Dataset Information

E-GEOD-55966

ABSTRACT: Gene expression of early craniofacial development through RNA-seq

OTHER RELATED OMICS DATASETS IN: PRJNA241444PRJNA241447PRJNA241443PRJNA241446

TISSUE(S): Olfactory Pit, Epidermal Ectoderm, Mesoderm, Caudal Brain Neural Epithelium, Head Mesenchyme, Lateral Prominence Neural Epithelium, Floor Plate, Maxillary Arch, Lateral Nasal Prominence, Medial Nasal Prominence, Dorsal Control Neural Epithelium, Mandibular Arch, Central Neural Epithelium, Non-floor Plate Neural Epithelium

PROVIDER: E-GEOD-55966 | ExpressionAtlas | 2016-05-13

REPOSITORIES: ExpressionAtlas

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			Action	DRS
	E-GEOD-55966-analysis-methods.tsv	Tabular
	E-GEOD-55966-atlasExperimentSummary.Rdata	Rdata
	E-GEOD-55966-coexpressions.tsv.gz	Tabular
	E-GEOD-55966-configuration.xml	Xml
	E-GEOD-55966-factors.xml	Xml

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Project description:Cyclin-dependent kinases (CDKs) are key regulators of the cell cycle or transcription, and are emerging as promising therapeutic targets in cancer cells. The transcriptional kinase, CDK12, is especially intriguing, as it modulates transcription elongation by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase (Pol II) with subsequent effects on expression of DNA damage response (DDR) genes. Yet the exact mechanism by which CDK12 regulates this vital process remains unclear. Using the selective inhibitor of CDK12/13, THZ5317 and transient transcriptome sequencing (TT-seq), we sought to capture the dynamic transcriptional changes linked to CDK12 by analyzing the immediate, early effects on nascent RNA production after CDK12 depletion in neuroblastoma (NB) cells. CDK12-induced inhibition resulted in gene length-dependent defects in transcription elongation, leading to a disproportionate loss of 3' reads in long genes. Short transcripts, by contrast, including those of replication-dependent histone genes, underwent 3' UTR extension. The effect on long genes was accompanied by premature cleavage and polyadenylation (PCPA), followed by early termination and loss of gene expression. DDR gene transcripts were the most prominent among those terminated by PCPA. Phosphoproteomic analysis indicated that pre-mRNA processing factors, including those involved in CPA , are direct phospho-targets of CDK12 and that CDK depletion phenocopied their effects on transcription. Importantly, sensitivity to CDK12 inhibition was predicted by a lower proportion of U1 snRNP binding sites compared to polyadenylation sites (PAS) and hence a higher propensity to intronic poly(A) site selection - a characteristic observed in most DDR genes. These results support a model in which CDK12 regulates expression of DDR genes not only by regulating transcription elongation through its effects on Pol II CTD phosphorylation, but also through direct phosphorylation of pre-mRNA processing factors. These mechanistic insights may enable the development of new anti-cancer strategies targeting multiple vulnerable steps in CDK12-dependent regulation of DNA damage repair.

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E-GEOD-55966

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