Barrett's metaplasia: molecular mechanisms and nutritional influences

2010 ◽  
Vol 38 (2) ◽  
pp. 313-319 ◽  
Author(s):  
Jonathan M.W. Slack ◽  
Benjamin J. Colleypriest ◽  
Jonathan M. Quinlan ◽  
Wei-Yuan Yu ◽  
Mark J. Farrant ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Adult Life ◽  
Tissue Type ◽  
Stem Cell Population ◽  
Increased Risk ◽  
The Future ◽  
Barrett's Metaplasia ◽  
Barrett’S Metaplasia

Barrett's metaplasia is discussed in the context of a general theory for the formation of metaplasias based on developmental biology. The phenotype of a particular tissue type becomes established during embryonic development by the expression of a specific set of transcription factors. If this combination becomes altered, then the tissue type can be altered. Such events may occur by mutation or by environmental effects on gene expression, normally within the stem cell population of the tissue. A macroscopic patch of metaplastic tissue will arise only if the new gene activity state is self-sustaining in the absence of its original causes, and if the new tissue type can outgrow the parent tissue type. An important candidate gene for the causation of Barrett's metaplasia is Cdx2 (Caudal-type homeobox 2). In normal development, this is expressed in the future intestine, but not the future foregut. Mouse knockout studies have shown that it is needed for intestinal development, and that its loss from adult intestine can lead to squamous transformations. It is also expressed in Barrett's metaplasia and can be activated in oesophageal cell cultures by treatment with bile acids. We have investigated the ability of Cdx2 to bring about intestinal transformations in oesophageal epithelium. Our results show that Cdx2 can activate a programme of intestinal gene expression when overexpressed in HET-1A cells, or in fetal epithelium, but not in the adult epithelium. This suggests that Cdx2, although necessary for formation of intestinal tissue, is not sufficient to provoke Barrett's metaplasia in adult life and that overexpression of additional transcription factors is necessary. In terms of diet and nutrition, there is a known association of Barrett's metaplasia with obesity. This may work through an increased risk of gastro-oesophageal reflux. Acid and bile are known to activate Cdx2 expression in oesophageal cells. It may also increase circulating levels of TNFα (tumour necrosis factor α), which activates Cdx2. In addition, there may be effects of diet on the composition of the bile.

The role of Cdx2 in Barrett's metaplasia

2010 ◽  
Vol 38 (2) ◽  
pp. 364-369 ◽  
Author(s):  
Benjamin J. Colleypriest ◽  
J. Mark Farrant ◽  
Jonathan M.W. Slack ◽  
David Tosh
Keyword(s):  
Molecular Mechanisms ◽  
Oesophageal Adenocarcinoma ◽  
Tissue Type ◽  
Conditional Deletion ◽  
Dismal Prognosis ◽  
Barrett's Metaplasia ◽  
Rising Incidence ◽  
Barrett’S Metaplasia ◽  
Small And Large Intestine

Metaplasia (or transdifferentiation) is defined as the transformation of one tissue type to another. Clues to the molecular mechanisms that control the development of metaplasia are implied from knowledge of the transcription factors that specify tissue identity during normal embryonic development. Barrett's metaplasia describes the development of a columnar/intestinal phenotype in the squamous oesophageal epithelium and is the major risk factor for oesophageal adenocarcinoma. This particular type of cancer has a rapidly rising incidence and a dismal prognosis. The homoeotic transcription factor Cdx2 (Caudal-type homeobox 2) has been implicated as a master switch gene for intestine and therefore for Barrett's metaplasia. Normally, Cdx2 expression is restricted to the epithelium of the small and large intestine. Loss of Cdx2 function, or conditional deletion in the intestine, results in replacement of intestinal cells with a stratified squamous phenotype. In addition, Cdx2 is sufficient to provoke intestinal metaplasia in the stomach. In the present paper, we review the evidence for the role of Cdx2 in the development of Barrett's metaplasia.

scholarly journals Shank3 Modulates Sleep and Expression of Circadian Transcription Factors

2018 ◽  
Author(s):  
Ashley M. Ingiosi ◽  
Taylor Wintler ◽  
Hannah Schoch ◽  
Kristan G. Singletary ◽  
Dario Righelli ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Sleep Problems ◽  
Wheel Running ◽  
The United States ◽  
Autism Spectrum ◽  
Wheel Running Activity ◽  
Falling Asleep ◽  
Circadian Transcription

AbstractAutism Spectrum Disorder (ASD) is the most prevalent neurodevelopmental disorder in the United States and often co-presents with sleep problems. Sleep problems in ASD predict the severity of ASD core diagnostic symptoms and have a considerable impact on the quality of life of caregivers. Little is known, however, about the underlying molecular mechanisms. We investigated the role of Shank3, a high confidence ASD gene candidate, in sleep architecture and regulation. We show that mice lacking exon 21 of Shank3 have problems falling asleep even when sleepy. Using RNA-seq we show that sleep deprivation increases the differences in gene expression between mutants and wild types, downregulating circadian transcription factors Per3, Dec2, Hlf, Tef, and Reverbα. Shank3 mutants also have trouble regulating wheel-running activity in constant darkness. Overall our study shows that Shank3 is an important modulator of sleep and clock gene expression.

scholarly journals The Western Diet Regulates Hippocampal Microvascular Gene Expression: An Integrated Genomic Analyses in Female Mice

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Saivageethi Nuthikattu ◽  
Dragan Milenkovic ◽  
John Rutledge ◽  
Amparo Villablanca
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Differential Expression ◽  
Differential Gene Expression ◽  
Gene Networks ◽  
Molecular Mechanisms ◽  
Western Diet ◽  
Protein Coding ◽  
Female Mice ◽  
Differential Gene

AbstractHyperlipidemia is a risk factor for dementia, and chronic consumption of a Western Diet (WD) is associated with cognitive impairment. However, the molecular mechanisms underlying the development of microvascular disease in the memory centers of the brain are poorly understood. This pilot study investigated the nutrigenomic pathways by which the WD regulates gene expression in hippocampal brain microvessels of female mice. Five-week-old female low-density lipoprotein receptor deficient (LDL-R−/−) and C57BL/6J wild type (WT) mice were fed a chow or WD for 8 weeks. Metabolics for lipids, glucose and insulin were determined. Differential gene expression, gene networks and pathways, transcription factors, and non-protein coding RNAs were evaluated by genome-wide microarray and bioinformatics analysis of laser captured hippocampal microvessels. The WD resulted in differential expression of 2,412 genes. The majority of differential gene expression was attributable to differential regulation of cell signaling proteins and their transcription factors, approximately 7% was attributable to differential expression of miRNAs, and a lesser proportion was due to other non-protein coding RNAs, primarily long non-coding RNAs (lncRNAs) and small nucleolar RNAs (snoRNAs) not previously described to be modified by the WD in females. Our findings revealed that chronic consumption of the WD resulted in integrated multilevel molecular regulation of the hippocampal microvasculature of female mice and may provide one of the mechanisms underlying vascular dementia.

scholarly journals Effects of Cutting, Pruning, and Grafting on the Expression of Age-Related Genes in Larix kaempferi

Forests ◽  
2020 ◽  
Vol 11 (2) ◽  
pp. 218
Author(s):  
Yao Zhang ◽  
Qiao-Lu Zang ◽  
Li-Wang Qi ◽  
Su-Ying Han ◽  
Wan-Feng Li
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Regular Expression ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Reproductive Development ◽  
Larix Kaempferi ◽  
Clonal Forestry ◽  
Cdna Sequences ◽  
Age Related

Grafting, cutting, and pruning are important horticultural techniques widely used in the establishment of clonal forestry. After the application of these techniques, some properties of the plants change, however, the underlying molecular mechanisms are still unclear. In our previous study, 27 age-related transcripts were found to be expressed differentially between the juvenile vegetative (1- and 2-year-old) and adult reproductive (25- and 50-year-old) phases of Larix kaempferi. Here, we re-analyzed the 27 age-related transcripts, cloned their full-length cDNA sequences, and measured their responses to grafting, cutting, and pruning. After sequence analysis and cloning, 20 transcription factors were obtained and annotated, most of which were associated with reproductive development, and six (LaAGL2-1, LaAGL2-2, LaAGL2-3, LaSOC1-1, LaAGL11, and LaAP2-2) showed regular expression patterns with L. kaempferi aging. Based on the expression patterns of these transcription factors in L. kaempferi trees subjected to grafting, cutting, and pruning, we concluded that (1) cutting and pruning rejuvenate the plants and change their expression, and the effects of cutting on gene expression are detectable within 14 years, although the cutting seedlings are still maturing during these years; (2) within three months after grafting, the rootstock is more sensitive to grafting than the scion and readily becomes mature with the effect of the scion, while the scion is not readily rejuvenated by the effect of the rootstock; and (3) LaAGL2-2 and LaAGL2-3 are more sensitive to grafting, while LaAP2-2 is impervious to it. These findings not only provide potential molecular markers to assess the state of plants but also aid in studies of the molecular mechanisms of rejuvenation.

scholarly journals Screening and identification of key biomarkers of papillary renal cell carcinoma by bioinformatic analysis

PLoS ONE ◽  
2021 ◽  
Vol 16 (8) ◽  
pp. e0254868
Author(s):  
Yingying Xu ◽  
Deyang Kong ◽  
Zhongtang Li ◽  
Lingling Qian ◽  
Junchao Li ◽  
...  
Keyword(s):  
Gene Expression ◽  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Cancer Genomics ◽  
Papillary Renal Cell Carcinoma ◽  
Tissue Type ◽  
Hub Genes

Background Papillary renal cell carcinoma (PRCC) is the most common type of renal cell carcinoma after clear cell renal cell carcinoma (ccRCC). Its pathological classification is controversial, and its molecular mechanism is poorly understood. Therefore, the identification of key genes and their biological pathways is of great significance to elucidate the molecular mechanisms of PRCC occurrence and progression. Methods The PRCC-related datasets GSE7023, GSE48352 and GSE15641 were downloaded from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) were identified, and gene ontology (GO) term enrichment analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed. Cytoscape and STRING were used to construct the protein-protein interaction network (PPI) and perform module analysis to identify hub genes and key pathways. A heatmap of hub genes was constructed using the UCSC cancer genomics browser. Overall survival and recurrence-free survival of patients stratified by the expression levels of hub genes were analysed using Kaplan-Meier Plotter. The online database UALCAN was applied to analyse gene expression based on tissue type, stage, subtype and race. Results A total of 214 DEGs, specifically, 205 downregulated genes and 9 upregulated genes, were identified. The DEGs were mainly enriched in angiogenesis, kidney development, oxidation-reduction process, metabolic pathways, etc. The 17 hub genes identified were mainly enriched in the biological processes of angiogenesis, cell adhesion, platelet degranulation, and leukocyte transendothelial migration. Survival analysis showed that EGF, KDR, CXCL12, REN, PECAM1, CDH5, THY1, WT1, PLAU and DCN might be related to the carcinogenesis, metastasis or recurrence of PRCC. UALCAN analysis showed that low expression of PECAM1 and PLAU in PRCC tissues was related to stage, subtype and race. Conclusions The DEGs and hub genes identified in the present study provide insight into the specific molecular mechanisms of PRCC occurrence and development and may be potential molecular markers and therapeutic targets for the accurate classification and efficient diagnosis and treatment of PRCC.

scholarly journals Mediterranean Diet Reduces Monocyte Inflammatory Gene Expression and Influences Social Behavior in Nonhuman Primates

2020 ◽  
Author(s):  
Corbin S.C. Johnson ◽  
Carol A. Shively ◽  
Kristofer T. Michalson ◽  
Amanda J. Lea ◽  
Ryne J. DeBo ◽  
...  
Keyword(s):  
Gene Expression ◽  
Mediterranean Diet ◽  
Molecular Mechanisms ◽  
Expression Profiles ◽  
Western Diet ◽  
Primate Model ◽  
Inflammatory Gene Expression ◽  
Inflammatory Gene ◽  
Increased Risk ◽  
Diet Manipulation

AbstractWestern diet consumption is associated with inflammation, cardiometabolic disease, and mortality in humans, while Mediterranean diet consumption confers protective effects. One likely pathway for this association is through environmentally induced changes in monocyte function, yet the underlying mechanisms remain elusive. We conducted the first randomized, long-term diet manipulation in a non-human primate model to determine whether Western- or Mediterranean-like diets alter monocyte polarization and health. Monocyte gene expression profiles differed markedly between the two diet groups, with significant differences in over 40% of expressed genes. The Western diet induced a more proinflammatory monocyte phenotype overall and upregulated specific monocyte polarization genes. Diet also disrupted the coexpression of numerous gene pairs, including small RNAs and transcription factors associated with metabolism and adiposity in humans. Diet altered affiliative and anxiety-associated behaviors and mediation analysis showed that the diet-altered behaviors contributed significantly (∼50% of the effect of diet on gene expression) to 25% of the differentially expressed genes, suggesting that diet effects on central mechanisms also modulate monocyte gene expression. Together, these results identify both behavioral and molecular mechanisms underlying the health benefits of a Mediterranean diet regimen.Significance StatementSome of our largest public health burdens are driven by dietary changes associated with industrialization, but we still know very little about the molecular mechanisms underlying this link. Characteristic “Western diets” have been associated with increased risk for diseases related to chronic inflammation, while Mediterranean diets have anti-inflammatory benefits. Here, we identify causal effects of diet on inflammatory gene expression where consumption of the Mediterranean diet reduced inflammatory gene expression in monocytes. Additionally, our diet manipulation induced behavioral changes associated with anxiety and social integration, where Mediterranean-fed animals exhibited more positive affiliative behaviors and reduced anxiety. These behaviors were associated with 25% of the diet-affected genes, suggesting an important behavioral route through which diet can impact immune function.

scholarly journals The biological characteristics of transcription factors AP-2α and AP-2γ and their importance in various types of cancers

2019 ◽  
Vol 39 (3) ◽  
Author(s):  
Damian Kołat ◽  
Żaneta Kałuzińska ◽  
Andrzej K. Bednarek ◽  
Elżbieta Płuciennik
Keyword(s):  
Gene Expression ◽  
Transcription Factor ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Regulation Of Gene Expression ◽  
Cancer Tissue ◽  
Diagnostic Biomarkers ◽  
Oncological Patients ◽  
Wide Range ◽  
Non Coding Rnas

Abstract The Activator Protein 2 (AP-2) transcription factor (TF) family is vital for the regulation of gene expression during early development as well as carcinogenesis process. The review focusses on the AP-2α and AP-2γ proteins and their dualistic regulation of gene expression in the process of carcinogenesis. Both AP-2α and AP-2γ influence a wide range of physiological or pathological processes by regulating different pathways and interacting with diverse molecules, i.e. other proteins, long non-coding RNAs (lncRNA) or miRNAs. This review summarizes the newest information about the biology of two, AP-2α and AP-2γ, TFs in the carcinogenesis process. We emphasize that these two proteins could have either oncogenic or suppressive characteristics depending on the type of cancer tissue or their interaction with specific molecules. They have also been found to contribute to resistance and sensitivity to chemotherapy in oncological patients. A better understanding of molecular network of AP-2 factors and other molecules may clarify the atypical molecular mechanisms occurring during carcinogenesis, and may assist in the recognition of new diagnostic biomarkers.

scholarly journals A full-length transcriptome and gene expression analysis reveal genes and molecular elements expressed during seed development in Gnetum luofuense

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Nan Deng ◽  
Chen Hou ◽  
Boxiang He ◽  
Fengfeng Ma ◽  
Qingan Song ◽  
...  
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Seed Development ◽  
Molecular Mechanisms ◽  
Immature Stage ◽  
Full Length ◽  
Differentially Expressed ◽  
Mature Stage ◽  
Medicinal Uses ◽  
A Site

Abstract Background Gnetum is an economically important tropical and subtropical gymnosperm genus with various dietary, industrial and medicinal uses. Many carbohydrates, proteins and fibers accumulate during the ripening of Gnetum seeds. However, the molecular mechanisms related to this process remain unknown. Results We therefore assembled a full-length transcriptome from immature and mature G. luofuense seeds using PacBio sequencing reads. We identified a total of 5726 novel genes, 9061 alternative splicing events, 3551 lncRNAs, 2160 transcription factors, and we found that 8512 genes possessed at least one poly(A) site. In addition, gene expression comparisons of six transcriptomes generated by Illumina sequencing showed that 14,323 genes were differentially expressed from an immature stage to a mature stage with 7891 genes upregulated and 6432 genes downregulated. The expression of 14 differentially expressed transcription factors from the MADS-box, Aux/IAA and bHLH families was validated by qRT-PCR, suggesting that they may have important roles in seed ripening of G. luofuense. Conclusions These findings provide a valuable molecular resource for understanding seed development of gymnosperms.

Role of Long Coding RNAs in Epigenetic Modulation of Hematopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. SCI-28-SCI-28
Author(s):  
Mitchell J. Weiss
Keyword(s):  
Gene Expression ◽  
Transcription Factors ◽  
Molecular Mechanisms ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
Protein Localization ◽  
Noncoding Rnas ◽  
Long Noncoding Rnas ◽  
Similar Degree ◽  
Erythroid Progenitors

Abstract Long noncoding (Lnc) RNAs are RNA transcripts greater than 200 nucleotides (nt) that regulate gene expression independent of protein coding potential (1-3). It is estimated that thousands of lncRNAs play vital roles in diverse cellular processes. LncRNAs modulate many stages of gene expression by regulating transcription, epigenetics, splicing, translation, and protein localization. We hypothesize that multiple lncRNAs are expressed specifically during erythrocyte and megakaryocyte differentiation, and are likely to have important roles. To identify lncRNAs in erythro-megakaryopoiesis, we performed strand-specific, paired-end deep sequencing (RNA-Seq) to a depth of 200 million reads per sample on two replicates each of murine Ter119+erythroblasts, CD41+ megakaryocytes and bipotential megakaryocyte-erythroid progenitors (MEPs) [lin- Kit+ Sca1- CD16/32- CD34-], and used bioinformatic filtering tools to identify approximately 1,100 candidate lncRNAs. Over 60 percent of these lncRNAs are novel unannotated transcripts with exquisite lineage-specific expression. Using erythroid and megakaryocytic primary cell ChIP-Seq for key transcription factors (TFs) GATA1, TAL1, GATA2,and FLI1, we found that the loci of lncRNAs show similar degree of TF binding as coding genes. We used the erythroid line G1E-ER4 (which expresses estrogen-activated GATA1) to confirm that lncRNAs bound by GATA1 are also directly regulated by it. Furthermore, we used histone methylation ChIP-Seq to show that most lncRNAs arise from classical “promoters” with high H3K4me3 levels and low H3K4me1 levels. Thus, we find that lncRNAs show epigenetic features similar to the promoters of coding genes and are directly regulated by similar TF networks. Comparison of the transcriptomes of mouse fetal liver and human cord blood erythroblasts demonstrated that lncRNAs are expressed in a highly species-specific fashion, i.e., most lncRNAs identifiable in one species are not transcribed in the other, even though the corresponding genomic region is present in both species. Numerous non-conserved but functional lncRNAs are reported in the literature, and the significance of conservation in lncRNA biology is greatly debated. In order to identify functional lncRNAs, we are currently performing RNAi knockdown on numerous candidates to assess how loss of function affects erythroid maturation. We are also performing HITS-CLIP of key chromatin modifying complexes and erythroid transcription factors to identify lncRNAs bound to them. Our studies are beginning to define new layers of gene regulation in normal erythro-megakaryopoiesis, which may be relevant to the pathophysiology of related disorders including various anemias, myeloproliferative and myelodysplastic syndromes and leukemias. 1. Wang K.C., Chang H.Y. Molecular mechanisms of long noncoding RNAs. Molecular Cell. 2011;43(6):904-914. Prepublished on 2011/09/20 as DOI 10.1016/j.molcel.2011.08.018. 2. Hu W., Alvarez-Dominguez J.R., Lodish H.F. Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO reports. 2012;13(11):971-983. Prepublished on 2012/10/17 as DOI 10.1038/embor.2012.145. 3. Paralkar V.R., Weiss M.J. Long noncoding RNAs in biology and hematopoiesis. Blood. 2013;121(24):4842-4846. Prepublished on 2013/05/07 as DOI 10.1182/blood-2013-03-456111. Disclosures: No relevant conflicts of interest to declare.

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