles. Single inhibition of CDK12 or CDK13 induced transcriptional responses associated with DNA-damage and cellular growth signaling pathways respectively, with minimal effects on cell viability. In contrast, dual-kinase inhibition potently induced cell death, which was associated with extensive genome-wide transcriptional changes including wide-spread use of alternative 3’ polyadenylation sites. At the molecular level dual-kinase inhibition resulted in the loss of POLII CTD phosphorylation and greatly reduced POLII elongation rates and processivity. These data define significant redundancy between CDK12 and CDK13, and identify both as fundamental regulators of global POLII processivity and transcription elongation.

2020-04-30 | PXD015453 | Pride

Quant-seq analysis of differential polyadenylation site usages in caused by different Pol II mutants with slow elongation rates in Flp-In-293 cells and dual inhibition of CDK12 and CDK13 by THZ531 HEK293T cells

Project description:We used 3' RNA-Seq to determine the effects of slow elongating Pol II on polyadenatltion site usages, also the effects of CDK12 and CDK13 inhibition caused by THZ531 on alternative polyadenylation

2020-04-29 | GSE141375 | GEO

DRB-PRO-Seq for measuring Pol II transcriptional elongation rate alteration up on CDK12 and CDK13 inhibition by THZ531

Project description:We performed PRO-Seq to measure the Pol II elongation rate by measruing the distance of Pol II travels at viarous time points after relased from DRB induced pausing. We compared DMSO/DRB or THZ531/DRB co-treated sample to assess the effect of CDK12 and CDK13 inhibtion by THZ531 on transcriptional elongation rate.

2020-04-29 | GSE141370 | GEO

Transcriptome profile of OVCAR3 cells treated with DMSO or THZ531 (200nM) for 6hr

Project description:Transcription-associated cyclin-dependent kinases (CDKs) regulate the transcription cycle through sequential phosphorylation of the RNA polymerase II (RNAPII). We report that dual inhibition of the highly homologous CDK12 and CDK13 impairs splicing of a subset of promoter-proximal introns characterized by weak 3’ splice sites located at larger distance from the branchpoint. Nascent transcript analysis indicated that these introns are selectively retained upon pharmacologic inhibition of CDK12/13 with respect to downstream introns of the same pre-mRNAs. Retention of these introns was also triggered by Pladienolide B (PdB), an inhibitor of the U2 snRNP factor SF3B1 that recognizes the branchpoint. CDK12/13 activity promotes the interaction of SF3B1 with the RNAPII phosphorylated on serine 2 and disruption of this interaction by treatment with the CDK12/13 inhibitor THZ531 impairs the association of SF3B1 with the chromatin and its recruitment to the 3’ splice site of these introns. Furthermore, by using suboptimal doses of THZ531 and PdB, we describe a synergic effect of these inhibitors on intron retention, cell cycle progression and cancer cell survival. These findings uncover a mechanism by which CDK12/13 couple RNA transcription and processing and suggest that combined inhibition of these kinases and the spliceosome represents an exploitable anticancer approach.

2023-03-29 | GSE222493 | GEO

Ex vivo screen identifies CDK12 as a metastatic vulnerability in osteosarcoma

Project description:Despite progress in intensification of therapy, outcomes for patients with metastatic osteosarcoma (OS) have not improved in thirty years. We developed a system that enables preclinical screening of compounds against metastatic OS cells in the context of the native lung microenvironment. Using this strategy to screen a library of epigenetically-targeted compounds, we identified inhibitors of CDK12 to be most effective, reducing OS cell outgrowth in the lung by >90% at sub-micromolar doses. CDK12 inhibition led to defects in transcription elongation in a gene length- and expression-dependent manner. These effects were accompanied by defects in RNA processing and altered the expression of genes involved in transcription regulation and the DNA damage response. We further identify OS models that differ in their sensitivity to CDK12 inhibition in the lung and provide evidence that upregulated MYC levels may mediate these differences. Our studies provide a framework for rapid preclinical testing of compounds with anti-metastatic activity and highlight CDK12 as a potential therapeutic target in osteosarcoma.

2019-06-06 | GSE132233 | GEO

Changes in gene expression in HOS and U2-OS cell lines after exposure to 600 Î¼g/mL OGE

Project description:Osteosarcoma (Osteosarcoma) is a type of bone cancer. Eighty percent of this tumor will be metastatic to the lungs or liver, and as a result, patients generally need chemotherapy to improve survival possibility. Recently, anti-tumor activity has been reported in Ocimum gratissimum aqueous extract (OGE), which has been the focus of recent extensive studies on therapeutic strategies due to its antioxidant properties. We used microarrays to identify potential and novel target genes responsive to the anticancer effect in OGE treatment in osteosarcoma cells, We performed pharmacogenomics analyses for the effect of OGE on human osteosarcoma U2-OS and HOS cell growth. Cell viability, Western blot and flow cytometry analysis were performed before performing pharmacogenomics analyses for the effect of OGE on human osteosarcoma U2-OS and HOS cell growth, including cDNA microarray and RT-PCR assays.

2013-06-26 | E-GEOD-48281 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data