The liver X-receptor gene promoter is hypermethylated in a mouse model of prenatal protein restriction

2010 ◽  
Vol 298 (2) ◽  
pp. R275-R282 ◽  
Author(s):  
Esther M. E. van Straten ◽  
Vincent W. Bloks ◽  
Nicolette C. A. Huijkman ◽  
Julius F. W. Baller ◽  
Hester van Meer ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Lipid Metabolism ◽  
Target Genes ◽  
Cpg Island ◽  
Fetal Liver ◽  
Gene Promoter ◽  
Liver X Receptor ◽  
Protein Restriction ◽  
Luciferase Expression ◽  
Adult Disease

Prenatal nutrition as influenced by the nutritional status of the mother has been identified as a determinant of adult disease. Feeding low-protein diets during pregnancy in rodents is a well-established model to induce programming events in offspring. We hypothesized that protein restriction would influence fetal lipid metabolism by inducing epigenetic adaptations. Pregnant C57BL/6J mice were exposed to a protein-restriction protocol (9% vs. 18% casein). Shortly before birth, dams and fetuses were killed. To identify putative epigenetic changes, CG-dinucleotide-rich region in the promoter of a gene (CpG island) methylation microarrays were performed on DNA isolated from fetal livers. Two hundred four gene promoter regions were differentially methylated upon protein restriction. The liver X-receptor (Lxr) alpha promoter was hypermethylated in protein-restricted pups. Lxr alpha is a nuclear receptor critically involved in control of cholesterol and fatty acid metabolism. The mRNA level of Lxra was reduced by 32% in fetal liver upon maternal protein restriction, whereas expression of the Lxr target genes Abcg5/ Abcg8 was reduced by 56% and 51%, respectively, measured by real-time quantitative PCR. The same effect, although less pronounced, was observed in the fetal intestine. In vitro methylation of a mouse Lxra-promoter/luciferase expression cassette resulted in a 24-fold transcriptional repression. Our study demonstrates that, in mice, protein restriction during pregnancy interferes with DNA methylation in fetal liver. Lxra is a target of differential methylation, and Lxra transcription is dependent on DNA methylation. It is tempting to speculate that perinatal nutrition may influence adult lipid metabolism by DNA methylation, which may contribute to the epidemiological relation between perinatal/neonatal nutrition and adult disease.

scholarly journals The Liver X‐Receptor (LXR) gene promoter is hypermethylated in a mouse model of prenatal protein restriction

2009 ◽  
Vol 23 (S1) ◽  
Author(s):  
Torsten Plosch ◽  
Esther M.E. Straten ◽  
Vincent W. Bloks ◽  
Nicolette C.A. Huijkman ◽  
Folkert Kuipers
Keyword(s):  
Mouse Model ◽  
Gene Promoter ◽  
Liver X Receptor ◽  
Protein Restriction

scholarly journals Expression of Sclerostin in Osteoporotic Fracture Patients Is Associated with DNA Methylation in the CpG Island of the SOST Gene

2019 ◽  
Vol 2019 ◽  
pp. 1-8 ◽  
Author(s):  
Yanming Cao ◽  
Bin Wang ◽  
Ding Wang ◽  
Dongxiang Zhan ◽  
Caiyuan Mai ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Osteoporotic Fracture ◽  
Cpg Island ◽  
Epigenetic Modification ◽  
Methylation Status ◽  
Gene Promoter ◽  
Primary Osteoporosis ◽  
Sost Gene ◽  
Fracture Bone

Purpose. SOST gene is one of the key factors in regulating bone absorption. Although there are reports showing diverse transcription factors, epigenetic modification could be responsible for regulating SOST gene expression. There is still little exploration on promoter methylation status of SOST gene in osteoporotic bone tissues. The aim of this study is to investigate the involvement of CpG methylation in regulation of SOST expression in patients with primary osteoporosis. Methods. The diagnosis of osteoporosis was established on the basis of dual energy X-ray absorptiometry to measure BMD. All femoral bone tissues were separated in surgeries. After extracting total RNA and protein, we checked the relative expression levels of SOST by quantitative real-time PCR and western blot. Also, immunohistochemical staining was performed to observe the expression of SOST protein in the bone samples. The genomic DNA of non-OPF (non-osteoporotic fracture bone tissues) and OPF (osteoporotic fracture bone tissues) were treated by bisulfite modification, and methylation status of CpG sites in the CpG island of SOST gene promoter was determined by DNA sequencing. Results. SOST gene expression in the non-OPF group was lower than that in OPF group. Bisulfite sequencing result showed that SOST gene promoter was slightly demethylated in the OPF group, as compared with non-OPF group. Conclusion. Our study demonstrated that DNA methylation influenced the transcriptional expression of SOST gene, which probably may play an important role in the pathogenesis of primary osteoporosis.

Elevated Levels Of γ-Globin Gene Promoter 5-Hydroxymethylcytosine are Associated With Increased DNA Hypomethylation and HbF Expression

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 438-438
Author(s):  
Maria Armila Ruiz ◽  
Angela Rivers ◽  
Kestis Vaitkus ◽  
Tatiana Kouznetsova ◽  
Nadim Mahmud ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Fetal Liver ◽  
Globin Gene ◽  
Gene Promoter ◽  
Erythroid Differentiation ◽  
Dna Demethylation ◽  
Dna Hypomethylation ◽  
Liquid Cultures ◽  
Erythroid Precursors ◽  
Globin Promoter

Abstract DNA methylation of the γ-globin gene promoter represses γ-globin expression in adult-stage erythroid cells while high level γ-globin expression in fetal liver erythroid cells is associated with DNA hypomethylation. Previously we showed that DNA demethylation of the γ-globin gene promoter during fetal liver erythroid differentiation is responsible for the nearly complete loss of DNA methylation, while much more limited DNA demethylation during adult bone marrow (BM) erythroid differentiation maintains a relatively high level of γ-globin promoter DNA methylation (Singh et al Exp Hematol 35:48, 2007). As recent studies have shown the importance of 5-hydroxymethylcytosine (5-hmC) as an intermediate in active and passive mechanisms of DNA demethylation that alter epigenetic modifications regulating development and hematopoietic differentiation, experiments were performed to 1) investigate the hypothesis that DNA demethylation of the γ-globin promoter during erythroid differentiation involves 5-hmC, and 2) evaluate the role of 5-hmC in γ-globin gene expression. Levels of 5-hmC and 5-methylcytosine (5-mC) located at a CpG residue within the context of a HpaII site within the 5' γ-globin promoter were measured in 1) baboon BM cells enriched for different stages of erythroid differentiation, and 2) CD34+ BM-derived erythroid progenitors expressing high levels of γ-globin grown in liquid culture or expressing low levels of γ-globin in co-culture with the AFT024 cell line. Analysis of BM cells showed that CD117+CD36+ BM cells enriched in clonogenic late BFUe/CFUe had nearly 3 fold higher levels of γ-globin promoter 5-hmC (6.91+1.41%) compared to BM-derived erythroid precursors (2.57+0.75%; p<0.0001). In erythroid precursors expressing low levels of HbF derived from CD34+ BM cells grown in co-culture with the AFT024 murine fetal liver cell line, the levels of γ-globin promoter 5-hmC (1.72+1.19%) and 5-mC (64.84+9.22%) were not significantly different from BM-derived erythroid precursors. In contrast, the level of γ-globin promoter 5-hmC in erythroid precursors derived from CD34+ BM cells grown in liquid cultures expressing elevated levels of HbF was significantly higher (6.18+1.35%) than terminal erythroid precursors from either adult BM (p<.0001) or AFT024 co-cultures (1.72+1.19%; p<.0001) but was not significantly different than the level in CD117+CD36+ BM cells. Levels of γ-globin promoter 5-hmC were similar in erythroid precursors from liquid cultures on d7 (5.57+1.24%), d11 (6.13+1.02%), d14 (6.73+1.74%), and more primitive d7 gly- basophilic erythroblasts (6.21+1.38%). The level of DNA methylation (5-mC) was significantly less in erythroid precursors derived from liquid cultures (40.37+14.33%) compared to erythroid precursors derived from adult BM (63.10+7.72%; p<0.0005), AFT024 co-cultures (64.84+9.22%; p<0.001) and CD117+CD36+ BM cells (67.71+7.45%; p<0.002). Reduced levels of 5-mC were observed in erythroid precursors from liquid cultures on d14 (34.87+14.67%) compared to d7 (48.64+15.56%; p<0.055) suggesting that the γ-globin gene is progressively demethylated during erythroid differentiation in liquid culture. We conclude that γ-globin promoter 5-hmC levels are modulated during adult BM erythroid differentiation with 3 fold higher levels in CD117+CD36+ cells enriched in late BFUe/CFUe compared to erythroid precursors. Similar levels of γ-globin promoter 5-hmC, 5-mC, and HbF are observed in adult BM erythroid precursors and erythroid precursors derived from AFT024 co-cultures. In contrast, high levels of levels of γ-globin promoter 5-hmC, similar to levels in CD117+CD36+ BM cells, are sustained in erythroid precursors derived from liquid cultures of CD34+ BM cells and are associated with decreased γ-globin promoter 5-mC and increased HbF. Supplementation of cultures with ascorbic acid, a co-factor of the TET oxygenases that catalyze 5-hmC, reduced levels of γ-globin promoter 5-mC (20.94+9.77%) compared to controls (51.24+14.61%; p<.025) and increased γ-globin expression. These results support the hypothesis that DNA demethylation of the γ-globin promoter during erythroid differentiation, resulting in high HbF expression, occurs through a 5-hmC-mediated mechanism subject to developmental regulation by factors in the micro-environment. Disclosures: No relevant conflicts of interest to declare.

scholarly journals A Long Polymorphic GT Microsatellite within a Gene Promoter Mediates Non-Imprinted Allele-Specific DNA Methylation of a CpG Island in a Goldfish Inter-Strain Hybrid

2019 ◽  
Vol 20 (16) ◽  
pp. 3923
Author(s):  
Zheng ◽  
Xu ◽  
Cao
Keyword(s):  
Dna Methylation ◽  
Cpg Island ◽  
Methylation Status ◽  
Repetitive Sequences ◽  
Gene Promoter ◽  
Dna Polymorphisms ◽  
Specific Expression ◽  
Cis Acting ◽  
Allele Specific ◽  
The Impact

It is now widely accepted that allele-specific DNA methylation (ASM) commonly occurs at non-imprinted loci. Most of the non-imprinted ASM regions observed both within and outside of the CpG island show a strong correlation with DNA polymorphisms. However, what polymorphic cis-acting elements mediate non-imprinted ASM of the CpG island remains unclear. In this study, we investigated the impact of polymorphic GT microsatellites within the gene promoter on non-imprinted ASM of the local CpG island in goldfish. We generated various goldfish heterozygotes, in which the length of GT microsatellites or some non-repetitive sequences in the promoter of no tail alleles was different. By examining the methylation status of the downstream CpG island in these heterozygotes, we found that polymorphisms of a long GT microsatellite can lead to the ASM of the downstream CpG island during oogenesis and embryogenesis, polymorphisms of short GT microsatellites and non-repetitive sequences in the promoter exhibited no significant effect on the methylation of the CpG island. We also observed that the ASM of the CpG island was associated with allele-specific expression in heterozygous embryos. These results suggest that a long polymorphic GT microsatellite within a gene promoter mediates non-imprinted ASM of the local CpG island in a goldfish inter-strain hybrid.

scholarly journals SCT promoter methylation is a highly discriminative biomarker for lung and many other cancers

2015 ◽  
Author(s):  
Adwait Sathe ◽  
Xiaotu Ma ◽  
Michael Zhang
Keyword(s):  
Dna Methylation ◽  
Cell Lines ◽  
Promoter Methylation ◽  
Cpg Island ◽  
Gene Promoter ◽  
Nsclc Cell ◽  
Primary Tumors ◽  
Lung Cancers ◽  
Cancer Types ◽  
Aberrant Dna Methylation

Aberrant DNA methylation has long been implicated in cancers. In this work we present a highly discriminative DNA methylation biomarker for non-small cell lung cancers and fourteen other cancers. Based on 69 NSCLC cell lines and 257 cancer-free lung tissues we identified a CpG island in SCT gene promoter which was verified by qMSP experiment in 15 NSCLC cell lines and 3 immortalized human respiratory epithelium cells. In addition, we found that SCT promoter was methylated in 23 cancer cell lines involving >10 cancer types profiled by ENCODE. We found that SCT promoter is hyper-methylated in primary tumors from TCGA lung cancer cohort. Additionally, we found that SCT promoter is methylated at high frequencies in fifteen malignancies and is not methylated in ~1000 non-cancerous tissues across >30 organ types. Our study indicates that SCT promoter methylation is a highly discriminative biomarker for lung and many other cancers.

scholarly journals Investigation of Capsule-Inspired Neural Network Approaches for DNA Methylation

2020 ◽  
Author(s):  
Joshua J. Levy ◽  
Youdinghuan Chen ◽  
Nasim Azizgolshani ◽  
Curtis L. Peterson ◽  
Alexander J. Titus ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Deep Learning ◽  
Cpg Island ◽  
Gene Promoter ◽  
Biological Knowledge ◽  
Learning Approaches ◽  
Biologically Relevant ◽  
Prior Biological Knowledge ◽  
Learning Software ◽  
Network Approaches

AbstractDNA methylation (DNAm) alterations are implicated with aging and diseases by regulating gene expression. DNAm deep-learning approaches can capture features associated with aging, cell type, and disease progression, but lack incorporation of prior biological knowledge. We present deep-learning software, MethylCapsNet and MethylSPWNet, that group CpGs into user-specified or predefined biologically relevant groupings (eg. gene promoter or CpG island context) related to diagnostic and prognostic outcomes. We train our models on a cohort (n=3,897) to classify central nervous system tumors and compare to existing approaches. Our methodology presents opportunities to increase interpretability of disease mechanisms through utilization of biologically relevant annotations.

Sign in / Sign up

Export Citation Format

Share Document