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T-bet deficiency and Hic1 induction override TGF-b-dependency in the formation of CD103+ intestine-resident memory CD8+ T cells

ABSTRACT: T-bet deficiency and Hic1 induction override TGF-b-dependency in the formation of CD103+ intestine-resident memory CD8+ T cells

PROVIDER: PRJNA1082371 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR28171268_1.fastq.gz	Fastqsanger.gz
	SRR28171268_2.fastq.gz	Fastqsanger.gz
	SRR28171269_1.fastq.gz	Fastqsanger.gz
	SRR28171269_2.fastq.gz	Fastqsanger.gz
	SRR28171270_1.fastq.gz	Fastqsanger.gz

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Project description:The pathognomonic EWS/ETS fusion transcription factors drive Ewing sarcoma (EWS) by orchestrating an oncogenic transcription program. Therapeutic targeting of EWS/ETS has not been successful; therefore identifying mediators of the EWS/ETS function could offer new therapeutic targets. Here we describe the dependency of chromatin reader BET bromodomain proteins in EWS/ETS driven transcription and investigate the potential of BET inhibitors in treating this lethal cancer. Similar to EWS/ETS fusions, knockdown of BET proteins BRD2/3/4 severely impaired the oncogenic phenotype of EWS cells. Notably, EWS/FLI1 and EWS/ERG was found to be in a transcriptional complex consisting of BRD4. RNA-Seq analysis upon BRD4 knockdown or its pharmacologic inhibition by the BET inhibitor JQ1 revealed an attenuated EWS/ETS transcriptional signature. In contrast to other reports, JQ1 reduced proliferation, and induced apoptosis through MYC-independent mechanism without affecting EWS/ETS protein levels, which was further confirmed by depleting BET proteins using PROTAC-BET degrader (BETd). Interestingly, polycomb repressive complex 2 (PRC2) associated factor PHF19 was downregulated by JQ1/BETd or BRD4 knockdown in multiple EWS cells. ChIP-seq analysis revealed occupancy of EWS/FLI1 at a distal regulatory element of PHF19 and its subsequent knockdown resulted in downregulation of PHF19 expression. Furthermore, deletion of PHF19 by CRISPR-Cas9 system lead to a decreased tumorigenic phenotype and increased sensitivity to JQ1. Importantly, PHF19 expression was associated with worse prognosis of Ewing sarcoma patients. In vivo, JQ1 demonstrated anti-tumor efficacy in multiple mouse xenograft models of EWS. Together, these results indicate that EWS/ETS require BET epigenetic reader proteins for its transcriptional program including PHF19 expression, which can be mitigated by BET inhibitors. Moreover, this study provides a clear rationale for the clinical utility of BET inhibitors in treating Ewing sarcoma.

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T-bet deficiency and Hic1 induction override TGF-b-dependency in the formation of CD103+ intestine-resident memory CD8+ T cells

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