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PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma [CUTnRun and ChIP]

ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), MYC is required for S-phase progression and escape from immune surveillance. Here we show that recruitment of the PAF1c transcription elongation complex to RNA polymerase depends on MYC and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for unperturbed proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with transcription-replication conflicts by being essential for expression of long DNA repair genes. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to restoration of immune surveillance. This occurs because CTR9 depletion releases RNA polymerase and the histone chaperone SPT6 from the body of long genes, promoting transcription of short genes that include MHC class-I genes. The data show that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

ORGANISM(S): Mus musculus

PROVIDER: GSE228795 | GEO | 2024/01/01

REPOSITORIES: GEO

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PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma [ChIP-seq/CUT&RUN]

Project description:In pancreatic ductal adenocarcinoma (PDAC), endogenous MYC is required for S-phase progression and escape from immune surveillance. Here we show that MYC in PDAC cells is needed for the recruitment of the PAF1c transcription elongation complex to RNA polymerase and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for normal proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with S-phase progression by being essential for the expression of long genes involved in replication and DNA repair. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to T-cell activation and restoration of immune surveillance. This is because CTR9 depletion releases RNA polymerase and elongation factors from the body of long genes and promotes the transcription of short genes, including MHC class I genes. The data argue that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

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PAF1c links S-phase progression to immune evasion and MYC function in pancreatic carcinoma [4sU-seq]

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Project description:In pancreatic ductal adenocarcinoma (PDAC), MYC is required for S-phase progression and escape from immune surveillance. Here we show that recruitment of the PAF1c transcription elongation complex to RNA polymerase depends on MYC and that depletion of CTR9, a PAF1c subunit, enables long-term survival of PDAC-bearing mice. PAF1c is largely dispensable for unperturbed proliferation and regulation of MYC target genes. Instead, PAF1c limits DNA damage associated with transcription-replication conflicts by being essential for expression of long DNA repair genes. Surprisingly, the survival benefit conferred by CTR9 depletion is not due to DNA damage, but to restoration of immune surveillance. This occurs because CTR9 depletion releases RNA polymerase and the histone chaperone SPT6 from the body of long genes, promoting transcription of short genes that include MHC class-I genes. The data show that functionally distinct gene sets compete for elongation factors and directly link MYC-driven S-phase progression to tumor immune evasion.

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RNAi profiling of mouse ES cells knocked down for Ctr9

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Project description:MYC family proteins are oncogenic transcription factors that can globally affect the function of RNA Polymerase II (RNAPII). The ability of MYC proteins to promote transcription elongation depends on their ubiquitination, but the underlying mechanism and its biological relevance are unknown. Here we show that MYC and the Polymerase II associated factor, PAF1c, interact directly and their function is mutually dependent, since the specific binding of MYC to active promoters depends on PAF1c and, conversely, PAF1c is required for MYC-dependent pause release. Upon binding, PAF1c is rapidly transferred from MYC onto RNAPII and this transfer is driven by the HUWE1 ubiquitin ligase. Both MYC and HUWE1 globally control histone H2B ubiquitylation, which promotes transcriptional elongation and alters chromatin structure for double-strand break repair. Consistently, MYC suppresses the accumulation of double-strand breaks at promoters in response to topoisomerase II inhibition. While depletion of PAF1c has only minor effects on MYC-dependent gene expression, MYC induces rampant transcription-dependent DNA damage in PAF1c-depleted cells. We propose that the HUWE1-dependent transfer of PAF1c from MYC onto RNAPII is critical for absorbing the topological stress accompanied with deregulated and oncogenic transcription.

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Ctr9 Promoter Region Binding

Project description:To study the function of Paf1C in mouse ESCs, we generated an ES cell line stably expressing a location and affinity purification (LAP)-tagged Ctr9 fusiuon protein using the bacterial astificial chromosome (BAC)-based TransgeneOmics approach. To investigate whether pluripotency and lineage control genes differentially regulated upon Paf1C depletion are direct targets of the Paf1C, we analyzed the binding of the Ctr9-LAP fusion protein by ChIP-chip and identified 2175 promoter regions that were bound by Ctr9. The supplementary bed file contains promoter regions bound by Ctr9. Keywords: ChIP-chip

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