Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Interplay of host microbiota, genetic perturbations, and inflammation promote local development of intestinal neoplasms in mice

ABSTRACT: This SuperSeries is composed of the SubSeries listed below. Refer to individual Series

ORGANISM(S): Mus musculus

SUBMITTER: Gerold Bongers

PROVIDER: E-GEOD-47736 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Project description:The preferential localization of some neoplasms, such as serrated polyps, in specific areas of the intestine suggests that non-genetic factors may be important for their development. To test this hypothesis, we took advantage of transgenic mice that expressed HB-EGF throughout the intestine, but develop serrated polyps only in the cecum. Here we show that a host-specific microbiome was associated with serrated polyps, and that alterations of the microbiota induced by antibiotic treatment or by embryo-transfer rederivation markedly inhibited the formation of serrated polyps in the cecum. Mechanistically, development of serrated polyps was associated with a local decrease in epithelial barrier-function, bacterial invasion, production of antimicrobials, and increased expression of several inflammatory factors such as IL-17, Cxcl2, Tnf-Œ±, and IL-1. Increased number of neutrophils were found within the serrated polyps, and their depletion significantly reduced polyp growth. Together these results indicate that non-genetic factors contribute to the development of serrated polyps and suggest that the development of these intestinal neoplasms in the cecum is driven by the interplay between genetic changes in the host, an inflammatory response, and a host-specific microbiota. SUMMARY: Serrated polyps (SP) are a heterogeneous group of neoplasms found in particular areas of the gut. To define the factors contributing to their specific localization, we analyzed a strain of transgenic mice that carry a genetic alteration throughout the intestinal epithelium, but only develop SP in the cecum. Transcriptome and immunostaining analyses showed increased expression of antimicrobial genes, inflammatory factors, and the presence of bacteria within SP. Alteration of the cecal microbiota by antibiotic treatment or by embryo-transfer rederivation dramatically reduced SP incidence. Microbiome analysis implicated a limited set of bacteria in the development of SP. Together, these results point to a crucial role for the microbiota in the localized development of SP in a genetically susceptible host. We obtained serrated polyp (SP) and surrounding normal (NM) tissue from the ceca of three affected mice (paired design) and assessed expression differences by RNA-Seq.

Project description:In Rspondin-based three-dimensional cultures, Lgr5 stem cells from multiple organs form ever-expanding epithelial organoids that retain their tissue identity. Here we report the establishment of tumor organoid cultures from 20 consecutive colorectal carcinoma (CRC) patients. For most, organoids were also generated from adjacent normal tissue. Organoids closely resemble the original tumor. The spectrum of genetic changes within the 'living biobank' agrees well with previous large-scale mutational analyses of CRC. Gene expression analysis indicates that the major CRC molecular subtypes are represented. Tumor organoids are amenable to high-throughput drug screens allowing detection of gene-drug associations. As an example, a single organoid culture was exquisitely sensitive to Wnt secretion (porcupine) inhibitors and carried a mutation in the negative Wnt feedback regulator RNF43, rather than in APC. Organoid technology may fill the gap between cancer genetics and patient trials, complement cell line- and xenograft-based drug studies and allow personalized therapy design. Self-renewal of the intestinal epithelium is driven by Lgr5 stem cells located in crypts. We have recently developed a long-term culture system that maintains basic crypt physiology. Wnt signals are required for the maintenance of active crypt stem cells. Indeed, the Wnt agonist R-spondin1 induces dramatic crypt hyperplasia in vivo. R-spondin-1 is the ligand for Lgr5. Epidermal growth factor (EGF) signaling is associated with intestinal proliferation, while transgenic expression of Noggin induces a dramatic increase in crypt numbers. The combination of R-spondin-1, EGF, and Noggin in Matrigel sustains ever-expanding small intestinal organoids, which display all hallmarks of the original tissue in terms of architecture, cell type composition, and self-renewal dynamics. We adapted the culture condition for long-term expansion of human colonic epithelium and primary colonic adenocarcinoma, by adding nicotinamide, A83-01 (Alk inhibitor), Prostaglandin E2 and the p38 inhibitor SB202190. Of note, a two-dimensional culture method for cells from normal and malignant primary tissue has been described by Schlegel and colleagues. Here, we explore organoid technology to routinely establish and phenotypically annotate ‘paired organoids’ derived from adjacent tumor and healthy epithelium from CRC patients.

Project description:modENCODE_submission_3168 Although C. elegans was the first multicellular organism with a completely sequenced genome, how this genome is arranged within the nucleus is not known. By chromatin immunoprecipitation of the nuclear transmembrane protein LEM-2, we determined the regions of the C. elegans genome associated with the nuclear membrane. We found that large regions of several megabases on the left and right arms of each autosome were associated with the nuclear membrane. The center of each autosome was free of such interactions, suggesting these regions are largely looped out from the nuclear membrane. The X chromosome, unlike the autosomes, was associated with the nuclear membrane only at its left end. At a finer scale, these large membrane-associated domains consist of smaller subdomains of LEM-2 associations. These subdomains are characterized by a high density of repetitive sequences, a low density of genes, and high levels of H3K27 trimethylation. The subdomains were punctuated by gaps containing genes with high transcriptional activity. Finally, we found that a chromosome arm translocated to the center of a chromosome retained its association with the nuclear membrane, although there was a decrease of association up to 400 kb from the fusion point. This indicates that local chromatin properties are the main determinant of interaction with the nuclear membrane, but the degree of association can be modulated by position along the chromosome. Our data provide the foundation for a model of the spatial arrangement of C.elegans chromosomes within the nucleus. Supplemental materials are available online at http://www.genome.org . Microarray and high-throughput sequencing data are available online at modENCODE Data Coordinating Center website, http://206.108.121.120/submit/public/list . These dataset are designed to confirm ChIP-chip experiments. The three experiments listed consist of: (1) LEM-2 ChIP-seq (seq-SDQ3891_LEM2_N2_MXemb_1_A_EE8_KI021); (2) control IgG ChIP-seq (seq-AB46540_NIgG_N2_MXemb_2_A_EE1432); and (3)Input-seq (seq-NA_N2_MXemb_3_A_EE1432) For data usage terms and conditions, please refer to http://www.genome.gov/27528022 and http://www.genome.gov/Pages/Research/ENCODE/ENCODEDataReleasePolicyFinal2008.pdf

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Interplay of host microbiota, genetic perturbations, and inflammation promote local development of intestinal neoplasms in mice

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