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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.

2024-01-01 | GSE243703 | GEO

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

2024-01-01 | GSE243701 | GEO

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

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.

2024-01-01 | GSE228797 | GEO

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

2024-01-01 | GSE228799 | GEO

RNAi profiling of mouse ES cells knocked down for Ctr9

Project description:To monitor global transcript changes after Paf1C depletion we transfected ESCs with esiRNA targeting Ctr9 and control esiRNA (Luc). Experiment Overall Design: 4 replicates of esiRNA tranfection controls (luciferase esiRNA) and 4 replicates of Ctr9 esiRNA tranfection samples

2008-10-21 | E-GEOD-12078 | biostudies-arrayexpress

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

2009-01-31 | GSE14654 | GEO

Ubiquitin-dependent transfer of PAF1c from MYC onto RNA Polymerase controls double-strand break repair at active promoters

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.

2021-02-15 | PXD023242 | Pride

RNA Polymerase II-associated factor 1 regulates the release and phosphorylation of paused RNA Polymerase II

Project description:Release of promoter-proximal paused RNA polymerase II (Pol II) during early elongation is a critical step in transcriptional regulation in metazoan cells. Paused Pol II release is thought to require the kinase activity of cyclin-dependent kinase 9 (CDK9) for the phosphorylation of DRB sensitivity-inducing factor, negative elongation factor, and C-terminal domain (CTD) serine-2 of Pol II. We found that Pol II-associated factor 1 (PAF1) is a critical regulator of paused Pol II release, that positive transcription elongation factor b (P-TEFb) directly regulates the initial recruitment of PAF1 complex (PAF1C) to genes, and that the subsequent recruitment of CDK12 is dependent on PAF1C. These findings reveal cooperativity among P-TEFb, PAF1C, and CDK12 in pausing release and Pol II CTD phosphorylation. Comparison of the chromatin occupancy of [1] PAF1, CDC73, LEO1, CTR9, total Pol II, and CTD serine 2-phosphorylated Pol II by ChIP-seq in THP1 cells; [2] PAF1, Pol II, Pol II (ser-5p), CDK12, and CDK9 by ChIP-seq in control and PAF1 knockdown cells; [3] LEO1 and Pol II by ChIP-seq in control and flavopiridol treated THP1 cells.

2015-12-11 | E-GEOD-62171 | biostudies-arrayexpress

Ctr9 knockdown in mouse ES cells

Project description:To monitor global transcript changes after Paf1C depletion we transfected ESCs with esiRNA targeting Ctr9 and control esiRNA (Luc).

2008-07-18 | GSE12078 | GEO

Ubiquitylation of MYC couples transcription elongation with double-strand break repair at active promoters (ChIPseq_TE_RRL)

2021-02-10 | GSE150209 | GEO

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