scholarly journals DNA Methylation Levels of the TBX5 Gene Promoter Are Associated with Congenital Septal Defects in Mexican Paediatric Patients

Biology ◽  
2022 ◽  
Vol 11 (1) ◽  
pp. 96
Author(s):  
Esbeidy García-Flores ◽  
José Manuel Rodríguez-Pérez ◽  
Verónica Marusa Borgonio-Cuadra ◽  
Gilberto Vargas-Alarcón ◽  
Juan Calderón-Colmenero ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Heart Development ◽  
Operating Characteristic ◽  
Morphological Changes ◽  
Heart Defects ◽  
Gene Promoter ◽  
Cpg Sites ◽  
Septal Defects ◽  
Average Methylation ◽  
Tbx5 Gene

The TBX5 gene regulates morphological changes during heart development, and it has been associated with epigenetic abnormalities observed in congenital heart defects (CHD). The aim of this research was to evaluate the association between DNA methylation levels of the TBX5 gene promoter and congenital septal defects. DNA methylation levels of six CpG sites in the TBX5 gene promoter were evaluated using pyrosequencing analysis in 35 patients with congenital septal defects and 48 controls. Average methylation levels were higher in individuals with congenital septal defects than in the controls (p < 0.004). In five CpG sites, we also found higher methylation levels in patients than in the controls (p < 0.05). High methylation levels were associated with congenital septal defects (OR = 3.91; 95% CI = 1.02–14.8; p = 0.045). The analysis of Receiver Operating Characteristic (ROC) showed that the methylation levels of the TBX5 gene could be used as a risk marker for congenital septal defects (AUC = 0.68, 95% CI = 0.56–0.80; p = 0.004). Finally, an analysis of environmental factors indicated that maternal infections increased the risk (OR = 2.90; 95% CI = 1.01–8.33; p = 0.048) of congenital septal defects. Our data suggest that a high DNA methylation of the TBX5 gene could be associated with congenital septal defects.

EPIGENETIC ALTERATIONS ASSOCIATED WITH PREMATURE OVARIAN FAILURE

2008 ◽  
Vol 31 (4) ◽  
pp. 11
Author(s):  
Manda Ghahremani ◽  
Courtney W Hannah ◽  
Maria Peneherrera ◽  
Karla L Bretherick ◽  
Margo R Fluker ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Premature Ovarian Failure ◽  
Promoter Region ◽  
Gene Promoter ◽  
Ovarian Failure ◽  
P Value ◽  
Epigenetic Alterations ◽  
Methylation Array ◽  
Cpg Sites ◽  
Deficient Mice

Background/Purpose: Premature ovarian failure (POF) affects 1% of women with a largely idiopathic and poorly understood etiology. The objective of this study was to identify specific epigenetic alterations by measuring DNA methylation of gene regulatory regions in women with POF vs. controls. Methods: Blood samples were collected from idiopathic POFpatients (Amenorrhea for at least 3 months and 2 serum FSH levels of > 40mIU/ml obtained > 1 month apart prior to age 40) and control women (CW) (healthy pregnancy after age 37 with out a pregnancy loss). Genomic DNA was extracted from EDTA anticoagulated blood and bisulfite converted for analysis using the Illumina Golden Gate Methylation Panel which measures DNA methylation at 1506 CpG sites in the promoter regions of 807 genes in 10 POF and 12 CW. Candidate genes with altered epigenetic marks between POF and CW at a nominal P-value < 0.05 were identified using a t-testcomparison within the Illumina bead studio software. Genes of interest were further analyzed for quantitative methylation at specific CpG sites using pyrosequencing in 30 POF and 30 CW. Results: Comparison of DNA methylation profiles of our initial POF and CW groups identified several genes with statistically significanthyper- or hypo- methylation in the POF group (P < 0.05), including the Androgen Receptor (AR)promoter region, which was significantly hypermethylated. To further validate these results, DNA methylation of the AR gene promoter was quantified bypryosequencing in a larger group of POF and CW. Pyrosequencing further confirmed a significantly higher DNA methylation of the AR promoter region inPOF vs. CW (P=0.007). Conclusions: This is a novel study identifying epigenetic alterations in POF. The hypermethylation of the AR gene in POF patients may cause decreased level of the AR in these women. This is especially interesting given a recent report of induced POF in AR deficient mice^1. Specific epigenetic markers, as identified by DNA methylation array profiling in blood, may serve as useful biomarkers for POF and other fertility disorders. However, it will need to be determined if these methylation changes are present prior to diagnosis, or are a consequence of menopause itself. Reference: 1.Hiroko S. et al. Premature ovarian failure in androgenreceptor deficient mice. PNAS;103:224-9

scholarly journals First report of polymorphisms in MTRR, GATA4, VEGF, and ISL1 genes in Pakistani children with isolated ventricular septal defects (VSD)

2021 ◽  
Vol 47 (1) ◽  
Author(s):  
Sumbal Sarwar ◽  
Farah Ehsan ◽  
Shabana ◽  
Amna Tahir ◽  
Mahrukh Jamil ◽  
...  
Keyword(s):  
Heart Development ◽  
Heart Defects ◽  
Demographic Data ◽  
Gene Variant ◽  
Nucleotide Polymorphisms ◽  
Ventricular Septal Defects ◽  
First Report ◽  
Number Of Children ◽  
Septal Defects ◽  
Genotype Frequencies

Abstract Background Ventricular septal defects (VSDs) are malformations in the septum separating the heart’s ventricles. VSDs may present as a single anomaly (isolated/nonsyndromic VSD) or as part of a group of phenotypes (syndromic VSD). The exact location of the defect is crucial in linking the defect to the underlying genetic cause. The number of children visiting cardiac surgery units is constantly increasing. However, there are no representative data available on the genetics of VSDs in Pakistani children. Methods Two hundred forty-two subjects (121 VSD children and 121 healthy controls) were recruited from pediatric cardiac units of Lahore. The clinical and demographic data of the subjects were collected. A total of four SNPs, one each from MTRR, GATA4, VEGF, and ISL1 genes were genotyped by PCR-RFLP. Results The results showed that the minor allele (T) frequency (MAFs) for the MTRR gene variant rs1532268 (c.524C > T) was 0.20 and 0.41 in the controls and the cases, respectively, with the genotype frequencies 3, 35, 62% in the controls and 12, 59 and 29% in the cases for TT, CT, CC genotypes, respectively (allelic OR: 5.73, CI: 3.82–8.61, p-value: 5.11 × 10− 7). For the GATA4 variant rs104894073 (c.886G > A), the MAF for the controls and the cases was 0.16 and 0.37, respectively, the frequencies of AA, GA and GG genotypes were 2, 28, and 70% in the controls and 5, 64 and 31% of the cases (allelic OR: 3.08, CI: 2.00–4.74, p-value: 8.36 × 10− 8). The rs699947 (c.-2578C > A) of VEGF gene showed MAF 0.36 and 0.53 for the controls and cases, respectively, with the genotype frequencies 13, 42, and 45% in the controls and 22, 15, and 63% in the cases for the AA, CA, CC (allelic OR: 2.03, CI: 1.41–2.92, p-value: 0.0001). The ISL1 gene variant rs6867206 (g.51356860 T > C), the MAFs were 0.26 and 0.31 in the controls and cases, respectively. The genotype frequencies were 48, 52, 0% in the controls and 39, 61, 0% in the cases for TT, TC, CC genotypes (allelic OR: 0.27, CI: 0.85–1.89, p-value: 0.227). The MTRR, GATA4 and VEGF variants showed association while ISL1 variant did not appear to be associated with the VSD in the recruited cohort. Conclusion This first report in Pakistani children demonstrates that single nucleotide polymorphisms in genes encoding transcription factors, signaling molecules and structural heart genes involved in fetal heart development are associated with developmental heart defects., however further work is needed to validate the results of the current investigation.

scholarly journals Changes in DNA methylation during pregnancy and after delivery

2021 ◽  
Author(s):  
Ming-Wei Lin ◽  
Mong-Hsun Tsai ◽  
Ching-Yu Shih ◽  
Yi-Yun Tai ◽  
Chien-Nan Lee ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Morphological Changes ◽  
Methylation Pattern ◽  
Fine Tuning ◽  
Cpg Sites ◽  
Protein Ubiquitination ◽  
Maternal Adaptation ◽  
Ubiquitination Pathway ◽  
Dna Methylation Pattern ◽  
Pregnant State

Abstract Background Gestational adaptation takes place soon after fertilization and continues throughout pregnancy, while women return to a pre-pregnancy state after delivery and lactation. However, little is known about the role of DNA methylation in the fine tuning of maternal physiology. In this study, we investigated whether and how the DNA methylation pattern changes in the three trimesters and after delivery in ten uncomplicated pregnancies. Results DNA methylation was measured using Human MethylationEPIC BeadChip. There are 14,018 CpG sites with statistically significant changes in DNA methylation over the four time periods (p < .001). Overall, DNA methylation of the non-pregnant state was higher than that of the three trimesters (p < .001), with the protein ubiquitination pathway the top canonical pathway involved. We classified these CpG sites into nine groups according to the changes in the three trimesters. During pregnancy, most CpG sites (61.63%) had subtle or no changes in DNA methylation (Group 9). There were 3,173 (22.64%) CpG sites in Group 7 and 995 (7.1%) CpG sites in Group 8, which were the two groups with DNA methylation changes between the first and second trimesters. The top systems involved in these two groups were associated with embryonic development and organ morphological changes, as shown by the IPA analysis. Conclusion The DNA methylation pattern changes between trimesters, which may be involved in maternal adaptation to pregnancy. Meanwhile, the DNA methylation patterns during pregnancy and in the postpartum period were different, implying that puerperium repair may also act through DNA methylation mechanisms.

Catechol-O-methyltransferase gene promoter methylation as a peripheral biomarker in male schizophrenia

2017 ◽  
Vol 44 ◽  
pp. 39-46 ◽  
Author(s):  
S. Gao ◽  
J. Cheng ◽  
G. Li ◽  
T. Sun ◽  
Y. Xu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Operating Characteristic ◽  
Epigenetic Modification ◽  
Gene Promoter ◽  
Clinical Value ◽  
Bisulfite Pyrosequencing ◽  
Methyltransferase Gene ◽  
Genetic And Environmental Factors ◽  
Male Specific ◽  
Pyrosequencing Technology

AbstractAs an epigenetic modification, DNA methylation may reflect the interaction between genetic and environmental factors in the development of schizophrenia (SCZ). Catechol-O-methyltransferase (COMT) gene is a promising candidate gene of SCZ. In the present study, we investigate the association of COMT methylation with the risk of SCZ using bisulfite pyrosequencing technology. Significant association between DNA methylation of COMT and the risk of SCZ is identified (P = 1.618e−007). A breakdown analysis by gender shows that the significance is driven by males (P = 3.310e−009), but not by females. DNA methylation of COMT is not significantly associated with SCZ clinical phenotypes, including p300 and cysteine level. No interaction is found between COMT genotypes and the percent methylation of this gene. Receiver operating characteristic (ROC) curve shows that DNA methylation of COMT is able to predict the SCZ risk in males (area under curve [AUC] = 0.802, P = 1.91e−007). The current study indicates the clinical value of COMT methylation as a potential male-specific biomarker in SCZ diagnosis.

scholarly journals Mechanosensitive Pathways in Heart Development: Findings from Chick Embryo Studies

2021 ◽  
Vol 8 (4) ◽  
pp. 32
Author(s):  
Maha Alser ◽  
Samar Shurbaji ◽  
Huseyin C. Yalcin
Keyword(s):  
Chick Embryo ◽  
Heart Development ◽  
Congenital Heart ◽  
Morphological Changes ◽  
Heart Defects ◽  
Genetic Regulation ◽  
The Body ◽  
Embryonic Chick ◽  
Chemical Treatments ◽  
Developing Heart

The heart is the first organ that starts to function in a developing embryo. It continues to undergo dramatic morphological changes while pumping blood to the rest of the body. Genetic regulation of heart development is partly governed by hemodynamics. Chick embryo is a major animal model that has been used extensively in cardiogenesis research. To reveal mechanosensitive pathways, a variety of surgical interferences and chemical treatments can be applied to the chick embryo to manipulate the blood flow. Such manipulations alter expressions of mechanosensitive genes which may anticipate induction of morphological changes in the developing heart. This paper aims to present different approaches for generating clinically relevant disturbed hemodynamics conditions using this embryonic chick model and to summarize identified mechanosensitive genes using the model, providing insights into embryonic origins of congenital heart defects.

scholarly journals NOX2 Is Critical to Endocardial to Mesenchymal Transition and Heart Development

2020 ◽  
Vol 2020 ◽  
pp. 1-12
Author(s):  
Hoda Moazzen ◽  
Yan Wu ◽  
Anish Engineer ◽  
Xiangru Lu ◽  
Simran Aulakh ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Heart Development ◽  
Ex Vivo ◽  
Heart Defects ◽  
Embryonic Heart ◽  
Abnormal Development ◽  
Endocardial Cushion ◽  
Atrioventricular Canal ◽  
Mesenchymal Transition ◽  
Septal Defects

NADPH oxidases (NOX) are a major source of reactive oxygen species (ROS) production in the heart. ROS signaling regulates gene expression, cell proliferation, apoptosis, and migration. However, the role of NOX2 in embryonic heart development remains elusive. We hypothesized that deficiency of Nox2 disrupts endocardial to mesenchymal transition (EndMT) and results in congenital septal and valvular defects. Our data show that 34% of Nox2-/- neonatal mice had various congenital heart defects (CHDs) including atrial septal defects (ASD), ventricular septal defects (VSD), atrioventricular canal defects (AVCD), and malformation of atrioventricular and aortic valves. Notably, Nox2-/- embryonic hearts show abnormal development of the endocardial cushion as evidenced by decreased cell proliferation and an increased rate of apoptosis. Additionally, Nox2 deficiency disrupted EndMT of atrioventricular cushion explants ex vivo. Furthermore, treatment with N-acetylcysteine (NAC) to reduce ROS levels in the wild-type endocardial cushion explants decreased the number of cells undergoing EndMT. Importantly, deficiency of Nox2 was associated with reduced expression of Gata4, Tgfβ2, Bmp2, Bmp4, and Snail1, which are critical to endocardial cushion and valvoseptal development. We conclude that NOX2 is critical to EndMT, endocardial cushion cell proliferation, and normal embryonic heart development.

Functional analysis of the novel sequence variants within TBX5 gene promoter in patients with ventricular septal defects

2012 ◽  
Vol 160 (3) ◽  
pp. 237-238 ◽  
Author(s):  
Jiping Shan ◽  
Shuchao Pang ◽  
Yanli Qiao ◽  
Liming Ma ◽  
Haihua Wang ◽  
...  
Keyword(s):  
Functional Analysis ◽  
Gene Promoter ◽  
Sequence Variants ◽  
The Novel ◽  
Ventricular Septal Defects ◽  
Septal Defects ◽  
Tbx5 Gene

scholarly journals Impaired labyrinth formation prevents the establishment of the maternal-fetal interface in conditional Hand1-deficient mice

2020 ◽  
Author(s):  
Jennifer A. Courtney ◽  
James Cnota ◽  
Helen Jones
Keyword(s):  
Heart Development ◽  
Histological Analysis ◽  
Heart Defects ◽  
Placental Development ◽  
Hypoplastic Left Heart ◽  
Septal Defects ◽  
And Function ◽  
Left Heart Syndrome ◽  
Deficient Mice ◽  
Fetal Vessels

AbstractIntroductionCongenital heart defects (CHD) affect approximately 1% of all live births, and often require complex surgeries at birth. Placental development and function is vital to ensure normal fetal development. We have previously demonstrated abnormal placental development and vascularization in human CHD placentas, and placental expression changes in genes important for heart development. Hand1 has roles in both heart and placental development and is implicated in CHDs including double right outlet, hypoplastic left heart syndrome, and septal defects; however, Hand1 involvement in placental vascularization and development is under-investigated. We utilized the Hand1A126fs/+ murine model to investigate Hand1 in placentation and vascularization.MethodsHand1A126fs/+ female mice were time-mated with Nkx2.5cre (placenta- and heart-specific) males to produce either Nkx2.5cre;Hand1+/+ or Nkx2.5cre;Hand1A126fs/+ fetuses. Feto-placental units were harvested at timepoints from E8.5 to E14.5 for histological analysis; vascular assessment by immunohistochemistry for Hand1, CD-31, and CK-7; and angiogenesis by qPCR.ResultsEmbryonic lethality occurs in Nkx2.5cre/Hand1A126fs/+ by E14.5 due to a failure of placental labyrinth formation and vascularization. Chorionic trophoblasts did not form, although trophoblast giant cell subtypes were present. Fetal vessels failed to develop properly and were significantly lower in the labyrinth by day E12.5. Placental growth factor levels were significantly increased, and Angiopoietin2 expression trended higher in Nkx2.5cre/Hand1 A126fs/+ placental labyrinths compared to control littermates.ConclusionWe demonstrate that Hand1 expression in placental chorion and trophoblast is necessary for proper patterning of the labyrinth and vascularization within the labyrinth. Multiple angiogenic factors known to be expressed in trophoblast were disrupted in Nkx2.5cre/Hand1 A126fs/+ placental labyrinths compared to control littermates. Alterations in Hand1 expression represent a potential mechanism for abnormal placentation and early miscarriage in cases of CHD.

scholarly journals A TBX5 NONSENSE MUTATION IN SIBLINGS WITH DIVERGENT PHENOTYPES ASSOCIATED WITH ISOLATED SEPTAL DEFECTS

2017 ◽  
Vol 10 (9) ◽  
pp. 126
Author(s):  
Yashvanthi Borkar ◽  
Krishnananda Nayak ◽  
Ranjan K Shetty ◽  
Rajasekhar Moka
Keyword(s):  
Heart Development ◽  
Sequence Variation ◽  
Stop Codon ◽  
Premature Stop Codon ◽  
Tryptophan Residue ◽  
Sequence Variant ◽  
Septal Defects ◽  
Congenital Heart Malformations ◽  
Tbx5 Gene

  Objective: Heart septal defects (HSD) account for 50% of the congenital heart malformations and are characterized by the hole in the wall of tissue which separates the heart chambers. The known causes of the SD are multifactorial and complex inheritance.Methods: Isolated 15 subjects with ostium secundum atrial SD (OS-ASD) and one subject with perimembranous ventricular SD (VSD) among 125 clinically diagnosed SD were included in the study. Sanger sequencing was performed for all the exons of TBX5 genes using genomic DNA of these patients.Results: Sequence variation c.444 G>A substitution, leads to the alteration of tryptophan residue into premature stop codon at codon 148. We observed a divergent phenotype within a family of four, where one sibling and the mother had OS-ASD, another sibling had phenotype of perimembranous VSD, and the father had normal genotype.Conclusion: We believe that this novel sequence variant in TBX5 gene is one of the factors in the SD and may hold a key determining the role of TBX5 gene in the heart development.

scholarly journals Birthweight DNA methylation signatures in infant saliva

2021 ◽  
Vol 13 (1) ◽  
Author(s):  
Chiara Moccia ◽  
Maja Popovic ◽  
Elena Isaevska ◽  
Valentina Fiano ◽  
Morena Trevisan ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cord Blood ◽  
Gestational Age ◽  
Low Birthweight ◽  
Continuous Variable ◽  
Linear Regression Models ◽  
Association Analyses ◽  
Cpg Sites ◽  
Adverse Health Outcomes ◽  
The Look

Abstract Background Low birthweight has been repeatedly associated with long-term adverse health outcomes and many non-communicable diseases. Our aim was to look-up cord blood birthweight-associated CpG sites identified by the PACE Consortium in infant saliva, and to explore saliva-specific DNA methylation signatures of birthweight. Methods DNA methylation was assessed using Infinium HumanMethylation450K array in 135 saliva samples collected from children of the NINFEA birth cohort at an average age of 10.8 (range 7–17) months. The association analyses between birthweight and DNA methylation variations were carried out using robust linear regression models both in the exploratory EWAS analyses and in the look-up of the PACE findings in infant saliva. Results None of the cord blood birthweight-associated CpGs identified by the PACE Consortium was associated with birthweight when analysed in infant saliva. In saliva EWAS analyses, considering a false discovery rate p-values < 0.05, birthweight as continuous variable was associated with DNA methylation in 44 CpG sites; being born small for gestational age (SGA, lower 10th percentile of birthweight for gestational age according to WHO reference charts) was associated with DNA methylation in 44 CpGs, with only one overlapping CpG between the two analyses. Despite no overlap with PACE results at the CpG level, two of the top saliva birthweight CpGs mapped at genes associated with birthweight with the same direction of the effect also in the PACE Consortium (MACROD1 and RPTOR). Conclusion Our study provides an indication of the birthweight and SGA epigenetic salivary signatures in children around 10 months of age. DNA methylation signatures in cord blood may not be comparable with saliva DNA methylation signatures at about 10 months of age, suggesting that the birthweight epigenetic marks are likely time and tissue specific.

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