DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 111-119 ◽  
Author(s):  
Hong Yin ◽  
K. L. Blanchard
Keyword(s):  
Dna Methylation ◽  
Untranslated Region ◽  
Cpg Island ◽  
Cell Types ◽  
High Density ◽  
Nuclear Proteins ◽  
Proximal Promoter ◽  
Signaling Cascade ◽  
Human Erythropoietin ◽  
Different Cell Types

Abstract The human erythropoietin gene is expressed predominantly in the kidney and liver in response to hypoxia. Although the signaling cascade for hypoxia is present in many different cell types, the expression of erythropoietin is restricted to only a few tissues. The authors show that the promoter and 5′-untranslated region (5′-UTR) of the erythropoietin gene comprise a CpG island and that methylation of the CpG island correlates inversely with expression. Methylation represses the expression of the erythropoietin gene in 2 ways: high-density methylation of the 5′-UTR recruits a methyl-CpG binding protein to the promoter, and methylation of CpGs in the proximal promoter blocks the association of nuclear proteins. (Blood. 2000;95:111-119)

DNA methylation represses the expression of the human erythropoietin gene by two different mechanisms

Blood ◽  
2000 ◽  
Vol 95 (1) ◽  
pp. 111-119 ◽  
Author(s):  
Hong Yin ◽  
K. L. Blanchard
Keyword(s):  
Dna Methylation ◽  
Untranslated Region ◽  
Cpg Island ◽  
Cell Types ◽  
High Density ◽  
Nuclear Proteins ◽  
Proximal Promoter ◽  
Signaling Cascade ◽  
Human Erythropoietin ◽  
Different Cell Types

The human erythropoietin gene is expressed predominantly in the kidney and liver in response to hypoxia. Although the signaling cascade for hypoxia is present in many different cell types, the expression of erythropoietin is restricted to only a few tissues. The authors show that the promoter and 5′-untranslated region (5′-UTR) of the erythropoietin gene comprise a CpG island and that methylation of the CpG island correlates inversely with expression. Methylation represses the expression of the erythropoietin gene in 2 ways: high-density methylation of the 5′-UTR recruits a methyl-CpG binding protein to the promoter, and methylation of CpGs in the proximal promoter blocks the association of nuclear proteins. (Blood. 2000;95:111-119)

scholarly journals Targets and genomic constraints of ectopic Dnmt3b expression

eLife ◽  
2018 ◽  
Vol 7 ◽  
Author(s):  
Yingying Zhang ◽  
Jocelyn Charlton ◽  
Rahul Karnik ◽  
Isabel Beerman ◽  
Zachary D Smith ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Cpg Island ◽  
Cpg Islands ◽  
Cell Types ◽  
Aberrant Methylation ◽  
Genome Wide Data ◽  
Mammalian Genomes ◽  
Different Cell Types

DNA methylation plays an essential role in mammalian genomes and expression of the responsible enzymes is tightly controlled. Deregulation of the de novo DNA methyltransferase DNMT3B is frequently observed across cancer types, yet little is known about its ectopic genomic targets. Here, we used an inducible transgenic mouse model to delineate rules for abnormal DNMT3B targeting, as well as the constraints of its activity across different cell types. Our results explain the preferential susceptibility of certain CpG islands to aberrant methylation and point to transcriptional state and the associated chromatin landscape as the strongest predictors. Although DNA methylation and H3K27me3 are usually non-overlapping at CpG islands, H3K27me3 can transiently co-occur with DNMT3B-induced DNA methylation. Our genome-wide data combined with ultra-deep locus-specific bisulfite sequencing suggest a distributive activity of ectopically expressed Dnmt3b that leads to discordant CpG island hypermethylation and provides new insights for interpreting the cancer methylome.

scholarly journals Separate cis-acting DNA elements of the mouse pro-alpha 1(I) collagen promoter direct expression of reporter genes to different type I collagen-producing cells in transgenic mice.

1995 ◽  
Vol 129 (5) ◽  
pp. 1421-1432 ◽  
Author(s):  
J Rossert ◽  
H Eberspaecher ◽  
B de Crombrugghe
Keyword(s):  
Transgenic Mice ◽  
Type I Collagen ◽  
Cell Types ◽  
Proximal Promoter ◽  
Type I ◽  
High Level Expression ◽  
Cis Acting ◽  
High Level ◽  
Different Cell Types ◽  
Beta Galactosidase

The genes coding for the two type I collagen chains, which are active selectively in osteoblasts, odontoblasts, fibroblasts, and some mesenchymal cells, constitute good models for studying the mechanisms responsible for the cell-specific activity of genes which are expressed in a small number of discrete cell types. To test whether separate genetic elements could direct the activity of the mouse pro-alpha 1(I) collagen gene to different cell types in which it is expressed, transgenic mice were generated harboring various fragments of the proximal promoter of this gene cloned upstream of the Escherichia coli beta-galactosidase gene. During embryonic development, X-gal staining allows for the precise identification of the different cell types in which the beta-galactosidase gene is active. Transgenic mice harboring 900 bp of the pro-alpha 1(I) proximal promoter expressed the transgene at relatively low levels almost exclusively in skin. In mice containing 2.3 kb of this proximal promoter, the transgene was also expressed at high levels in osteoblasts and odontoblasts, but not in other type I collagen-producing cells. Transgenic mice harboring 3.2 kb of the proximal promoter showed an additional high level expression of the transgene in tendon and fascia fibroblasts. The pattern of expression of the lacZ transgene directed by the 0.9- and 2.3-kb pro-alpha 1(I) proximal promoters was confirmed by using the firefly luciferase gene as a reporter gene. The pattern of expression of this transgene, which can be detected even when it is active at very low levels, paralleled that of the beta-galactosidase gene. These data strongly suggest a modular arrangement of separate cell-specific cis-acting elements that can activate the mouse pro-alpha(I) collagen gene in different type I collagen-producing cells. At least three different types of cell-specific elements would be located in the first 3.2 kb of the promoter: (a) an element that confers low level expression in dermal fibroblasts; (b) a second that mediates high level expression in osteoblasts and odontoblasts; and (c) one responsible for high level expression in tendon and fascia fibroblasts. Our data also imply that other cis-acting cell-specific elements which direct activity of the gene to still other type I collagen-producing cells remain to be identified.

scholarly journals DISCREPANCIES BETWEEN CYTOPHOTOMETRIC FEULGEN VALUES AND DEOXYRIBONUCLEIC ACID CONTENT

1971 ◽  
Vol 19 (3) ◽  
pp. 169-174 ◽  
Author(s):  
K. NOESKE
Keyword(s):  
Functional State ◽  
Acid Content ◽  
Deoxyribonucleic Acid ◽  
Cell Types ◽  
Nuclear Proteins ◽  
Feulgen Reaction ◽  
Template Activity ◽  
Colored Product ◽  
Different Cell Types ◽  
Low Template

Diploid nuclei of different cell types of the granulocytopoietic and erythropoietic series showed different Feulgen values. The highest values were found in the most immature nuclei, and the lowest values in the most mature cells. Extraction of acid-soluble nuclear proteins brought the different values to the same level. Examples of similar findings in other cell types, as described in the literature, are discussed. The Feulgen reaction and its colored product depend on the functional state of the chromatin in such a way that nuclei with high template activity of deoxyribonucleic acid show high Feulgen values whereas mature, dense nuclei with low template activity have lower Feulgen values, although both kinds of nuclei contain identical amounts of deoxyribonucleic acid.

scholarly journals Understanding the Relevance of DNA Methylation Changes in Immune Differentiation and Disease

Genes ◽  
2020 ◽  
Vol 11 (1) ◽  
pp. 110 ◽  
Author(s):  
Carlos de la Calle-Fabregat ◽  
Octavio Morante-Palacios ◽  
Esteban Ballestar
Keyword(s):  
Dna Methylation ◽  
Cell Types ◽  
Epigenetic Modifications ◽  
Human Organism ◽  
Cell Phenotype ◽  
Effector Cells ◽  
Technological Advances ◽  
And Function ◽  
Different Cell Types ◽  
External Stimuli

Immune cells are one of the most complex and diverse systems in the human organism. Such diversity implies an intricate network of different cell types and interactions that are dependently interconnected. The processes by which different cell types differentiate from progenitors, mature, and finally exert their function requires an orchestrated succession of molecular processes that determine cell phenotype and function. The acquisition of these phenotypes is highly dependent on the establishment of unique epigenetic profiles that confer identity and function on the various types of effector cells. These epigenetic mechanisms integrate microenvironmental cues into the genome to establish specific transcriptional programs. Epigenetic modifications bridge environment and genome regulation and play a role in human diseases by their ability to modulate physiological programs through external stimuli. DNA methylation is one of the most ubiquitous, stable, and widely studied epigenetic modifications. Recent technological advances have facilitated the generation of a vast amount of genome-wide DNA methylation data, providing profound insights into the roles of DNA methylation in health and disease. This review considers the relevance of DNA methylation to immune system cellular development and function, as well as the participation of DNA methylation defects in immune-mediated pathologies, illustrated by selected paradigmatic diseases.

scholarly journals GENE-40. CHARACTERIZING EPIGENETIC INTRATUMORAL HETEROGENEITY IN GLIOMA USING SINGLE-CELL BISULFITE SEQUENCING

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi106-vi106
Author(s):  
Kevin C Johnson ◽  
Kevin Anderson ◽  
Elise Courtois ◽  
Floris Barthel ◽  
Michael Samuels ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Single Cell ◽  
Bisulfite Sequencing ◽  
Cpg Island ◽  
Regulatory Element ◽  
Cell Types ◽  
Intratumoral Heterogeneity ◽  
Gene Promoters ◽  
Cpg Island Methylator Phenotype ◽  
Reduced Representation

Abstract Genetic and epigenetic alterations contribute to the observed intratumoral heterogeneity in adult glioma. Current glioma classification, based on genotype (e.g., IDH1 mutations) and DNA methylation profiles (e.g., glioma CpG Island Methylator Phenotype), can provide clinically relevant tumor subgroups. However, traditional bulk sampling fails to adequately capture the full complement of epigenomic heterogeneity, and may mask deadly features present in less abundant glioma cells. To more precisely characterize the glioma epigenome, we separately profiled single-cell DNA methylation (Reduced Representation Bisulfite Sequencing, RRBS), single-cell RNA expression (10X genomics), and bulk whole genome sequencing in nine gliomas. The genomic regions profiled by scRRBS were primarily gene promoters, but adequate coverage was also reached for glioma-specific enhancer elements and binding sites of chromatin remodelers. Unsupervised clustering of single-cell DNA methylation data revealed intratumoral variability in epigenetic classification and these cell types were distinguished by regulatory element DNA methylation. We further integrated single-cell epigenetic, single-cell transcriptomic, and genomic features to better understand gene regulation and reconstruct each tumor’s lineage history. Together, our study aims to generate a glioma cellular hierarchy shaped by the epigenetic programs that drive tumor growth.

Abstract 1492: Epigenetic Control of the eNOS Promoter by DNA Methylation in Vasculogenic Progenitor Cell Populations

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Georgios J Vlachojannis ◽  
Carmen Urbich ◽  
Andreas M Zeiher ◽  
Stefanie Dimmeler
Keyword(s):  
Dna Methylation ◽  
Stem Cell ◽  
Endothelial Cell ◽  
Progenitor Cells ◽  
Cell Biology ◽  
Promoter Region ◽  
Progenitor Cell ◽  
Cell Types ◽  
Proximal Promoter ◽  
Enos Gene

DNA methylation has been shown to play an essential role in both the transcriptional regulation and endothelial cell-specific expression of the human endothelial nitric oxide synthase (eNOS) gene. Further, recent data emphasizes an important role of eNOS in stem cell biology in particular with regard to progenitor cell mobilization and vasculoprotective properties. We assessed the hypothesis that stem and vasculogenic progenitor cells will exhibit different DNA methylation patterns of the eNOS promoter region dependent on their vascular fate. Endothelial progenitor cells (EPCs), mesangioblasts, CD34+, HUVECs and microvascular endothelial cells (MVECs) were cultivated and genomic DNA was subjected to sodium bisulfite treatment. The final PCR products were subcloned and sequenced (5–10 clones). Whereas the eNOS proximal promoter was either devoid or very lightly methylated in the human endothelial cell types including HUVECs and MVECs, the promoter was heavily methylated in the examined progenitor and stem cell types namely CD34+ and mesangioblasts. Surprisingly, EPCs also exhibit a profound methylation of the eNOS promoter (see Figure ). In conclusion, we have demonstrated that progenitor and stem cells including EPCs, CD34+ and mesangioblasts - although committed to a vascular fate - are in contrast to endothelial cell types heavily methylated in the promoter region of the eNOS gene suggesting epigenetic silencing at this level of maturation. The functional importance of this finding in particular regarding vasculoprotective potency and the modulation of methylation during progenitor cell maturation is subject of future studies. Methylation pattern of the eNOS promoter

scholarly journals Complete deconvolution of DNA methylation signals from complex tissues: a geometric approach

2020 ◽  
Author(s):  
Weiwei Zhang ◽  
Hao Wu ◽  
Ziyi Li
Keyword(s):  
Dna Methylation ◽  
Geometric Approach ◽  
Real Data ◽  
Cell Types ◽  
Supplementary Information ◽  
Data Sets ◽  
Methylation Data ◽  
Cell Type ◽  
Tissue Samples ◽  
Different Cell Types

Abstract Motivation It is a common practice in epigenetics research to profile DNA methylation on tissue samples, which is usually a mixture of different cell types. To properly account for the mixture, estimating cell compositions has been recognized as an important first step. Many methods were developed for quantifying cell compositions from DNA methylation data, but they mostly have limited applications due to lack of reference or prior information. Results We develop Tsisal, a novel complete deconvolution method which accurately estimate cell compositions from DNA methylation data without any prior knowledge of cell types or their proportions. Tsisal is a full pipeline to estimate number of cell types, cell compositions, and identify cell-type-specific CpG sites. It can also assign cell type labels when (full or part of) reference panel is available. Extensive simulation studies and analyses of seven real data sets demonstrate the favorable performance of our proposed method compared with existing deconvolution methods serving similar purpose. Availability The proposed method Tsisal is implemented as part of the R/Bioconductor package TOAST at https://bioconductor.org/packages/TOAST. Contact [email protected] and [email protected]. Supplementary information Supplementary data are available at Bioinformatics online.

scholarly journals Human Ubiquitin-Specific Peptidase 18 Is Regulated by microRNAs via the 3'Untranslated Region, A Sequence Duplicated in Long Intergenic Non-coding RNA Genes Residing in chr22q11.21

2021 ◽  
Vol 11 ◽  
Author(s):  
Erminia Rubino ◽  
Melania Cruciani ◽  
Nicolas Tchitchek ◽  
Anna Le Tortorec ◽  
Antoine D. Rolland ◽  
...  
Keyword(s):  
Untranslated Region ◽  
Cell Types ◽  
Type I ◽  
Rna Seq ◽  
Non Coding Rna ◽  
Human Ubiquitin ◽  
Different Cell Types ◽  
Fine Tune ◽  
Rna Genes ◽  
Stat Pathway

Ubiquitin-specific peptidase 18 (USP18) acts as gatekeeper of type I interferon (IFN) responses by binding to the IFN receptor subunit IFNAR2 and preventing activation of the downstream JAK/STAT pathway. In any given cell type, the level of USP18 is a key determinant of the output of IFN-stimulated transcripts. How the baseline level of USP18 is finely tuned in different cell types remains ill defined. Here, we identified microRNAs (miRNAs) that efficiently target USP18 through binding to the 3’untranslated region (3’UTR). Among these, three miRNAs are particularly enriched in circulating monocytes which exhibit low baseline USP18. Intriguingly, the USP18 3’UTR sequence is duplicated in human and chimpanzee genomes. In humans, four USP18 3’UTR copies were previously found to be embedded in long intergenic non-coding (linc) RNA genes residing in chr22q11.21 and known as FAM247A-D. Here, we further characterized their sequence and measured their expression profile in human tissues. Importantly, we describe an additional lincRNA bearing USP18 3’UTR (here linc-UR-B1) that is expressed only in testis. RNA-seq data analyses from testicular cell subsets revealed a positive correlation between linc-UR-B1 and USP18 expression in spermatocytes and spermatids. Overall, our findings uncover a set of miRNAs and lincRNAs, which may be part of a network evolved to fine-tune baseline USP18, particularly in cell types where IFN responsiveness needs to be tightly controlled.

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