Differentiation-Specific Histone Modifications Reveal Dynamic Chromatin Interactions and Partners for the Intestinal Transcription Factor CDX2

Verzi, Michael P.; Shin, Hyunjin; He, H. Hansen; Sulahian, Rita; Meyer, Clifford A.; Montgomery, Robert K.; Fleet, James C.; Brown, Myles; Liu, X. Shirley; Shivdasani, Ramesh A.

doi:10.1016/j.devcel.2014.12.006

Cited by 26 publications

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“…For NPC1L1 , recent publications of the Encyclopedia of DNA Elements (ENCODE) Consortium identifi ed a region extremely close to rs17725246 as being hypersensitive to DNase I enzymatic activity and also being involved in chromatin structure and histone modifications (45)(46)(47). In addition, separate reports using chromatin immunoprecipitation sequencing have reported the genomic 5 ′ untranslated region around rs17725246 to bind the proteins GATA2 ( 48 ) and CDX2 ( 49 ). These results in conjunction with the eQTL study fi ndings of enrichment at gene starts and ends may implicate altered gene expression as a possible explanation for our fi ndings of SNP-by-dietary cholesterol interactions for APOB and NPC1L1 .…”

Section: Discussionsupporting

confidence: 76%

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Kim

Burt

Ranchalis

et al. 2013

Journal of Lipid Research

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This article is available online at http://www.jlr.org Supplementary key words dietary cholesterol • total cholesterol • cardiovascular disease • Niemann-Pick C1-like 1 Cardiovascular disease (CVD), including coronary heart disease and carotid artery disease (CAAD), is the leading cause of death in developed countries, accounting for approximately one-third of all deaths in adults over age 35 ( 1 ). One of the key risk factors for CVD is hypercholesterolemia ( 2 ), with epidemiologic studies demonstrating a graded relationship between total plasma cholesterol and CVD risk ( 3 ). Levels of total cholesterol and other lipids and lipoproteins are both heritable and targets for pharmacologic and lifestyle interventions ( 4 ). One of the primary methods of lifestyle intervention to alter lipid levels is through dietary changes, such as decreasing total fat intake ( 5, 6 ).Genome-wide association studies (GWASs) have implicated numerous genetic loci for association with total cholesterol levels. A recent meta-analysis by Teslovich et al. ( 7 ) of over 100,000 individuals of European ancestry confi rmed numerous previous GWAS fi ndings and identifi ed novel variants and loci for prediction of total lipid phenotypes, including total cholesterol levels.While genetic evidence is accumulating for many of these loci, less is known about the specifi c mechanisms through which these genetic variants affect cholesterol levels. We hypothesized that one pathway through which these genetic variants could alter cholesterol homeostasis is through differential absorption or processing of dietary Abstract Cardiovascular disease (CVD) is the leading cause of death in developed countries. Plasma cholesterol level is a key risk factor in CVD pathogenesis. Genetic and dietary variation both infl uence plasma cholesterol; however, little is known about dietary interactions with genetic variants infl uencing the absorption and transport of dietary cholesterol . We sought to determine whether gut expressed variants predicting plasma cholesterol differentially affected the relationship between dietary and plasma cholesterol levels in 1,128 subjects (772/356 in the discovery/replication cohorts, respectively). Four single nucleotide polymorphisms (SNPs) within three genes ( APOB , CETP , and NPC1L1 ) were signifi cantly associated with plasma cholesterol in the discovery cohort. These were subsequently evaluated for geneby-environment (GxE) interactions with dietary cholesterol for the prediction of plasma cholesterol, with signifi cant fi ndings tested for replication. Novel GxE interactions were identifi ed and replicated for two variants: rs1042034, an APOB Ser4338Asn missense SNP and rs2072183 (in males only), a synonymous NPC1L1 SNP in linkage disequilibrium with SNPs 5 ′ of NPC1L1 . This study identifi es the presence of novel GxE and gender interactions implying that differential gut absorption is the basis for the variant associations with plasma cholesterol. These GxE interactions may account for part of the "missing heritability" no...

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Section: Discussionsupporting

confidence: 76%

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Kim

Burt

Ranchalis

et al. 2013

Journal of Lipid Research

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“…For example, the homeodomain protein CDX2, a critical regulator of intestinal homeostasis, plays an important role in intestinal cell proliferation by interacting with GATA6 at active chromatins 25 . Hepatocyte nuclear factor (HNF) family proteins also cooperate with GATA6 to regulate gene expression 36,37 .…”

Section: Discussionmentioning

confidence: 99%

“…GATA6 has also been reported to be involved in colorectal tumour invasion and in the conversion of Barrett metaplasia to adenocarcinoma 27,28 . Furthermore, GATA6 is known to be expressed in the proliferative crypt compartment of the small intestine, similar to Lgr5, although expression is found elsewhere as well 19,25 . We therefore focused our analyses on GATA6.…”

Section: Gata6 Upregulates Lgr5 Expression In Colorectal Cancer Cellsmentioning

confidence: 99%

“…GATA6 is a zinc finger transcription factor that is required for the proliferation, development and specific gene regulation of the gastrointestinal tract and other tissues [24][25][26] . GATA6 has also been reported to be involved in colorectal tumour invasion and in the conversion of Barrett metaplasia to adenocarcinoma 27,28 .…”

Section: Gata6 Upregulates Lgr5 Expression In Colorectal Cancer Cellsmentioning

confidence: 99%

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The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

et al. 2014

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Aberrant activation of Wnt signalling results in colorectal tumours. Lgr5 is specifically expressed in stem cells of the intestine and has an essential role in maintaining tissue homeostasis. Lgr5-positive stem cells are responsible for the intestinal adenoma initiated by mutations in adenomatous polyposis coli. Furthermore, Lgr5 interacts with R-spondins and thereby activates Wnt signalling. However, the function of Lgr5 in colorectal tumourigenesis is unclear. Here we show that LGR5 is required for the tumourigenicity of colorectal cancer cells. We show that the transcription factor GATA6 directly enhances the expression of LGR5. We further demonstrate that GATA6 is upregulated in colorectal cancer cells due to the downregulation of miR-363, which directly targets GATA6. Moreover, we show that overexpression of miR-363 suppresses the tumourigenicity of colorectal cancer cells. These results suggest that the miR-363-GATA6-LGR5 pathway is critical for colorectal tumourigenesis and would be a promising target for the treatment of colorectal cancer.

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“…It is of interest that this polymorphism lies inside a large CpG island consisting of 98 CpG sites [27] and near to the transcription factor-binding motifs corresponding to a critical regulator of the intestine, the CDX2 (caudal-type homeobox transcription factor 2, OMIM: 600297 [28];). A potential linkage of genetic with epigenetic changes thus should also be considered.…”

Section: Discussionmentioning

confidence: 99%

267 Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma

Kunická¹,

Procházka²,

Krus³

et al. 2015

European Journal of Cancer

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Differentiation-Specific Histone Modifications Reveal Dynamic Chromatin Interactions and Partners for the Intestinal Transcription Factor CDX2

Abstract: In the originally published version of this paper, the Supplemental Experimental Procedures contained an erroneous catalog number.

Cited by 26 publications

References 0 publications

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

Novel gene-by-environment interactions: APOB and NPC1L1 variants affect the relationship between dietary and total plasma cholesterol

The miR-363-GATA6-Lgr5 pathway is critical for colorectal tumourigenesis

267 Molecular profile of 5-fluorouracil pathway genes in colorectal carcinoma

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