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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [ATAC-Seq]

ABSTRACT: Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [ATAC-Seq]

PROVIDER: PRJNA906469 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR22442610.fastq.gz	Fastqsanger.gz
	SRR22442611.fastq.gz	Fastqsanger.gz
	SRR22442612.fastq.gz	Fastqsanger.gz
	SRR22442613.fastq.gz	Fastqsanger.gz
	SRR22442614.fastq.gz	Fastqsanger.gz

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [RNA-Seq]

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [RNA-Seq]

Project description:More than 500 kinases are implicated in the control of virtually every cellular process in mammals and deregulation of their activity is causally linked to diseases ranging from cancer to inflammatory and degenerative disorders. In the last three decades, massive worldwide efforts led to the approval of 62 clinical kinase inhibitors (CKI), with hundreds of additional molecules in various stages of pre-clinical or clinical development. In addition to the intended target(s), small molecule CKI commonly inhibit multiple additional kinases, resulting in both enhanced clinical effects and undesired side effects that are largely unpredictable based on in vitro selectivity profiling. To complement current CKI profiling methods, we set out a novel experimental and analytical approach grounded on the use of chromatin modifications as unbiased and information-rich readouts of the functional effects of CKI on macrophage activation, a complex biological response of biomedical relevance. This approach allowed us to characterize and dissect the distinctive behaviors of CKI with identical intended targets as well as to discover undescribed activities of CKI on macrophage activation programs.

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [ChIP-Seq]

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [ATAC-Seq]

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [Chromatin associated RNA-seq]

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [Chromatin associated RNA-seq]

Project description:Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts [Chromatin associated RNA-seq]

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Unbiased profiling of clinical kinase inhibitors’ effects in activated macrophages using chromatin modifications as high-content readouts

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

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DRUG-seq Provides Unbiased Biological Activity Readouts for Neuroscience Drug Discovery.

Project description:Unbiased transcriptomic RNA-seq data has provided deep insights into biological processes. However, its impact in drug discovery has been narrow given high costs and low throughput. Proof-of-concept studies with Digital RNA with pertUrbation of Genes (DRUG)-seq demonstrated the potential to address this gap. We extended the DRUG-seq platform by subjecting it to rigorous testing and by adding an open-source analysis pipeline. The results demonstrate high reproducibility and ability to resolve the mechanism(s) of action for a diverse set of compounds. Furthermore, we demonstrate how this data can be incorporated into a drug discovery project aiming to develop therapeutics for schizophrenia using human stem cell-derived neurons. We identified both an on-target activation signature, induced by a set of chemically distinct positive allosteric modulators of the N-methyl-d-aspartate (NMDA) receptor, and independent off-target effects. Overall, the protocol and open-source analysis pipeline are a step toward industrializing RNA-seq for high-complexity transcriptomics studies performed at a saturating scale.

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