FOXO3 Deficiency in Neutrophils Drives Colonic Inflammation and Tumorigenesis
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA979263 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR24820318_1.fastq.gz | Fastqsanger.gz | |||
| SRR24820318_2.fastq.gz | Fastqsanger.gz | |||
| SRR24820319_1.fastq.gz | Fastqsanger.gz | |||
| SRR24820319_2.fastq.gz | Fastqsanger.gz | |||
| SRR24820320_1.fastq.gz | Fastqsanger.gz |
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Project description:Inflammatory bowel disease (IBD), characterized by infiltration of polymorphonuclear neutrophils (PMNs), increases the risk of colon cancer. PMN activation corresponds to accumulation of their intracellular Lipid Droplets (LDs). As increased LDs are negatively regulated by transcription factor FOXO3, our aim is to determine the significance of this regulatory network in PMN-mediated IBD and tumorigenesis. Affected tissue of IBD and colon cancer patients, colonic and infiltrated immune cells, have increased LDs’ coat protein, PLIN2. Mouse peritoneal PMNs with increased LDs and FOXO3 deficiency have elevated transmigratory activity. Transcriptomic analysis of these FOXO3-deficient PMNs showed differentially expressed genes (DEGs; FDR < 0.05) involved in metabolism, inflammation, and tumorigenesis. Upstream regulators of these DEGs, similar to colonic inflammation and dysplasia in mice, were linked to IBD and human colon cancer. Additionally, a transcriptional signature representing FOXO3-deficient PMNs (PMN-FOXO3389) separated transcriptomes of affected tissue in IBD (p=0.00018) and colon cancer (p=0.0037) from control. PMN-FOXO3389 predicted colon cancer invasion (lymphovascular p= 0.015; vascular p= 0.046; perineural p=0.03), and poor survival. Validated DEGs from PMN-FOXO3389 (P2RX1, MGLL, MCAM, CDKN1A, RALBP1, CCPG1, PLA2G7) are involved in metabolism, inflammation, and tumorigenesis (p<0.05). These findings highlight the significance of LDs and FOXO3-mediated PMN functions that promote colonic pathobiology.
2023-06-05 | GSE234072 | GEO
Project description:Obesity, characterized by augmented inflammation and tumorigenesis, is linked to genetic predispositions, such as FOXO3 polymorphisms. As obesity is associated with aberrant macrophages infiltrating different tissue including the colon, we aimed to identify FOXO3-dependent transcriptomic changes in macrophages that drive obesity-mediated colonic inflammation and tumorigenesis. We found that in mouse colons, high-fat-diet-(HFD)-obesity led to diminished FOXO3 levels and increased macrophages. Transcriptomic analysis of mouse peritoneal FOXO3-deficient macrophages showed significant differentially expressed genes (DEGs; FDR<0.05) similar to HFD-obese colon. These DEGs related pathways, linked to mouse colonic inflammation and tumorigenesis, were similar to those in inflammatory bowel disease (IBD) and human colon cancer. Additionally, we identified a specific transcriptional signature for the macrophage-FOXO3 axis (MAC-FOXO382), which separated the transcriptome of affected tissue from control in both IBD (p=5.2E-08) and colon cancer (p=1.9E-11), revealing its significance in human colonic pathobiologies. Further, we identified (heatmap) and validated (qPCR) DEGs specific to FOXO3-deficient macrophages with established roles both in IBD and colon cancer (IL-1B, CXCR2, S100A8, S100A9, and TREM1) and those with unexamined roles in these colonic pathobiologies (STRA6, SERPINH1, LAMB1, NFE2L3, OLR1, DNAJC28 and VSIG10). These findings establish an important understanding of how HFD-obesity and related metabolites promote colonic pathobiologies.
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Project description:FOXO3 expression in macrophages is lowered by high fat diet and regulates colonic inflammation and tumorigenesis
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Project description:Mature myeloid cells play a crucial role in the pathogenesis of Crohn disease (CD) but the molecular players that regulate their functions in CD are not fully characterized. Here we show that Trim33 mRNA level is decreased in CD patient’s blood monocytes and characterize TRIM33 functions in monocytes during dextran sulfate sodium (DSS) induced colitis. Mice deleted for trim33 only in mature myeloid cells (Trim33-/- mice) display an impaired resolution of colonic inflammation. This deficiency is associated with an increased number of blood and colon neutrophils and monocytes and a decreased number of colonic macrophages. In accordance, Trim33-/- monocytes are less competent that wild type monocytes for recruitment and differentiation into macrophages at the inflammatory site. Furthermore, during resolution of DSS-induced colitis, Trim33-/- colonic macrophages display an impaired M1/M2 switch and express a low level of membrane bound TNFα known to regulate resolution of inflammation. Altogether, these results show an important role of TRIM33 in monocytes/macrophages during the resolution of DSS-induced colonic inflammation and pinpoint TRIM33 as a novel Crohn disease biomarker and as a potential therapeutic target.
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Project description:FOXO transcription factors are key players in diverse cellular responses affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into mechanisms of FOXO regulated gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II (RNAPII) changes shows FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNAPII ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to and activates enhancers as shown by the presence of and changes in enhancer-specific histone modifications and RNAPII occupancy. In addition, FOXO3-mediated enhancer regulation correlates with regulation of adjacent genes and existence of chromatin loops between FOXO3 bound enhancers and regulated genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture.
2012-12-30 | GSE36835 | GEO
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Project description:FOXO transcription factors are key players in diverse cellular responses affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into mechanisms of FOXO regulated gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II (RNAPII) changes shows FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNAPII ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to and activates enhancers as shown by the presence of and changes in enhancer-specific histone modifications and RNAPII occupancy. In addition, FOXO3-mediated enhancer regulation correlates with regulation of adjacent genes and existence of chromatin loops between FOXO3 bound enhancers and regulated genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture. seven 4C view point were analyzed on DLD1 colon carcinoma cells containing 4OH-Tamoxifen inducible FOXO3A3-ER (DL23 cells, Kops et al., 2002, Mol Cell Biol), to investigate 3D topology around FOXO3 bound regions and FOXO3 regulated genes before and 4 hours after addition of tamoxifen. 4C procedure, as published before (Splinter et al., 2001, Genes Dev). Cells are cross linked using 1% formaldehyde for 10min at room temperature, nuclei are isolated, after which chromatin is digested with DpnII and subsequently ligated under diluted conditions. After reversal of the cross links the DNA is purified and treated with the second restriction enzyme treatment (Csp). After a second re-ligation step the sample is purified and ligated fragments are analyzed by inverse PCR.
2012-12-30 | E-GEOD-36835 | biostudies-arrayexpress
Project description:We have analysed transcriptomic changes of colonic macrophages due to TGFβR1 deficiency.
2017-02-28 | GSE84765 | GEO
Project description:FOXO transcription factors are key players in diverse cellular processes affecting tumorigenesis, stem cell maintenance and lifespan. To gain insight into mechanisms of FOXO regulated target gene expression, we studied genome-wide effects of FOXO3 activation. Profiling RNA polymerase II changes shows FOXO3 regulates gene expression through transcription initiation. Correlative analysis of FOXO3 and RNA polymerase II ChIP-seq profiles demonstrates FOXO3 to act as a transcriptional activator. Furthermore, this analysis reveals a significant part of FOXO3 gene regulation proceeds through enhancer regions. FOXO3 binds to pre-existing enhancers and further activates these enhancers as shown by changes in histone acetylation and RNA polymerase II recruitment. In addition, FOXO3-mediated enhancer activation correlates with regulation of adjacent genes and pre-existence of chromatin loops between FOXO3 bound enhancers and target genes. Combined, our data elucidate how FOXOs regulate gene transcription and provide insight into mechanisms by which FOXOs can induce different gene expression programs depending on chromatin architecture. Paper with published gene expression: PMID 22139133. Examination of FOXO3 binding and changes in RNAPII occupancy (0, 4, 24 hours after induction) in colorectal cell line
2012-11-15 | E-GEOD-35486 | biostudies-arrayexpress
Project description:Forkhead Box O (FOXO) transcription factors are versatile players in diverse cellular processes, affecting tumorigenesis, metabolism, stem cell maintenance and lifespan. To understand the transcriptional output of FOXO3 activation, we investigate features that define the subset of enhancer binding events that actually contribute to gene regulation. We show FOXO3 transcriptional output is determined by the amount of bound FOXO3, which in turn is determined by motif presence, pre-existing enhancer activity and accessibility. In this manner, FOXO3 amplifies pre-existing levels of activity marks and potentiates enhancer RNA transcription. We conclude that not only enhancer presence and sequence content, but also the pre-existing activity dictates FOXO3 binding and transcriptional output. Considering the flexible and cell type specific nature of regulatory regions and their activity, our observations provide a novel explanation for the diversity in FOXO transcriptional programs and introduce chromatin context as a new player in the regulation of FOXO activity in ageing and disease. Examination of histone modifications and transcriptome changes upon FOXO activation
2013-11-26 | E-GEOD-50243 | biostudies-arrayexpress