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Homo sapiens

ABSTRACT: Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands [RNA-seq]

PROVIDER: PRJNA392162 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR5762030.fastq.gz	Fastqsanger.gz
	SRR5762040.fastq.gz	Fastqsanger.gz
	SRR5762031.fastq.gz	Fastqsanger.gz
	SRR5762032.fastq.gz	Fastqsanger.gz
	SRR5762023.fastq.gz	Fastqsanger.gz

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Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands

Project description:Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands

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Project description:Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands [ChIP-seq]

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Functional TRIM24 degraders via conjugation of ineffectual bromodomain and VHL ligands [RNA-seq]

Project description:The addressable pocket of a target protein is often not functionally relevant. This is particularly true for multidomain gene regulatory proteins, such as the bromodomain-containing transcriptional regulator TRIM24. TRIM24 has been posited as a dependency in numerous human cancers, yet potent and selective ligands for the TRIM24 bromodomain do not exert effective anti-proliferative responses. We therefore repositioned these probes as targeting features for heterobifunctional protein degraders.

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Functional genomics identify distinct and overlapping genes mediating resistance to different classes of heterobifunctional degraders of oncoproteins

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Project description:Cancer arises from the malignant interplay between oncogenic signaling and cell specification. Transcriptionally activated stem, growth and survival programs reshape an epigenomic identity defined by a transcriptional core regulatory circuitry. To study and disrupt oncogenic transcription, we first created inhibitors of BET bromodomains. Selective antagonism of oncogenic transcriptional signaling arises from bromodomain-specific activity. Recently, we innovated a strategy to induce selective and pronounced degradation of BET coactivator proteins via phthalimide conjugation for E3 ubiquitin ligase recruitment. Degraders of BET bromdomains (dBETs) exhibited superior efficacy to bromodomain inhibitors in cultivated leukemia cells, through unknown mechanisms. Here, we use chemically optimized small-molecule degronimids and kinetic measures of chromatin structure and function to unveil an unrecognized, essential role for BRD4 in the control of global productive transcriptional elongation. Rapid loss of BRD4 attenuates phosphorylation of the carboxy-terminal domain of RNA polymerase II, independent of genomewide recruitment of CDK9 to promoters, leading to a collapse of the transcriptional core regulatory circuitry. These mechanistic studies are performed in translational models of T-cell acute lymphoblastic leukemia, a disease emblematic for transcriptional addiction, to establish a rationale for human clinical investigation. RNA-Seq for DMSO, dBET6, or JQ1 treated MOLT4 cells

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BET bromodomain proteins function as master transcription elongation factors independent of CDK9 recruitment [NET-seq]

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