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2.
Nat Commun ; 14(1): 497, 2023 01 30.
Article in English | MEDLINE | ID: mdl-36717563

ABSTRACT

Epithelial-mesenchymal signaling in the gastrointestinal system is vital in establishing regional identity during organogenesis and maintaining adult stem cell homeostasis. Although recent work has demonstrated that Wnt ligands expressed by mesenchymal cells are required during gastrointestinal development and stem cell homeostasis, epigenetic mechanisms driving spatiotemporal control of crosstalk remain unknown. Here, we demonstrate that gastrointestinal mesenchymal cells control epithelial fate and function through Polycomb Repressive Complex 2-mediated chromatin bivalency. We find that while key lineage-determining genes possess tissue-specific chromatin accessibility, Polycomb Repressive Complex 2 controls Wnt expression in mesenchymal cells without altering accessibility. We show that reduction of mesenchymal Wnt secretion rescues gastrointestinal fate and proliferation defects caused by Polycomb Repressive Complex 2 loss. We demonstrate that mesenchymal Polycomb Repressive Complex 2 also regulates niche signals to maintain stem cell function in the adult intestine. Our results highlight a broadly permissive chromatin architecture underlying regionalization in mesenchymal cells, then demonstrate further how chromatin architecture in niches can influence the fate and function of neighboring cells.


Subject(s)
Gastrointestinal Tract , Intestines , Gastrointestinal Tract/metabolism , Polycomb Repressive Complex 2/metabolism , Chromatin/genetics , Epigenesis, Genetic , Cell Differentiation/genetics
3.
Exp Mol Med ; 55(1): 22-31, 2023 01.
Article in English | MEDLINE | ID: mdl-36653445

ABSTRACT

Gastric cancer (GC) is one of the most common and deadly cancers in the world. It is a multifactorial disease highly influenced by environmental factors, which include radiation, smoking, diet, and infectious pathogens. Accumulating evidence suggests that epigenetic regulators are frequently altered in GC, playing critical roles in gastric tumorigenesis. Epigenetic regulation involves DNA methylation, histone modification, and noncoding RNAs. While it is known that environmental factors cause widespread alterations in DNA methylation, promoting carcinogenesis, the chromatin- and noncoding RNA-mediated mechanisms of gastric tumorigenesis are still poorly understood. In this review, we focus on discussing recent discoveries addressing the roles of histone modifiers and noncoding RNAs and the mechanisms of their interactions in gastric tumorigenesis. A better understanding of epigenetic regulation would likely facilitate the development of novel therapeutic approaches targeting specific epigenetic regulators in GC.


Subject(s)
RNA, Long Noncoding , Stomach Neoplasms , Humans , Chromatin/genetics , Epigenesis, Genetic , DNA Methylation , RNA, Untranslated/genetics , RNA, Untranslated/metabolism , Carcinogenesis/genetics , Stomach Neoplasms/genetics , Cell Transformation, Neoplastic/genetics , Gene Expression Regulation, Neoplastic
4.
J Exp Med ; 218(6)2021 06 07.
Article in English | MEDLINE | ID: mdl-33822841

ABSTRACT

Gastric cancer (GC) is one of the most common deadly cancers in the world. Although patient genomic data have identified AT-rich interaction domain 1A (ARID1A), a key chromatin remodeling complex subunit, as the second most frequently mutated gene after TP53, its in vivo role and relationship to TP53 in gastric tumorigenesis remains unclear. Establishing a novel mouse model that reflects the ARID1A heterozygous mutations found in the majority of human GC cases, we demonstrated that Arid1a heterozygosity facilitates tumor progression through a global loss of enhancers and subsequent suppression of the p53 and apoptosis pathways. Moreover, mouse genetic and single-cell analyses demonstrated that the homozygous deletion of Arid1a confers a competitive disadvantage through the activation of the p53 pathway, highlighting its distinct dosage-dependent roles. Using this unique vulnerability of Arid1a mutated GC cells, our combined treatment with the epigenetic inhibitor, TP064, and the p53 agonist, Nutlin-3, inhibited growth of Arid1a heterozygous tumor organoids, providing a novel therapeutic option for GC.


Subject(s)
Carcinogenesis/genetics , Carcinogenesis/pathology , DNA-Binding Proteins/genetics , Stomach Neoplasms/genetics , Stomach Neoplasms/pathology , Stomach/pathology , Transcription Factors/genetics , Animals , Cell Proliferation/genetics , Gene Expression Regulation, Neoplastic/genetics , Homozygote , Mice , Sequence Deletion/genetics , Signal Transduction/genetics , Tumor Suppressor Protein p53/genetics
5.
Cancer Metab ; 9(1): 13, 2021 Mar 24.
Article in English | MEDLINE | ID: mdl-33762012

ABSTRACT

BACKGROUND: Majority of chondrosarcomas are associated with a number of genetic alterations, including somatic mutations in isocitrate dehydrogenase 1 (IDH1) and IDH2 genes, but the downstream effects of these mutated enzymes on cellular metabolism and tumor energetics are unknown. As IDH mutations are likely to be involved in malignant transformation of chondrosarcomas, we aimed to exploit metabolomic changes in IDH mutant and non-mutant chondrosarcomas. METHODS: Here, we profiled over 69 metabolites in 17 patient-derived xenografts by targeted mass spectrometry to determine if metabolomic differences exist in mutant IDH1, mutant IDH2, and non-mutant chondrosarcomas. UMAP (Uniform Manifold Approximation and Projection) analysis was performed on our dataset to examine potential similarities that may exist between each chondrosarcoma based on genotype. RESULTS: UMAP revealed that mutant IDH chondrosarcomas possess a distinct metabolic profile compared with non-mutant chondrosarcomas. More specifically, our targeted metabolomics study revealed large-scale differences in organic acid intermediates of the tricarboxylic acid (TCA) cycle, amino acids, and specific acylcarnitines in chondrosarcomas. Lactate and late TCA cycle intermediates were elevated in mutant IDH chondrosarcomas, suggestive of increased glycolytic metabolism and possible anaplerotic influx to the TCA cycle. A broad elevation of amino acids was found in mutant IDH chondrosarcomas. A few acylcarnitines of varying carbon chain lengths were also elevated in mutant IDH chondrosarcomas, but with minimal clustering in accordance with tumor genotype. Analysis of previously published gene expression profiling revealed increased expression of several metabolism genes in mutant IDH chondrosarcomas, which also correlated to patient survival. CONCLUSIONS: Overall, our findings suggest that IDH mutations induce global metabolic changes in chondrosarcomas and shed light on deranged metabolic pathways.

6.
Trends Cell Biol ; 31(3): 152-165, 2021 03.
Article in English | MEDLINE | ID: mdl-33349527

ABSTRACT

Mesenchymal-epithelial crosstalk plays a crucial role in organ development and stem cell function. However, the identity of the mesenchymal cells involved in this exchange was unclear. Recent significant advances in single-cell transcriptomics have defined the heterogeneity of these mesenchymal niches. By combining multiomic profiling, animal models, and organoid culture, new studies have not only demonstrated the roles of diverse mesenchymal cell populations but also defined the mechanisms underlying their regulation of niche signals. Focusing on several digestive organs, we describe how similar and diverse mesenchymal cell populations promote organ development and maintain proper stem cell activity, and how the heterogeneity of mesenchymal niches is altered in digestive diseases such as inflammation and cancer.


Subject(s)
Mesenchymal Stem Cells , Neoplasms , Animals , Homeostasis , Inflammation , Neoplasms/genetics , Stem Cells
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