scholarly journals Examination of CA1 Hippocampal DNA Methylation as a Mechanism for Closing of Estrogen’s Critical Window

2021 ◽  
Vol 13 ◽  
Author(s):  
Puja Sinha ◽  
Asha Rani ◽  
Ashok Kumar ◽  
Alberto Riva ◽  
Jason Orr Brant ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Brain Aging ◽  
Differential Methylation ◽  
Female Rats ◽  
Signaling Cascades ◽  
Estrogen Signaling ◽  
Critical Window ◽  
Protein Receptor ◽  
Nmda Receptor Function ◽  
Genome Bisulfite Sequencing

There is a critical window for estrogen replacement therapy, beyond which estradiol (E2) fails to enhance cognition and N-methyl-D-aspartate (NMDA) receptor function, and E2-responsive transcription decreases. Much less attention has been given to the mechanism for closing of the critical window, which is thought to involve the decline in estrogen signaling cascades, possibly involving epigenetic mechanisms, including DNA methylation. This study investigated changes in DNA methylation in region CA1 of the hippocampus of ovariectomized female rats over the course of brain aging and in response to E2-treatment, using whole genome bisulfite sequencing. Differential methylation of CpG and non-CpG (CHG and CHH) sites and associated genes were characterized in aged controls (AC), middle-age controls (MC), and young controls (YC) and differential methylation in response to E2-treatment (T) was examined in each age group (AT-AC, MT-MC, and YT-YC). Possible candidate genes for the closing of the critical window were defined as those that were hypomethylated by E2-treatment in younger animals, but were unresponsive in aged animals. Gene ontology categories for possible critical window genes were linked to response to hormones (Adcyap1, Agtr2, Apob, Ahr, Andpro, Calm2, Cyp4a2, Htr1b, Nr3c2, Pitx2, Pth, Pdk4, Slc2a2, Tnc, and Wnt5a), including G-protein receptor signaling (Gpr22 and Rgs4). Other possible critical window genes were linked to glutamate synapses (Nedd4, Grm1, Grm7, and Grin3a). These results suggest that decreased E2 signaling with advanced age, and/or prolonged E2 deprivation, results in methylation of E2-responsive genes, including those involved in rapid E2 signaling, which may limit subsequent transcription.

scholarly journals At the X-Roads of Sex and Genetics in Pulmonary Arterial Hypertension

Genes ◽  
2020 ◽  
Vol 11 (11) ◽  
pp. 1371
Author(s):  
Meghan M. Cirulis ◽  
Mark W. Dodson ◽  
Lynn M. Brown ◽  
Samuel M. Brown ◽  
Tim Lahm ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Bone Morphogenetic Protein ◽  
Pulmonary Arteries ◽  
Bmp Signaling ◽  
Signaling Cascades ◽  
Estrogen Signaling ◽  
Protein Receptor ◽  
Morphogenetic Protein ◽  
Pulmonary Arterial

Group 1 pulmonary hypertension (pulmonary arterial hypertension; PAH) is a rare disease characterized by remodeling of the small pulmonary arteries leading to progressive elevation of pulmonary vascular resistance, ultimately leading to right ventricular failure and death. Deleterious mutations in the serine-threonine receptor bone morphogenetic protein receptor 2 (BMPR2; a central mediator of bone morphogenetic protein (BMP) signaling) and female sex are known risk factors for the development of PAH in humans. In this narrative review, we explore the complex interplay between the BMP and estrogen signaling pathways, and the potentially synergistic mechanisms by which these signaling cascades increase the risk of developing PAH. A comprehensive understanding of these tangled pathways may reveal therapeutic targets to prevent or slow the progression of PAH.

scholarly journals Environment-driven reprogramming of gamete DNA methylation occurs during maturation and is transmitted intergenerationally in Atlantic Salmon

2021 ◽  
Author(s):  
Kyle Wellband ◽  
David Roth ◽  
Tommi Linnansaari ◽  
R Allen Curry ◽  
Louis Bernatchez
Keyword(s):  
Dna Methylation ◽  
Atlantic Salmon ◽  
Early Life ◽  
Empirical Support ◽  
Differential Methylation ◽  
Transgenerational Plasticity ◽  
Phenotypic Differences ◽  
Genome Bisulfite Sequencing ◽  
First Time

Abstract An epigenetic basis for transgenerational plasticity in animals is widely theorized, but convincing empirical support is limited by taxa-specific differences in the presence and role of epigenetic mechanisms. In teleost fishes, DNA methylation generally does not undergo extensive reprogramming and has been linked with environmentally-induced intergenerational effects, but solely in the context of early life environmental differences. Using whole genome bisulfite sequencing, we demonstrate that differential methylation of sperm occurs in response to captivity during the maturation of Atlantic Salmon (Salmo salar), a species of major economic and conservation significance. We show that adult captive exposure further induces differential methylation in an F1 generation that is associated with fitness-related phenotypic differences. Some genes targeted with differential methylation were consistent with genes differential methylated in other salmonid fishes experiencing early-life hatchery rearing, as well as genes under selection in domesticated species. Our results support a mechanism of transgenerational plasticity mediated by intergenerational inheritance of DNA methylation acquired late in life for salmon. To our knowledge, this is the first-time environmental variation experienced later in life has been directly demonstrated to influence gamete DNA methylation in fish.

scholarly journals Environment-driven reprogramming of gamete DNA methylation occurs during maturation and influences offspring fitness in salmon

2020 ◽  
Author(s):  
Kyle Wellband ◽  
David Roth ◽  
Tommi Linnansaari ◽  
R. Allen Curry ◽  
Louis Bernatchez
Keyword(s):  
Dna Methylation ◽  
Early Life ◽  
Bisulfite Sequencing ◽  
Empirical Support ◽  
Differential Methylation ◽  
Transgenerational Plasticity ◽  
Phenotypic Differences ◽  
Genome Bisulfite Sequencing ◽  
F1 Generation

AbstractAn epigenetic basis for transgenerational plasticity is widely theorized but convincing empirical support is limited by taxa-specific differences in the presence and role of epigenetic mechanisms. In teleost fishes, DNA methylation does not undergo extensive reprogramming and has been linked with environmentally-induced intergenerational effects, but solely in the context of early life environmental differences. Using whole genome bisulfite sequencing, we demonstrate that differential methylation of sperm occurs in response to captivity during maturation for Atlantic Salmon (Salmo salar), a species of major economic and conservation significance. We show that adult captive exposure further induces differential methylation in an F1 generation that is associated with fitness-related phenotypic differences. Gene targets of differential methylation are consistent with salmonid fishes experiencing early-life hatchery rearing as well as targets of selection in domesticated species. Our results support a mechanism of transgenerational plasticity mediated by intergenerational inheritance of DNA methylation acquired late in life for salmon.

scholarly journals Differential Methylation in the GSTT1 Regulatory Region in Sudden Unexplained Death and Sudden Unexpected Death in Epilepsy

2021 ◽  
Vol 22 (6) ◽  
pp. 2790
Author(s):  
Steffan Noe Christiansen ◽  
Stine Bøttcher Jacobsen ◽  
Jeppe Dyrberg Andersen ◽  
Marie-Louise Kampmann ◽  
Linea Christine Trudsø ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Cardiac Tissue ◽  
Heart Diseases ◽  
Regulatory Region ◽  
Differential Methylation ◽  
Sudden Unexpected Death ◽  
Diagnostic Challenge ◽  
Unexpected Death ◽  
Sudden Unexplained Death ◽  
Unexplained Death

Sudden cardiac death (SCD) is a diagnostic challenge in forensic medicine. In a relatively large proportion of the SCDs, the deaths remain unexplained after autopsy. This challenge is likely caused by unknown disease mechanisms. Changes in DNA methylation have been associated with several heart diseases, but the role of DNA methylation in SCD is unknown. In this study, we investigated DNA methylation in two SCD subtypes, sudden unexplained death (SUD) and sudden unexpected death in epilepsy (SUDEP). We assessed DNA methylation of more than 850,000 positions in cardiac tissue from nine SUD and 14 SUDEP cases using the Illumina Infinium MethylationEPIC BeadChip. In total, six differently methylated regions (DMRs) between the SUD and SUDEP cases were identified. The DMRs were located in proximity to or overlapping genes encoding proteins that are a part of the glutathione S-transferase (GST) superfamily. Whole genome sequencing (WGS) showed that the DNA methylation alterations were not caused by genetic changes, while whole transcriptome sequencing (WTS) showed that DNA methylation was associated with expression levels of the GSTT1 gene. In conclusion, our results indicate that cardiac DNA methylation is similar in SUD and SUDEP, but with regional differential methylation in proximity to GST genes.

scholarly journals Stable DNMT3L overexpression in SH-SY5Y neurons recreates a facet of the genome-wide Down syndrome DNA methylation signature

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Benjamin I. Laufer ◽  
J. Antonio Gomez ◽  
Julia M. Jianu ◽  
Janine M. LaSalle
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Neuronal Differentiation ◽  
Molecular Mechanisms ◽  
Cpg Island ◽  
Differential Methylation ◽  
Chromosome 21 ◽  
Pairwise Comparisons ◽  
Genome Wide ◽  
A Genome

Abstract Background Down syndrome (DS) is characterized by a genome-wide profile of differential DNA methylation that is skewed towards hypermethylation in most tissues, including brain, and includes pan-tissue differential methylation. The molecular mechanisms involve the overexpression of genes related to DNA methylation on chromosome 21. Here, we stably overexpressed the chromosome 21 gene DNA methyltransferase 3L (DNMT3L) in the human SH-SY5Y neuroblastoma cell line and assayed DNA methylation at over 26 million CpGs by whole genome bisulfite sequencing (WGBS) at three different developmental phases (undifferentiated, differentiating, and differentiated). Results DNMT3L overexpression resulted in global CpG and CpG island hypermethylation as well as thousands of differentially methylated regions (DMRs). The DNMT3L DMRs were skewed towards hypermethylation and mapped to genes involved in neurodevelopment, cellular signaling, and gene regulation. Consensus DNMT3L DMRs showed that cell lines clustered by genotype and then differentiation phase, demonstrating sets of common genes affected across neuronal differentiation. The hypermethylated DNMT3L DMRs from all pairwise comparisons were enriched for regions of bivalent chromatin marked by H3K4me3 as well as differentially methylated sites from previous DS studies of diverse tissues. In contrast, the hypomethylated DNMT3L DMRs from all pairwise comparisons displayed a tissue-specific profile enriched for regions of heterochromatin marked by H3K9me3 during embryonic development. Conclusions Taken together, these results support a mechanism whereby regions of bivalent chromatin that lose H3K4me3 during neuronal differentiation are targeted by excess DNMT3L and become hypermethylated. Overall, these findings demonstrate that DNMT3L overexpression during neurodevelopment recreates a facet of the genome-wide DS DNA methylation signature by targeting known genes and gene clusters that display pan-tissue differential methylation in DS.

scholarly journals Aberrant G protein-receptor expression is associated with DNA methylation in aldosterone-producing adenoma

2018 ◽  
Vol 461 ◽  
pp. 100-104 ◽  
Author(s):  
Kiyotaka Itcho ◽  
Kenji Oki ◽  
Kazuhiro Kobuke ◽  
Yoko Yoshii ◽  
Haruya Ohno ◽  
...  
Keyword(s):  
Dna Methylation ◽  
G Protein ◽  
Receptor Expression ◽  
Protein Receptor ◽  
Aldosterone Producing Adenoma

106 The Effects of Fetal Programming on Offspring Pancreas DNA Methylation

2021 ◽  
Vol 99 (Supplement_3) ◽  
pp. 54-55
Author(s):  
Maria L Hoffman
Keyword(s):  
Dna Methylation ◽  
Fetal Programming ◽  
Maternal Nutrition ◽  
Maternal Diet ◽  
Multiple Generations ◽  
Livestock Species ◽  
Maternal Programming ◽  
Genome Bisulfite Sequencing ◽  
The Many ◽  
Methylation Patterns

Abstract It has been well documented that fetal programming, caused by changes to the maternal environment during pregnancy, can impact the overall health and growth of the offspring in livestock and non-livestock species alike. These effects are observed in the F1 offspring as well as across subsequent generations; however, the mechanisms by which this occurs are still poorly understood. Epigenetics is one of the many mechanisms that is hypothesized to have a role in fetal programming and may be mediating the observed effects across multiple generations. It has been demonstrated by others that DNA methylation patterns can be altered by an individuals’ diet and that the pancreas is vulnerable to the effects of fetal programming. Therefore, we evaluated the effects of poor maternal nutrition during gestation on the pancreas tissue of lambs. We have demonstrated that maternal under- or overnutrition during gestation alters the DNA methylation patterns of the offspring pancreas tissue with these effects being diet dependent and sex specific. We have also begun evaluating the effects of maternal diet in murine models using whole-genome bisulfite sequencing to compare species differences and determine if there are any changes conserved across species. This will allow us to focus on a smaller number of critical factors in individuals as they age and across multiple generations in livestock species such as sheep and cattle. From these data we will be able to elucidate the role DNA methylation has in mediating the effects of maternal programming in the pancreas tissue.

scholarly journals Low-pass whole genome bisulfite sequencing of neonatal dried blood spots identifies a role for RUNX1 in Down syndrome DNA methylation profiles

2020 ◽  
Author(s):  
Benjamin I Laufer ◽  
Hyeyeon Hwang ◽  
Julia M Jianu ◽  
Charles E Mordaunt ◽  
Ian F Korf ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Down Syndrome ◽  
Early Life ◽  
Trisomy 21 ◽  
Bisulfite Sequencing ◽  
Dried Blood Spots ◽  
Whole Genome ◽  
Genome Wide ◽  
Low Pass ◽  
Genome Bisulfite Sequencing

Abstract Neonatal dried blood spots (NDBS) are a widely banked sample source that enables retrospective investigation into early life molecular events. Here, we performed low-pass whole genome bisulfite sequencing (WGBS) of 86 NDBS DNA to examine early life Down syndrome (DS) DNA methylation profiles. DS represents an example of genetics shaping epigenetics, as multiple array-based studies have demonstrated that trisomy 21 is characterized by genome-wide alterations to DNA methylation. By assaying over 24 million CpG sites, thousands of genome-wide significant (q < 0.05) differentially methylated regions (DMRs) that distinguished DS from typical development and idiopathic developmental delay were identified. Machine learning feature selection refined these DMRs to 22 loci. The DS DMRs mapped to genes involved in neurodevelopment, metabolism, and transcriptional regulation. Based on comparisons with previous DS methylation studies and reference epigenomes, the hypermethylated DS DMRs were significantly (q < 0.05) enriched across tissues while the hypomethylated DS DMRs were significantly (q < 0.05) enriched for blood-specific chromatin states. A ~28 kb block of hypermethylation was observed on chromosome 21 in the RUNX1 locus, which encodes a hematopoietic transcription factor whose binding motif was the most significantly enriched (q < 0.05) overall and specifically within the hypomethylated DMRs. Finally, we also identified DMRs that distinguished DS NDBS based on the presence or absence of congenital heart disease (CHD). Together, these results not only demonstrate the utility of low-pass WGBS on NDBS samples for epigenome-wide association studies, but also provide new insights into the early life mechanisms of epigenomic dysregulation resulting from trisomy 21.

scholarly journals Age-related disturbances in DNA (hydroxy)methylation in APP/PS1 mice

2018 ◽  
Vol 9 (1) ◽  
pp. 190-202 ◽  
Author(s):  
Leonidas Chouliaras ◽  
Roy Lardenoije ◽  
Gunter Kenis ◽  
Diego Mastroeni ◽  
Patrick R. Hof ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Dna Methylation ◽  
Brain Aging ◽  
Wild Type ◽  
Dna Hydroxymethylation ◽  
Quantitative Immunohistochemistry ◽  
Age Related ◽  
Aberrant Dna Methylation ◽  
Methylation Patterns ◽  
Age Related Changes

Abstract Brain aging has been associated with aberrant DNA methylation patterns, and changes in the levels of DNA methylation and associated markers have been observed in the brains of Alzheimer’s disease (AD) patients. DNA hydroxymethylation, however, has been sparsely investigated in aging and AD. We have previously reported robust decreases in 5-methylcytosine (5-mC) and 5-hydroxymethylcytosine (5-hmC) in the hippocampus of AD patients compared to non-demented controls. In the present study, we investigated 3- and 9-month-old APPswe/PS1ΔE9 transgenic and wild-type mice for possible age-related alterations in 5-mC and 5-hmC levels in three hippocampal sub-regions using quantitative immunohistochemistry. While age-related increases in levels of both 5-mC and 5-hmC were found in wild-type mice, APPswe/PS1ΔE9 mice showed decreased levels of 5-mC at 9 months of age and no age-related changes in 5-hmC throughout the hippocampus. Altogether, these findings suggest that aberrant amyloid processing impact on the balance between DNA methylation and hydroxymethylation in the hippocampus during aging in mice.

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