CDX1 and CDX2 suppress colon cancer stemness by inhibiting b-catenin-facilitated formation of Pol II–DSIF–PAF1C complex
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ABSTRACT:
PROVIDER: PRJNA1212081 | ENA |
REPOSITORIES: ENA
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Project description:Homeobox transcription factors CDX1 and CDX2 (hereafter, CDX1/2) play key roles in determining the identity of intestinal epithelial cells and regulating their stem cell functions. However, the role of CDX1/2 in regulating colon cancer stemness and the underlying mechanism have been unclear. Here, we show that the complete loss of Cdx1 or concurrent loss of Cdx1/2 increased the stemness and malignancy of intestinal tumors. Consistently, CDX1/2 reduced the expression levels of cancer stemness-related genes including LGR5. CDX1/2 bound to the downstream region of the LGR5 transcription start site (TSS), where b-catenin also binds. Despite increased H3 acetylation and an open chromatin structure, CDX1/2 reduced the levels of DRB sensitivity-inducing factor (DSIF), RNA polymerase II-associated factor 1 (PAF1), and Pol II complexes around the LGR5 TSS. Through a homeodomain, CDX1/2 cooperatively inhibited the b-catenin-promoted formation of the active Pol II complex containing DSIF and PAF1 complexes by preventing interactions between b-catenin and these complexes, in an additive manner. Our findings suggest that CDX1/2 cooperatively suppress colonic tumorigenesis and cancer stemness by antagonizing b-catenin through the DSIF and PAF1 complexes. Additionally, DSIF and PAF1 complexes act as transcriptional platforms that integrate both tumor-suppressive and oncogenic signals into the expression of genes that controls colonic tumorigenesis.
2025-04-29 | GSE287500 | GEO
Project description:CDX1 and CDX2 suppress colon cancer stemness by inhibiting beta-catenin-facilitated formation of Pol II-DSIF-PAF1C complex
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Project description:Gene expression profiles of DLD1-TetOff cells comparing control TetOff cells with TetOff cells expressing Cdx1 or Cdx2 for 12 and 24 hours.
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Project description:We conditionally inactivated mouse Cdx2, a dominant regulator of intestinal development, and mapped its genome occupancy in adult intestinal villi. Although homeotic transformation, observed in Cdx2-null embryos, was absent in mutant adults, gene expression and cell morphology were vitally compromised. Lethality was accelerated in mice lacking both Cdx2 and its homolog Cdx1, with exaggeration of defects in crypt cell replication and enterocyte differentiation. Cdx2 occupancy correlated with hundreds of transcripts that fell but not with equal numbers that rose with Cdx loss, indicating a predominantly activating role at intestinal cis-regulatory regions. Integrated consideration of a mutant phenotype and cistrome hence reveals the continued and distinct requirement in adults of a master developmental regulator that activates tissue-specific genes. Cdx2 ChIP-seq in mouse villus, and gene expression data from Cdx1, Cdx2 and compound knockout mouse intestine
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Project description:We have found that Cdx1 can promote ectopic gene expression in thymic epithelial cells. We isolated MHCIIhi CD80hi medullary thymic epithelial cells from Cdx1-/- and Cdx1+/+ and compare gene expression between the two subsets, also in the context of Cdx1-mediated changes in intestinal epithelial cells.
2018-05-01 | GSE68880 | GEO
Project description:In vitro studies identified various factors including P-TEFb, SEC, SPT6, PAF1, DSIF, and NELF functioning at different stages of transcription elongation driven by RNA polymerase II (RNA Pol II). What remains unclear is how these factors cooperatively regulate pause/release and productive elongation in the context of living cells. Using an acute 5 protein-depletion approach, prominent release and a subsequent increase in mature transcripts, whereas long genes fail to yield mature transcripts due to a loss of processivity. Mechanistically, loss of SPT6 results in loss of PAF1 complex (PAF1C) from RNA Pol II, leading to NELF-bound RNA Pol II release into the gene bodies. Furthermore, SPT6 and/or PAF1 depletion impairs heat shock-induced pausing, pointing to a role for SPT6 in regulating RNA Pol II pause/release through the recruitment of PAF1C during the early elongation.
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Project description:The PAF complex (Paf1C) has been shown to regulate chromatin modifications, gene transcription, and PolII elongation. Here, we provide the first genome-wide analysis of chromatin occupancy by the entire PAF complex in mammalian cells. We show that Paf1C is recruited not only to promoters and gene bodies, but also to regions downstream of cleavage/polyadenylation (pA) sites at 3â ends, a profile that sharply contrasted with the yeast complex. Remarkably, our studies identified novel, subunit-specific links between Paf1C and regulation of alternative cleavage and polyadenylation (APA) and upstream antisense transcription. Moreover, we found that depletion of Paf1C subunits also resulted in the accumulation of RNA polymerase II (PolII) over gene bodies, which coincided with APA. Depletion of specific Paf1C subunits leads to global loss of histone H2B ubiquitylation, but surprisingly, there is little impact of Paf1C depletion on other histone modifications, including the tri-methylation of histone H3 on lysines 4 and 36 (H3K4me3 and H3K36me3), previously associated with this complex. Our results provide surprising differences with yeast, while unifying observations that link Paf1C with PolII elongation and RNA processing, and suggest that Paf1C could play a role in protecting transcripts from premature cleavage by preventing PolII accumulation at TSS-proximal pA sites. ChIP-seq, RNA-seq and 3'READS of Paf1C factors in mouse C2C12 myoblast cells
2016-01-15 | E-GEOD-72574 | biostudies-arrayexpress
Project description:We conditionally inactivated mouse Cdx2, a dominant regulator of intestinal development, and mapped its genome occupancy in adult intestinal villi. Although homeotic transformation, observed in Cdx2-null embryos, was absent in mutant adults, gene expression and cell morphology were vitally compromised. Lethality was accelerated in mice lacking both Cdx2 and its homolog Cdx1, with exaggeration of defects in crypt cell replication and enterocyte differentiation. Cdx2 occupancy correlated with hundreds of transcripts that fell but not with equal numbers that rose with Cdx loss, indicating a predominantly activating role at intestinal cis-regulatory regions. Integrated consideration of a mutant phenotype and cistrome hence reveals the continued and distinct requirement in adults of a master developmental regulator that activates tissue-specific genes.
2011-04-13 | GSE24633 | GEO
Project description:This study is to identify downstream targets of homeobox gene CDX1. The study assayed the expression of 2 pairs of stably transfected colorectal cancer cell lines: The CDX1 nonexpressing CRC cell line HCT116 was stably transfected with either CDX1 cDNA in the pRC/CMV expression vector (HCT116-CDX1) or with vector control (HCT116-Vec). The CDX1-expressing CRC cell line LS174T was similarly transfected with either a pSilencer vector containing a short sequence of CDX1 siRNA (LS174T-siRNA) , or a pSilencer vector containing a scrambled siRNA sequence as a control (LS174T-Vec).
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Project description:In vitro studies identified various factors including P-TEFb, SEC, SPT6, PAF1, DSIF, and NELF functioning at different stages of transcription elongation driven by RNA polymerase II (RNA Pol II). What remains unclear is how these factors cooperatively regulate pause/release and productive elongation in the context of living cells. Using an acute protein-depletion approach, we report that SPT6 depletion results in release of paused RNA Pol II. Short genes demonstrate a prominent release and a subsequent increase in mature transcripts, whereas long genes fail to yield mature transcripts due to a loss of processivity. Unexpectedly, the recruitment of PAF1 complex (PAF1C) to RNA Pol II fails upon SPT6 depletion, leading to the release of NELF-bound RNA Pol II into the gene bodies. Furthermore, SPT6 depletion impairs heat shock-induced pausing, pointing to a role for SPT6 in regulating RNA Pol II pause-release through PAF1C recruitment and NELF removal during the early elongation.
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