Mthfd1 is a modifier of intestinal carcinogenesis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE15419 | GEO | 2010/03/20
SECONDARY ACCESSION(S): PRJNA115887
REPOSITORIES: GEO
Similar Datasets
Project description:The metabolic pathways that underlie the association between folate deficiency and increased risk for colorectal cancer (CRC) remain unclear. We have studied the effect of C1THF synthase (encoded by the Mthfd1 gene) and dietary folate and choline on intestinal tumor development in Apcmin/+ mice and azoxymethane (AOM)-induced colon cancer in mice. Mthfd1 deficiency did not alter tumor number or load in Apcmin/+ mice, but did result in a decreased incidence of colon tumors. Conversely, Mthfd1 deficiency increased tumor number 3.5-fold and tumor load 2-fold in AOM-treated mice. Here we tested colons isolated from wildtype and Mthfd1-deficient animals for alterations in gene expression. Keywords: genetic modification RNA was isolated from proximal colons of MTHFD heterozygous and wild-type mice raised on a control diet. Three colon samples were isolated from each genotype to provide biological replication.
2010-03-20 | E-GEOD-15419 | biostudies-arrayexpress
Project description:[Abstract] The R653Q variant in the synthetase domain of the folate-metabolizing enzyme MTHFD1 has been shown to increase risk for birth defects, but it does not affect risk for development of colorectal cancer (CRC). However, since we have shown that this variant reduces purine synthesis, the goal of this study was to determine whether it could affect tumor growth. Using our mouse model for MTHFD1-synthetase deficiency (Mthfd1S+/-), we induced tumor formation with azoxymethane (AOM) and dextran sodium sulfate (DSS) in male and female wild-type and Mthfd1S+/- mice. Tumor size was significantly smaller due to mutant genotype, particularly in males. Tumor size was increased in female mice compared with males, regardless of genotype. Tumor number was not influenced by genotype and was lower in females. Inflammation within tumors of male Mthfd1S+/- mice was lower than in wild-type mice. Proliferation of mouse embryonic fibroblasts from mutant lines was slower than that in wild-type fibroblasts. Gene expression analysis in tumor adjacent normal (preneoplastic) tissue identified several genes involved in proliferation (Fosb, Fos, Ptk6, Esr2, Atf3) or inflammation (Atf3, Saa1, TNF-α) that were downregulated in mutant male mice. Female mutants did not have changes in expression for those genes, nor in tumor inflammation levels, compared with wild-type, suggesting a different mechanism directing tumor growth in females. We suggest that restriction of purine synthesis and reduced expression of critical tumor-promoting genes leads to slower tumor growth in MTHFD1-synthetase deficiency. These findings may have implications for CRC tumor growth and prognosis in individuals with the R653Q variant.
2017-03-01 | GSE77931 | GEO
Project description:The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for functional regulators and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.
2019-04-04 | GSE105786 | GEO
Project description:Folate metabolism provides the building blocks of many classes of biomolecules including purine nucleotides, thymidylate, serine and methionine and is an important target of antimetabolite drugs. A central enzyme in the pathway is the trifunctional MTHFD1, that catalyzes the interconversion of folates by its formyltetrahydrofolate synthetase and methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase domains. Here, we employ large-scale chemical and genome-wide genetic screens to investigate the chemical and genetic dependencies caused by MTHFD1 loss-of-function and uncover a central role of the enzyme in balancing the response to extracellular adenosine. We show that adenosine is essential in MTHFD1KO cells, where adenine-containing compounds counter AMPK activation and increase proliferation in a PARP8, ATF7 and PML-dependent manner. In contrast, adenosine supplementation causes strong toxicity in patient-derived MTHFD1-derived cells harboring dehydrogenase/cyclohydrolase domain mutations. This response, mediated by replication stress and activation of the DNA damage response, is dependent on the nucleotide salvage enzyme HRPT1 and on NUDT5, an enzyme involved in nuclear ATP generation. Our findings suggest an evolutionary rationale for integrating three distinct enzymatic activities within the single MTHFD1 protein and propose the application of dehydrogenase/cyclohydrolase inhibitors in tumors located in an adenosine-rich microenvironment.
2023-04-26 | GSE201334 | GEO
Project description:The histone acetyl-reader BRD4 is an important regulator of chromatin structure and transcription, yet factors modulating its activity have remained elusive. Here we describe two complementary screens for genetic and physical interactors of BRD4, which converge on the folate pathway enzyme MTHFD1. We show that a fraction of MTHFD1 resides in the nucleus, where it is recruited to distinct genomic loci by direct interaction with BRD4. Inhibition of either BRD4 or MTHFD1 results in similar changes in nuclear metabolite composition and gene expression, and pharmacologic inhibitors of the two pathways synergize to impair cancer cell viability in vitro and in vivo. Our finding that MTHFD1 and other metabolic enzymes are chromatin-associated suggests a direct role for nuclear metabolism in the control of gene expression.
2019-04-04 | PXD012715 | Pride
Project description:In order to further investigate silencing mechanisms, we screened a mutagenized Arabidopsis thaliana population for expression of SDCpro-GFP, redundantly controlled by DNA methyltransferases DRM2 and CMT3. We identified the hypomorphic mutant mthfd1-1, carrying a mutation (R175Q) in the cytoplasmic bifunctional methylenetetrahydrofolate dehydrogenase/methenyltetrahydrofolate cyclohydrolase (MTHFD1). Accumulation of homocysteine and S-adenosylhomocysteine, genome-wide DNA hypomethylation, loss of H3K9me, and transposon derepression indicate that S-adenosylmethionine-dependent transmethylation is inhibited in mthfd1-1.
2016-06-07 | GSE77966 | GEO
Project description:MTHFD1 links folate metabolism to BRD4-mediated transcriptional regulation
| PRJNA415413 | ENA
Project description:This study identifies a novel mechanism linking IL-17A with colon tissue repair and tumor development. Abrogation of IL-17A signaling mice attenuated tissue repair of DSS-induced damage in colon epithelium and markedly reduced tumor development in AOM/DSS model of colitis-associated cancer. The goal of these studies is to identify genes associated with IL-17RC deficiency during AOM-DSS induced tumorigenesis
2017-09-25 | GSE104122 | GEO
Project description:The Runx1 transcription factor plays an important role in tissue homeostasis through its effects on stem/progenitor cell populations and differentiation. The effect of Runx1 on epithelial differentiation of the secretory cell lineage of the colon was recently demonstrated. This study aimed to examine the role of Runx1 in tumor development in epithelial cells of the gastrointestinal tract. Conditional knockout mice were generated that lacked Runx1 expression in epithelial cells of the GI tract. These mice were crossed onto the ApcMin background, sacrificed, and their intestinal tumor phenotypes were compared with ApcMin Runx1 wildtype control mice. Apc-wildtype Runx1-mutant mice were also examined for tumor development. Colons from Runx1 knockout and wildtype mice were used for genome-wide mRNA expression analyses followed by gene-specific quantitative RT-PCR of whole colon and colon epithelium, to identify Runx1 target genes. Runx1 deficiency in intestinal epithelial cells significantly enhanced tumorigenesis in ApcMin mice. Notably, epithelial Runx1 deficiency in Apc-wildtype mice was sufficient to cause tumor development. Absence of Runx1 was associated with global changes in expression of genes involved in inflammation and intestinal metabolism, and with gene sets indicative of metastatic phenotype and poor prognosis. Gene-specific analysis of Runx1 deficient colon epithelium revealed increased expression of genes linked to an expansion of the stem/progenitor cell population. These results identify Runx1 as a novel tumor suppressor gene for gastrointestinal tumors and support a role for Runx1 in maintaining the balance between the intestinal stem/progenitor cell population and epithelial differentiation of the GI tract. A total of 8 colon tissue RNA samples were analyzed, comprising 4 colon samples from wild-type mice (Villin-Cre negative / Runx1-floxed) and 4 colon samples from mice that lack epithelial expression of Runx1 (Villin-Cre positive/Runx1-floxed).
2012-09-13 | E-GEOD-34292 | biostudies-arrayexpress
Project description:To identify the precise molecular mechanisms that could contribute to the increase in colon carcinogenesis, microarray gene expression analysis was performed on colon RNA isolated from 5-week-old VhlF/F and VhlΔIE, VhlΔIE/Apcmin/+ and VhlF/F/Apcmin/+ mice. Hypoxia-inducible factor (HIF) is a key modulator of the transcriptional response to hypoxia and is increased in colon cancer. However, the role of HIF in colon carcinogenesis in vivo remains unclear. Intestinal epithelium-specific disruption of the von Hippel-Lindau tumor suppressor protein (VHL) resulted in constitutive HIF signaling, and increased HIF expression augmented colon tumorigenesis in the Apcmin/+ intestinal tumor model. Intestine-specific disruption of Vhl increased colon tumor multiplicity and progression from adenomas to carcinomas. These effects were ameliorated in mice with double disruption of Vhl and Hif-2α. Activation of HIF signaling resulted in increased cell survival in normal colon tissue, however tumor apoptosis was not affected. Interestingly, a robust activation of cyclin D1 was observed in tumors of Apcmin/+ mice in which HIF-2α was activated in the intestine. Consistent with this result, BrdU incorporation indicated that cellular proliferation was increased in colon tumors following HIF activation. Further analysis demonstrated that dysregulation of the intestinal iron absorption transporter divalent metal transporter-1 (DMT-1) was a critical event in HIF-2α-mediated colon carcinogenesis. These data provide a mechanistic basis for the widely reported link between iron accumulation and colon cancer risk. Together, our findings demonstrate that a chronic increase in HIF-2α in the colon initiates pro-tumorigenic signaling which may have important implications in developing preventive and therapeutic strategies for colon cancer. Global gene expression profiling in colon RNAs isolated from 5-week-old VhlF/F (n=4, Shah 001), VhlF/F/Apcmin/+(n=3, Shah 003), VhlΔIE (n=3, Shah 002) and VhlΔIE/Apcmin/+ mice (n=5, Shah 004).
2012-03-07 | E-GEOD-36091 | biostudies-arrayexpress