scholarly journals Gene promoter DNA methylation patterns have a limited role in orchestrating transcriptional changes in the fetal liver in response to maternal folate depletion during pregnancy

2016 ◽  
Vol 60 (9) ◽  
pp. 2031-2042 ◽  
Author(s):  
Jill A. McKay ◽  
Michiel Adriaens ◽  
Chris T. Evelo ◽  
Dianne Ford ◽  
John C. Mathers
Keyword(s):  
Dna Methylation ◽  
Fetal Liver ◽  
Gene Promoter ◽  
Limited Role ◽  
Promoter Dna Methylation ◽  
Transcriptional Changes ◽  
Promoter Dna ◽  
Methylation Patterns ◽  
Folate Depletion

scholarly journals Developmental- and differentiation-specific patterns of human γ- and β-globin promoter DNA methylation

Blood ◽  
2007 ◽  
Vol 110 (4) ◽  
pp. 1343-1352 ◽  
Author(s):  
Rodwell Mabaera ◽  
Christine A. Richardson ◽  
Kristin Johnson ◽  
Mei Hsu ◽  
Steven Fiering ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Promoter Methylation ◽  
Fetal Liver ◽  
Globin Gene ◽  
Erythroid Cells ◽  
Promoter Dna Methylation ◽  
Globin Promoter ◽  
Promoter Dna

AbstractThe mechanisms underlying the human fetal-to-adult β-globin gene switch remain to be determined. While there is substantial experimental evidence to suggest that promoter DNA methylation is involved in this process, most data come from studies in nonhuman systems. We have evaluated human γ- and β-globin promoter methylation in primary human fetal liver (FL) and adult bone marrow (ABM) erythroid cells. Our results show that, in general, promoter methylation and gene expression are inversely related. However, CpGs at −162 of the γ promoter and −126 of the β promoter are hypomethylated in ABM and FL, respectively. We also studied γ-globin promoter methylation during in vitro differentiation of erythroid cells. The γ promoters are initially hypermethylated in CD34+ cells. The upstream γ promoter CpGs become hypomethylated during the preerythroid phase of differentiation and are then remethylated later, during erythropoiesis. The period of promoter hypomethylation correlates with transient γ-globin gene expression and may explain the previously observed fetal hemoglobin production that occurs during early adult erythropoiesis. These results provide the first comprehensive survey of developmental changes in human γ- and β-globin promoter methylation and support the hypothesis that promoter methylation plays a role in human β-globin locus gene switching.

scholarly journals Promoter DNA Methylation Patterns of Differentiated Cells Are Largely Programmed at the Progenitor Stage

2010 ◽  
Vol 21 (12) ◽  
pp. 2066-2077 ◽  
Author(s):  
Anita L. Sørensen ◽  
Bente Marie Jacobsen ◽  
Andrew H. Reiner ◽  
Ingrid S. Andersen ◽  
Philippe Collas
Keyword(s):  
Dna Methylation ◽  
Cell Types ◽  
Molecular Evidence ◽  
Mesenchymal Progenitors ◽  
H3k27 Methylation ◽  
Differentiated Cells ◽  
Promoter Dna Methylation ◽  
Promoter Dna ◽  
A Minor ◽  
Methylation Patterns

Mesenchymal stem cells (MSCs) isolated from various tissues share common phenotypic and functional properties. However, intrinsic molecular evidence supporting these observations has been lacking. Here, we unravel overlapping genome-wide promoter DNA methylation patterns between MSCs from adipose tissue, bone marrow, and skeletal muscle, whereas hematopoietic progenitors are more epigenetically distant from MSCs as a whole. Commonly hypermethylated genes are enriched in signaling, metabolic, and developmental functions, whereas genes hypermethylated only in MSCs are associated with early development functions. We find that most lineage-specification promoters are DNA hypomethylated and harbor a combination of trimethylated H3K4 and H3K27, whereas early developmental genes are DNA hypermethylated with or without H3K27 methylation. Promoter DNA methylation patterns of differentiated cells are largely established at the progenitor stage; yet, differentiation segregates a minor fraction of the commonly hypermethylated promoters, generating greater epigenetic divergence between differentiated cell types than between their undifferentiated counterparts. We also show an effect of promoter CpG content on methylation dynamics upon differentiation and distinct methylation profiles on transcriptionally active and inactive promoters. We infer that methylation state of lineage-specific promoters in MSCs is not a primary determinant of differentiation capacity. Our results support the view of a common origin of mesenchymal progenitors.

scholarly journals Leptin gene promoter DNA methylation in WNIN obese mutant rats

2014 ◽  
Vol 13 (1) ◽  
Author(s):  
Rajender Rao Kalashikam ◽  
Padmavathi JN Inagadapa ◽  
Anju Elizabeth Thomas ◽  
Sugeetha Jeyapal ◽  
Nappan Veettil Giridharan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Gene Promoter ◽  
Promoter Dna Methylation ◽  
Promoter Dna

Dnmt3b Has Few Specific Functions In Adult Hematopoietic Stem Cells But Shows Abnormal Activity In The Absence Of Dnmt3a

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 734-734
Author(s):  
Grant A Challen ◽  
Allison Mayle ◽  
Deqiang Sun ◽  
Mira Jeong ◽  
Min Luo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Bone Marrow ◽  
De Novo ◽  
Hematopoietic Stem ◽  
Empty Vector ◽  
Closed Circle ◽  
Wide Range ◽  
Promoter Dna Methylation ◽  
Promoter Dna ◽  
Methylation Patterns

Abstract DNA methylation is one of the major epigenetic modifications in the vertebrate genome and is important for development, stem cell differentiation, and malignant transformation. DNA methylation is catalyzed by the DNA methyltransferase enzymes Dnmt1, Dnmt3a, and Dnmt3b. We have recently shown that Dnmt3a is essential for hematopoietic stem cell (HSC) differentiation. Ablation of Dnmt3a in hematopoietic cells (Mx1-CRE; Dnmt3a-KO) resulted in HSCs that could not sustain peripheral blood generation after serial transplantation, while phenotypically defined HSCs accumulated in the bone marrow. Recurrent somatic mutations in DNTM3A have been discovered in patients with a wide range of hematopoietic malignancies (AML, MDS, MPN, CML, T-ALL, T-cell lymphoma) suggesting a critical role for de novo DNA methylation in normal and leukemic hematopoiesis. As Dnmt3b is also highly expressed in HSCs and congenital mutations in DNMT3B can cause ICF (immunodeficiency, centromeric instability, and facial anomalies) syndrome, in this study we used a mouse model to investigate if Dnmt3b had distinct roles in HSCs. We conditionally inactivated Dnmt3b in HSCs using the Mx1-CRE system (Dnmt3b-KO) and performed serial competitive transplantation. Loss of Dnmt3b had minimal functional consequences for adult HSC function even after three rounds of transplantation. However, combinatorial deletion of both Dnmt3a and Dnmt3b (Dnmt3ab-dKO) exacerbated the differentiation defect seen in Dnmt3a-KO HSCs, leading to a dramatic accumulation of mutant HSCs in the bone marrow (>50-fold), suggesting a synergistic effect resulting from simultaneous ablation of both de novo DNA methyltransferases. The accumulation of Dnmt3ab-dKO HSCs cannot be attributed to altered proliferation or apoptosis, but is due to an imbalance between self-renewal and differentiation. RNA-SEQ of the mutant HSCs revealed loss of transcriptional integrity in Dnmt3ab-dKO HSCs including increased expression of repetitive elements, inappropriate mRNA splicing, and over-expression of HSC-specific genes. To examine the impact of loss of Dnmt3a and -3b on DNA methylation in HSCs, we performed Whole Genome Bisulfite Sequencing (WGBS). Ablation of both enzymes resulted in loss of DNA methylation that was much more extensive than that seen in the absence of Dnmt3a alone, while loss of Dnmt3b alone showed only minimal changes in DNA methylation compared to control HSCs. One puzzling finding was the observation that a subset of promoter CpG islands (CGIs) actually gained DNA methylation in Dnmt3a-KO HSCs. This CGI hypermethylation is a cancer methylome phenotype and was specific to Dnmt3a-KO HSCs (Figure 1A). The HSC transplant experiments suggest that Dnmt3a can compensate for Dnmt3b in HSCs, but Dnmt3b cannot reciprocate in the reverse situation. An explanation for increases in DNA methylation is that in the absence of Dnmt3a, abnormal function of Dnmt3b may lead to aberrant CGI hypermethylation as the hypermethylation was lost when both enzymes were conditionally inactivated. To confirm the mechanism, post-transplant Dnmt3ab-dKO HSCs were transduced with a retroviral vector encoding ectopic expression of Dnmt3b (MIG-Dnmt3b) or a control empty vector (MIG) and assessed for DNA methylation by bisulfite PCR. Using the promoter CGI of Praf2 as an example, enforced expression of Dnmt3b in Dnmt3ab-dKO HSCs resulted in increased DNA methylation at this loci compared to Dnmt3ab-dKO HSCs transduced with a control empty vector (MIG), control HSCs transduced with either MIG or MIG-Dnmt3b and untransduced HSCs (Figure 1B). It is possible that when Dnmt3b tries to compensate for Dnmt3a, the locus-specificity for targets is reduced, leading to aberrant DNA methylation patterns. Promoter CGI hypermethylation is a cancer phenotype observed in a wide range of tumors, including hematopoietic neoplasms driven by mutation in DNMT3A. Targeting DNMT3B in DNMT3A-mutation hematopoietic pathologies may be a therapeutic option for restoring normal DNA methylation and gene expression patterns.Figure 1Praf2 promoter DNA methylation. Open circle = unmethylated CpG, closed circle = methylated CpG. (A) DNA methylation patterns in control (Ctl), Dnmt3a-KO (3aKO), Dnmt3b-KO (3bKO) and Dnmt3ab-dKO HSCs (dKO). (B) Patterns in control and Dnmt3ab-dKO HSCs transduced with empty vector (MIG) or ectopic Dnmt3b, compared to untransduced HSCs.Figure 1. Praf2 promoter DNA methylation. Open circle = unmethylated CpG, closed circle = methylated CpG. (A) DNA methylation patterns in control (Ctl), Dnmt3a-KO (3aKO), Dnmt3b-KO (3bKO) and Dnmt3ab-dKO HSCs (dKO). (B) Patterns in control and Dnmt3ab-dKO HSCs transduced with empty vector (MIG) or ectopic Dnmt3b, compared to untransduced HSCs. Disclosures: No relevant conflicts of interest to declare.

α-Adducin gene promoter DNA methylation and the risk of essential hypertension

2017 ◽  
Vol 39 (8) ◽  
pp. 764-768 ◽  
Author(s):  
Nervana M. K. Bayoumy ◽  
Mohamed M. El-Shabrawi ◽  
Ola Farouk Leheta ◽  
Hamdy Hassan Omar
Keyword(s):  
Dna Methylation ◽  
Essential Hypertension ◽  
Gene Promoter ◽  
Promoter Dna Methylation ◽  
Promoter Dna

scholarly journals Lower ADD1 Gene Promoter DNA Methylation Increases the Risk of Essential Hypertension

PLoS ONE ◽  
2013 ◽  
Vol 8 (5) ◽  
pp. e63455 ◽  
Author(s):  
Li-Na Zhang ◽  
Pan-Pan Liu ◽  
Lingyan Wang ◽  
Fang Yuan ◽  
Leiting Xu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Essential Hypertension ◽  
Gene Promoter ◽  
Promoter Dna Methylation ◽  
Promoter Dna

A Phase I Biological Study of Azacitidine (Vidaza) to Determine the Optimal Biological Dose and Route of Administration.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1753-1753
Author(s):  
Ilan Bernstein ◽  
Hyang-Min Byun ◽  
Ann Mohrbacher ◽  
Dan Douer ◽  
Gerry Gorospe ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Phase I ◽  
Peripheral Blood ◽  
Gene Promoter ◽  
Hematologic Malignancies ◽  
Global Dna Methylation ◽  
Promoter Dna Methylation ◽  
Illumina Goldengate ◽  
Promoter Dna ◽  
Dose Levels

Abstract Abstract 1753 Poster Board I-779 Background Azacitidine (5-azacytidine, Vidaza) is a DNA methylation inhibitor with used to treat myelodysplastic syndrome (MDS). The studies which led to FDA approval based dosing and administration guidelines on clinical response. In vitro studies have demonstrated that azacitidine exerts its effect by inhibiting DNA methyltransferase in hypermethylated tumor suppressor genes in malignant cells. Research to date has not linked azacitidine dosing with biochemical and clinical response in vivo. The degree of DNA repetitive element sequence methylation (such as LINE-1) has been demonstrated to correlate with global DNA methylation and may be used to determine DNA methylation changes after treatment with azacitidine. We have conducted a phase I study to link clinical and biologic response to azacitidine. This study aims to determine the optimal dose and route of administration for azacitidine to inhibit global DNA methylation levels in the peripheral blood of patients with hematologic malignancies. Methods Patients with hematologic malignancy who provided informed consent were eligible for study inclusion, with enrollment criteria based on the specific malignancy. Patients were enrolled into one of five dose level treatment groups (25mg, 50mg, 75mg, 100mg or 150mg IV per m2 per day for 5 days) for the first course of therapy. On day 28, all patients received a course of 75mg/m2/day IV for 5 days. Subcutaneous dosing of 75mg/m2/day for 5 days was used for course three. Patients received 75mg/m2/day either SQ or IV x 5 days every 4 weeks for course four and beyond. Peripheral blood was collected on days 1, 3, and 5 during each course, and global DNA methylation was measured using bisulfite-PCR Pyrosequencing of the 6 DNA repetitive elements (LINE1, AluYb8, AluSq, Sat-alpha, D4Z4, NBL-2). Additionally, gene promoter specific DNA methylation was assessed in a subset of patients using the Illumina GoldenGate Bead Array DNA Methylation Assay which measures DNA methylation of 1505 CpG sites (807 genes). Results Seventeen patients were treated (3 at 25mg, 4 at 50mg, 4 at 75mg, 3 at 100mg, and 3 at 150mg/m2). Diagnosis included 5 patients with MDS, 10 patients with AML (2 untreated older patients, 7 relapsed or refractory patients), 1 patient with CML (Imatinib refractory), and 1 patient with non-Hodgkin's lymphoma (relapsed disease). At the time of submission, 14 patients were evaluable for response with 4 CR (1 mCr, 1 CRp), 1 PR, 6 SD and 3 PD reported. The median number of cycles given was 3 (range 1-14+). LINE1 DNA methylation decreased by 1.4, 2.3, 4.8, 1.9 and 4.0% on day 5 for the 25mg, 50mg, 75mg, 100mg, and 150mg/m2 course one dose levels respectively. Mean decrease in LINE1 DNA methylation with 75mg/m2 IV was 3.7% and only 2.6% by 75mg/m2 of azacitidine SQ. There was a large amount of inter-patient variability but less intra-patient variability in DNA methylation response to azacitidine. Conclusion Azacitidine is effective at inhibiting DNA methylation at multiple dose levels for both IV and SQ routes of administration. There is a high degree of patient-to-patient variability in DNA methylation changes, although 75mg/m2 lead to the greatest mean decrease in DNA methylation by a 5 day IV regimen. Measurement of DNA methylation of LINE1 and AluYb8 repetitive elements were the best surrogate markers for measuring overall changes in gene specific promoter DNA methylation when compared with 807 genes assessed by the Illumina GoldenGate platform. High-throughput gene promoter DNA methylation analysis revealed subtle changes in DNA methylation, though gene specific changes could not be linked to therapeutic activity. Disclosures Off Label Use: Azacitidine in hematologic malignancies other than MDS. Mohrbacher:Celgene: Honoraria, Speakers Bureau. Gorospe:Novartis: Honoraria, Speakers Bureau. Yang:Celgene: Honoraria, Research Funding, Speakers Bureau.

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