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Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems

ABSTRACT: Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems

PROVIDER: PRJNA945833 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23885715_1.fastq.gz	Fastqsanger.gz
	SRR23885715_2.fastq.gz	Fastqsanger.gz
	SRR23885716_1.fastq.gz	Fastqsanger.gz
	SRR23885716_2.fastq.gz	Fastqsanger.gz
	SRR23885717_1.fastq.gz	Fastqsanger.gz

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Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems [RNA-seq]

Project description:Fibroblasts can be chemically induced to pluripotent stem cells (CiPSCs) through an extraembryonic endoderm (XEN)-like state or directly converted into other differentiated cell lineages. However, the mechanisms underlying chemically-induced cell fate reprogramming remain unclear. Here, a transcriptome-based screen of biologically active compounds uncovered that CDK8 inhibition was essential to enable chemically-induced reprogramming from fibroblasts into XEN-like cells, then CiPSCs. RNA-seq analysis showed that a CDK8 inhibitor, MSC2530818, inhibited pro-inflammatory pathways that suppress chemical reprogramming, and facilitated the induction of a multi-lineage priming state, indicating the establishment of plasticity in fibroblasts. CDK8 inhibition also resulted in chromatin accessibility profile and Pol II occupation profile similar to that under initial chemical reprogramming. Moreover, CDK8 inhibition greatly promoted transgene-mediated reprogramming of mouse fibroblasts into hepatocyte-like cells, and chemical reprogramming of human fibroblasts into adipocytes. These collective findings thus define CDK8 as a general molecular barrier in multiple cell reprogramming processes, and as a common target for inducing plasticity and cell fate conversion.

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Transcriptome-based chemical screens identify CDK8 as a common barrier in multiple cell reprogramming systems

Project description:This SuperSeries is composed of the SubSeries listed below.

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Identification of a potent and selective chemical probe for exploring the role of Mediator complex-associated protein kinases CDK8 and CDK19 in human disease [Colo205]

Project description:There is an unmet need for chemical tools to explore the role of the Mediator complex in human pathologies ranging from cancer to cardiovascular disease. Here we determine that CCT251545 a WNT-pathway inhibitor discovered by cell-based screening is a potent and selective chemical probe for the Mediator complex-associated protein kinases CDK8 and CDK19. CCT251545 is an ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand binding site. In contrast to Type II inhibitors of CDK8/19 CCT251545 displays potent cell-based activity. We show that CCT251545 and close analogues not only alter WNT-pathway regulated gene expression but also other CDK8/19 targets including STAT1-regulated gene expression. Consistent with this we find that phospho-STAT1SER727 is a biomarker of CDK8 kinase activity in vitro and in vivo. Finally we demonstrate in vivo activity of CCT251545 in WNT-dependent tumours. Colo205 colon cancer cells were treated with 350 nM of Compound 1 or with vehicle (DMSO) for 2 or 6h. Four samples with four biological repeats each. Samples were hybridized against human reference. Compound 1 is a close analogue of a 3,4,5-trisubstituted pyridine series identified from a high-throughput cell-based reporter assay of WNT signalling. It was shown to be potent and selective inhibitor of the Mediator complex-associated protein kinases CDK8 and CDK19. Its is ATP competitive inhibitor with >100-fold selectivity over 291 other kinases. X-ray crystallography demonstrates Type 1 binding involving insertion of the CDK8 C-terminus into the ligand-binding site.

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