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JAK inhibition selectively suppresses melanoma lacking IFN-γ pathway

ABSTRACT: JAK inhibition selectively suppresses melanoma lacking IFN-γ pathway

PROVIDER: PRJNA828250 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR18825276_1.fastq.gz	Fastqsanger.gz
	SRR18825276_2.fastq.gz	Fastqsanger.gz
	SRR18825277_1.fastq.gz	Fastqsanger.gz
	SRR18825277_2.fastq.gz	Fastqsanger.gz
	SRR18825278_1.fastq.gz	Fastqsanger.gz

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JAK inhibition selectively suppresses melanoma lacking IFN-γ pathway

Project description:Immune checkpoint blockers (ICBs) showed unprecedented clinical benefits. But the overall efficacy of ICBs is limited to a small subset of cancer patients due to therapeutic resistance. Concerted efforts from our group and others have identified that loss of IFN-g signaling genes in melanoma is a major mechanism of resistance to ICBs. We therefore generated B16 melanoma model with IFNgR1 knocked out by CRISPR-Cas9. We sequenced the whole transcriptomes and identified activated PI3K-Akt-mTOR pathway in IFNgR1 knocked out cells. This may represent an attractive target for therapeutic interventions to bypassing ICB resistance in melanoma lacking functional IFN-g signaling.

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization [RNA-seq]

Project description:Complete polarization of macrophages towards an M1-like proinflammatory and antimicrobial state requires combined action of IFN-γ and LPS. Synergistic activation of canonical inflammatory NF-κB target genes by IFN-γ and LPS is well appreciated, but less is known about whether IFN-γ negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-γ selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-γ-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-γ-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-γ. These findings reveal that IFN-γ suppresses feedback inhibitory and metabolic components of the TLR response to achieve full M1 polarization, and provide insights into mechanisms by which IFN-γ selectively inhibits TLR4-induced transcription.

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization [ChIP-seq]

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization [ATAC-seq]

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization [RNA-seq II]

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization [ChIP-seq II]

Project description:Complete activation of macrophage proinflammatory and antimicrobial phenotype is promoted by combined action of IFN-g and LPS. Synergistic activation of canonical inflammatory NF-kB target genes by IFN-g and LPS is well appreciated, but less is known about whether IFN-g negatively regulates components of the LPS response, and how this affects polarization. A combined transcriptomic and epigenomic approach revealed that IFN-g selectively abrogates LPS-induced feedback and select metabolic pathways by suppressing TLR4-mediated activation of gene enhancers. In contrast to superinduction of inflammatory genes via enhancers that harbor IRF sequences and bind STAT1, IFN-g-mediated repression targeted enhancers with STAT sequences that bound STAT3. TLR4-activated IFN-g-suppressed enhancers comprised two subsets distinguished by differential regulation of histone acetylation and recruitment of STAT3, CDK8 and cohesin, and were functionally inactivated by IFN-g. These findings reveal that IFN-g suppresses feedback inhibitory and metabolic components of the TLR response to achieve full macrophage activation and provide insights into mechanisms by which IFN-g selectively inhibits TLR4-induced transcription.

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Epigenomic Landscapes Define Differential JAK Inhibitor Sensitivity in IFN-γ-Primed Human Macrophages

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IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization

Project description:IFN-γ selectively suppresses a subset of TLR4-activated genes and enhancers to potentiate M1-like macrophage polarization

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Epigenomic Landscapes Define Differential JAK Inhibitor Sensitivity in IFN-γ-Primed Human Macrophages [RNA-seq]

Project description:Epigenomic Landscapes Define Differential JAK Inhibitor Sensitivity in IFN-γ-Primed Human Macrophages [RNA-seq]

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