scholarly journals Blood‐Based Epigenetic Markers of FKBP5 Gene Methylation in Patients With Dilated Cardiomyopathy

2021 ◽  
Author(s):  
Kento Wada ◽  
Tomofumi Misaka ◽  
Tetsuro Yokokawa ◽  
Yusuke Kimishima ◽  
Takashi Kaneshiro ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dilated Cardiomyopathy ◽  
Dna Methyltransferase ◽  
Cpg Island ◽  
Epigenetic Modification ◽  
Quantitative Polymerase Chain Reaction ◽  
Pressure Overload ◽  
Cpg Methylation ◽  
Promoter Regions

Background Blood‐based DNA methylation patterns are linked to types of diseases. FKBP prolyl isomerase 5 (FKBP5), a protein cochaperone, is known to be associated with the inflammatory response, but the regulatory mechanisms by leukocyte FKBP5 DNA methylation in patients with dilated cardiomyopathy (DCM) remain unclear. Methods and Results The present study enrolled patients with DCM (n=31) and age‐matched and sex‐matched control participants (n=43). We assessed FKBP5 CpG (cytosine‐phosphate‐guanine) methylation of CpG islands at the 5′ side as well as putative promoter regions by methylation‐specific quantitative polymerase chain reaction using leukocyte DNA isolated from the peripheral blood. FKBP5 CpG methylation levels at the CpG island of the gene body and the promoter regions were significantly decreased in patients with DCM. Leukocyte FKBP5 and IL‐1β (interleukin 1β) mRNA expression levels were significantly higher in patients with DCM than in controls. The protein expressions of DNMT1 (DNA methyltransferase 1) and DNMT3A (DNA methyltransferase 3A) in leukocytes were significantly reduced in patients with DCM. In vitro methylation assay revealed that FKBP5 promoter activity was inhibited at the methylated conditions in response to immune stimulation, suggesting that the decreased FKBP5 CpG methylation was functionally associated with elevation of FKBP5 mRNA expressions. Histological analysis using a mouse model with pressure overload showed that FKBP5‐expressing cells were substantially infiltrated in the myocardial interstitium in the failing hearts, indicating a possible role of FKBP5 expressions of immune cells in the cardiac remodeling. Conclusions Our findings demonstrate a link between specific CpG hypomethylation of leukocyte FKBP5 and DCM. Blood‐based epigenetic modification in FKBP5 may be a novel molecular mechanism that contributes to the pathogenesis of DCM.

scholarly journals Continuous Zebularine Treatment Effectively Sustains Demethylation in Human Bladder Cancer Cells

2004 ◽  
Vol 24 (3) ◽  
pp. 1270-1278 ◽  
Author(s):  
Jonathan C. Cheng ◽  
Daniel J. Weisenberger ◽  
Felicidad A. Gonzales ◽  
Gangning Liang ◽  
Guo-Liang Xu ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Promoter Regions ◽  
Bladder Cancer Cells ◽  
Continuous Application ◽  
Aberrant Dna Methylation ◽  
Human Bladder Cancer Cells ◽  
Partial Depletion

ABSTRACT During tumorigenesis, tumor suppressor and cancer-related genes are commonly silenced by aberrant DNA methylation in their promoter regions. Recently, we reported that zebularine [1-(β-d-ribofuranosyl)-1,2-dihydropyrimidin-2-one] acts as an inhibitor of DNA methylation and exhibits chemical stability and minimal cytotoxicity both in vitro and in vivo. Here we show that continuous application of zebularine to T24 cells induces and maintains p16 gene expression and sustains demethylation of the 5′ region for over 40 days, preventing remethylation. In addition, continuous zebularine treatment effectively and globally demethylated various hypermethylated regions, especially CpG-poor regions. The drug caused a complete depletion of extractable DNA methyltransferase 1 (DNMT1) and partial depletion of DNMT3a and DNMT3b3. Last, sequential treatment with 5-aza-2′-deoxycytidine followed by zebularine hindered the remethylation of the p16 5′ region and gene resilencing, suggesting the possible combination use of both drugs as a potential anticancer regimen.

Abstract 100: An Altered Epigenomic Mark Predisposes to Dilated Cardiomyopathy Through Alternative Splicing of Sarcomeric Gene Expression in Mice

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Ana Vujic ◽  
Emma Robinson ◽  
Mitsutero Ito ◽  
Syed Haider ◽  
Jeremy Skepper ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Dilated Cardiomyopathy ◽  
Dna Methyltransferase ◽  
Complex Disease ◽  
Interstitial Fibrosis ◽  
Pressure Overload ◽  
Hypertrophic Response ◽  
Sarcomeric Gene ◽  
End Stage

Distinct epigenomic patterns of DNA methylation exist in important elements of the cardiac genome in human end-stage cardiomyopathy but whether these contribute to disease progression is unknown. We examined and found that the main DNA methyltransferase expressed in the adult mammalian heart is DNMT3B. We therefore generated a conditional inducible Dnmt3b knockout mouse to test the effect of altered DNA methylation in the heart. Upon induction in the adult mouse, Dnmt3b knockout (CKO) led rapidly to severe systolic insufficiency and myocardial thinning. Examination of myocyte nuclei reflected a loss of homogeniety and re-distribution of heterochromatin. This was accompanied by widespread myocardial interstitial fibrosis and myofibrillary disarray. We examined the myocardial transcriptome of CKO mice by RNA-seq and discovered significant changes in levels of transcript splicing isoforms especially those of sarcomeric genes. When subjected to pressure overload, CKO mice failed to mount a compensatory hypertrophic response and instead developed accelerated fulminant dilated cardiomyopathy. Our results demonstrate that DNA methylation has a distinct role with regulating transcript isoform splicing apart from gene expression. In particular, we have highlighted a mechanism by which the epigenome may mediate the development and progression of a complex disease.

scholarly journals SALL3 Interacts with DNMT3A and Shows the Ability To Inhibit CpG Island Methylation in Hepatocellular Carcinoma

2009 ◽  
Vol 29 (7) ◽  
pp. 1944-1958 ◽  
Author(s):  
Yuko Shikauchi ◽  
Akio Saiura ◽  
Takahiko Kubo ◽  
Yasuharu Niwa ◽  
Junji Yamamoto ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Cpg Island ◽  
Functional Characterization ◽  
Direct Interaction ◽  
Aberrant Methylation ◽  
Pwwp Domain ◽  
Cpg Island Methylation

ABSTRACT The mechanisms of aberrant CpG island methylation in oncogenesis are not fully characterized. In particular, little is known about the mechanisms of inhibition of CpG island methylation. Here we show that sal-like 3 (SALL3) is a novel inhibitory factor for DNA methyltransferase 3 alpha (DNMT3A). SALL3 binds to DNMT3A by a direct interaction between the double zinc finger motif of SALL3 and the PWWP domain of DNMT3A. SALL3 expression reduces DNMT3A-mediated CpG island methylation in cell culture and in vitro. CpG island methylation is enhanced in SALL3-depleted cells. Consistently, DNMT3A from SALL3-depleted cells increases methyltransferase activity in vitro. Binding of DNMT3A to chromatin is reduced or increased by SALL3 expression or depletion, respectively, accounting for the mechanism by which SALL3 inhibits DNMT3A-mediated CpG island methylation. We also show that SALL3 is inducible by BMP-4 and silenced by associated DNA methylation in hepatocellular carcinoma (HCC). Our results suggest that silencing of SALL3 results in acceleration of DNA methylation in HCC. This functional characterization of SALL3 sheds light on regulatory mechanisms for DNMT3A and provides new strategies to inhibit aberrant methylation in cancer.

scholarly journals Exploring Differentially Methylated Genes in Vulvar Squamous Cell Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3580
Author(s):  
Shatavisha Dasgupta ◽  
Patricia C. Ewing-Graham ◽  
Sigrid M. A. Swagemakers ◽  
Thierry P. P. van den Bosch ◽  
Peggy N. Atmodimedjo ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Squamous Cell ◽  
Dna Sequences ◽  
Cpg Island ◽  
Epigenetic Modification ◽  
Vulvar Squamous Cell Carcinoma ◽  
Differentially Methylated Genes ◽  
Methylation Profiling

DNA methylation is the most widely studied mechanism of epigenetic modification, which can influence gene expression without alterations in DNA sequences. Aberrations in DNA methylation are known to play a role in carcinogenesis, and methylation profiling has enabled the identification of biomarkers of potential clinical interest for several cancers. For vulvar squamous cell carcinoma (VSCC), however, methylation profiling remains an under-studied area. We sought to identify differentially methylated genes (DMGs) in VSCC, by performing Infinium MethylationEPIC BeadChip (Illumina) array sequencing, on a set of primary VSCC (n = 18), and normal vulvar tissue from women with no history of vulvar (pre)malignancies (n = 6). Using a false-discovery rate of 0.05, beta-difference (Δβ) of ± 0.5, and CpG-island probes as cut-offs, 199 DMGs (195 hyper-methylated, 4 hypo-methylated) were identified for VSCC. Most of the hyper-methylated genes were found to be involved in transcription regulator activity, indicating that disruption of this process plays a vital role in VSCC development. The majority of VSCCs harbored amplifications of chromosomes 3, 8, and 9. We identified a set of DMGs in this exploratory, hypothesis-generating study, which we hope will facilitate epigenetic profiling of VSCCs. Prognostic relevance of these DMGs deserves further exploration in larger cohorts of VSCC and its precursor lesions.

scholarly journals DNA Methyltransferase 3A Is Involved in the Sustained Effects of Chronic Stress on Synaptic Functions and Behaviors

2020 ◽  
Author(s):  
Jing Wei ◽  
Jia Cheng ◽  
Nicholas J Waddell ◽  
Zi-Jun Wang ◽  
Xiaodong Pang ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Epigenetic Modification ◽  
Substantial Reduction ◽  
Dna Methyltransferases ◽  
Male Rats ◽  
Neural Pathways ◽  
Dnmt Inhibitors ◽  
Synaptic Functions

Abstract Emerging evidence suggests that epigenetic mechanisms regulate aberrant gene transcription in stress-associated mental disorders. However, it remains to be elucidated about the role of DNA methylation and its catalyzing enzymes, DNA methyltransferases (DNMTs), in this process. Here, we found that male rats exposed to chronic (2-week) unpredictable stress exhibited a substantial reduction of Dnmt3a after stress cessation in the prefrontal cortex (PFC), a key target region of stress. Treatment of unstressed control rats with DNMT inhibitors recapitulated the effect of chronic unpredictable stress on decreased AMPAR expression and function in PFC. In contrast, overexpression of Dnmt3a in PFC of stressed animals prevented the loss of glutamatergic responses. Moreover, the stress-induced behavioral abnormalities, including the impaired recognition memory, heightened aggression, and hyperlocomotion, were partially attenuated by Dnmt3a expression in PFC of stressed animals. Finally, we found that there were genome-wide DNA methylation changes and transcriptome alterations in PFC of stressed rats, both of which were enriched at several neural pathways, including glutamatergic synapse and microtubule-associated protein kinase signaling. These results have therefore recognized the potential role of DNA epigenetic modification in stress-induced disturbance of synaptic functions and cognitive and emotional processes.

Abstract 130: Hypercholesterolemia Suppresses Carotid Artery Endothelial NOS3 Expression via Epigenetic Mechanisms

2015 ◽  
Vol 35 (suppl_1) ◽  
Author(s):  
Alex Sotolongo ◽  
Yi-Zhou Jiang ◽  
John Karanian ◽  
William Pritchard ◽  
Peter Davies
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Endothelial Cells ◽  
Dna Methyltransferase ◽  
Control Group ◽  
High Cholesterol Diet ◽  
Cholesterol Diet ◽  
High Cholesterol ◽  
High Fat

Objective: One of the first clinically detectable changes in the vasculature during atherogenesis is the accumulation of cholesterol within the vessel wall. Hypercholesterolemia is characterized by dysfunctional endothelial-dependent vessel relaxation and impaired NOS3 function. Since DNA methylation at gene promoter regions strongly suppresses gene expression, we postulated that high-fat/high-cholesterol diet suppresses endothelial NOS3 through promoter DNA methylation. Methods: Domestic male pigs were fed control diet (CD) or isocaloric high fat and high cholesterol diet (HC; 12% fat and 1.5% cholesterol) for 2, 4, 8 or 12 weeks prior to tissue collection. Furthermore, to determine the effects of risk factor withdrawal, an additional group of swine received HC for 12 weeks and then CD for 8 weeks; a control group received HC continuously for 20 weeks. Endothelial cells were harvested from common carotid aorta. In parallel in vitro studies, cultured human aortic endothelial cells (HAEC) were treated with human LDL, GW3956 (LXR agonist) and RG108 (DNA methyltransferase [DNMT] inhibitor). In cells from both sources, DNA methylation at the NOS3 promoter was measured using methylation specific pyro sequencing, and endothelial gene expression was measured using RT PCR. Results: HC diet increased plasma cholesterol level from 75 mg/dl on CD to a plateau of about 540 mg/dl within 2 weeks. Endothelial NOS3 expression was significantly reduced (71±9 % of CD) after 4 weeks of HC, a level sustained at subsequent time points. Withdrawal of HC for 8 weeks did not recover NOS3 expression. After 12-week HC, the NOS3 promoter was hypermethylated. Withdrawal of HC did not reverse NOS3 promoter methylation. In vitro treatment of HAEC with human LDL (200 mg/dl total cholesterol) or GW3956 (5μM) suppressed NOS3 mRNA to 50% and 30% respectively, suggesting that LXR/RXR is involved in suppression of NOS3. Nitric oxide production was consistently suppressed by GW3959. Both could be reversed through inhibition of DNMTs by RG108. Conclusions: DNA methylation and LXR/RXR pathway can mediate the HC-suppression of endothelial NOS3. The study identifies novel pharmaceutical targets in treating endothelial dysfunction. Crosstalk between these pathways is under investigation.

scholarly journals Fetal and Neonatal Exposure to the Endocrine Disruptor Methoxychlor Causes Epigenetic Alterations in Adult Ovarian Genes

Endocrinology ◽  
2009 ◽  
Vol 150 (10) ◽  
pp. 4681-4691 ◽  
Author(s):  
Aparna Mahakali Zama ◽  
Mehmet Uzumcu
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
Ovarian Function ◽  
Endocrine Disrupting Chemicals ◽  
Neonatal Exposure ◽  
Dna Hypermethylation ◽  
Promoter Regions ◽  
Altered Expression ◽  
Arbitrarily Primed Pcr ◽  
Methylation Patterns

Abstract Exposure to endocrine-disrupting chemicals during development could alter the epigenetic programming of the genome and result in adult-onset disease. Methoxychlor (MXC) and its metabolites possess estrogenic, antiestrogenic, and antiandrogenic activities. Previous studies showed that fetal/neonatal exposure to MXC caused adult ovarian dysfunction due to altered expression of key ovarian genes including estrogen receptor (ER)-β, which was down-regulated, whereas ERα was unaffected. The objective of the current study was to evaluate changes in global and gene-specific methylation patterns in adult ovaries associated with the observed defects. Rats were exposed to MXC (20 μg/kg·d or 100 mg/kg·d) between embryonic d 19 and postnatal d 7. We performed DNA methylation analysis of the known promoters of ERα and ERβ genes in postnatal d 50–60 ovaries using bisulfite sequencing and methylation-specific PCRs. Developmental exposure to MXC led to significant hypermethylation in the ERβ promoter regions (P < 0.05), whereas the ERα promoter was unaffected. We assessed global DNA methylation changes using methylation-sensitive arbitrarily primed PCR and identified 10 genes that were hypermethylated in ovaries from exposed rats. To determine whether the MXC-induced methylation changes were associated with increased DNA methyltransferase (DNMT) levels, we measured the expression levels of Dnmt3a, Dnmt3b, and Dnmt3l using semiquantitative RT-PCR. Whereas Dnmt3a and Dnmt3l were unchanged, Dnmt3b expression was stimulated in ovaries of the 100 mg/kg MXC group (P < 0.05), suggesting that increased DNMT3B may cause DNA hypermethylation in the ovary. Overall, these data suggest that transient exposure to MXC during fetal and neonatal development affects adult ovarian function via altered methylation patterns.

scholarly journals Identification of transcription termination defects at DNA hypomethylated transcription termination sites in DNA methyltransferase 3a-deficient vertebrates.

2021 ◽  
Author(s):  
Masaki Shirai ◽  
Takuya Nara ◽  
Haruko Takahashi ◽  
Kazuya Takayama ◽  
Yuan Chen ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Dna Methyltransferase ◽  
De Novo ◽  
Es Cells ◽  
Transcription Termination ◽  
Promoter Regions ◽  
Zebrafish Model ◽  
Body Regions ◽  
Chimeric Transcripts ◽  
Dna Methyltransferase 3A

CpG methylation in genomic DNA is well known as a repressive epigenetic marker in eukaryotic transcription, and DNA methylation of the promoter regions is correlated with silencing of gene expression. In contrast to the promoter regions, the function of DNA methylation during transcription termination remains to be elucidated. A recent study has revealed that mouse DNA methyltransferase 3a (Dnmt3a) mainly functions in de novo methylation in the promoter and gene body regions (including transcription termination sites (TTSs)) during development. To investigate the relationship between DNA methylation overlapping the TTSs and transcription termination, we employed two strategies: informatic analysis using already deposited datasets of Dnmt3a-/- mouse cells and the zebrafish model system. Bioinformatic analysis using methylome and transcriptome data showed that hypomethylated differentially methylated regions overlapping the TTSs were associated with increased read counts and chimeric transcripts downstream of TTSs in Dnmt3a-/- Agouti-related protein neurons, but not in Dnmt3a-/- ES cells and MEFs. We experimentally detected increased read-through and chimeric transcripts downstream of hypomethylated TTSs in zebrafish maternal-zygotic dnmt3aa-/- mutants. This study is the first to identify transcription termination defects in DNA hypomethylated TTSs in Dnmt3a-/- vertebrates.

scholarly journals DNA Methylation of Endoglin Pathway Genes in Pregnant Women With and Without Preeclampsia

2020 ◽  
Vol 13 ◽  
pp. 251686572095968
Author(s):  
Allison H Rietze ◽  
Yvette P Conley ◽  
Dianxu Ren ◽  
Cindy M Anderson ◽  
James M Roberts ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Cpg Island ◽  
Methylation Status ◽  
Cpg Islands ◽  
Control Participant ◽  
Sample Collection ◽  
Promoter Regions ◽  
Participant Group

Objective: We compared blood-based DNA methylation levels of endoglin ( ENG) and transforming growth factor beta receptor 2 ( TGFβR2) gene promoter regions between women with clinically-overt preeclampsia and women with uncomplicated, normotensive pregnancies. Methods: We used EpiTect Methyl II PCR Assays to evaluate DNA methylation of CpG islands located in promoter regions of ENG (CpG Island 114642) and TGFβR2 (CpG Island 110111). Preeclampsia was diagnosed based on blood pressure, protein, and uric acid criteria. N = 21 nulliparous preeclampsia case participants were 1:1 frequency matched to N = 21 nulliparous normotensive control participants on gestational age at sample collection (±2 weeks), smoking status, and labor status at sample collection. Methylation values were compared between case and control participant groups [( ENG subset: n = 20 (9 cases, 11 controls); TGFβR2 subset: n = 28 (15 cases, 13 controls)]. Results: The majority of the preeclampsia cases delivered at ⩾34 weeks’ gestation (83%). Average methylation levels for ENG ([M ± (SD)]; Case Participant Group = 6.54% ± 4.57 versus Control Participant group = 4.81% ± 5.08; P = .102) and TGFβR2 (Case Participant Group = 1.50% ± 1.37 vs Control Participant Group = 1.70% ± 1.40; P = .695) promoter CpG islands did not differ significantly between the participant groups. Removal of 2 extreme outliers in the ENG analytic subset revealed a trend between levels of ENG methylation and pregnancy outcome (Case Participant Group = 5.17% ± 2.16 vs Control Participant Group = 3.36% ± 1.73; P = .062). Conclusion: Additional epigenetic studies that include larger sample sizes, investigate preeclampsia subtypes, and capture methylation status of CpG island shores and shelves are needed to further inform us of the potential role that ENG and TGFβR2 DNA methylation plays in preeclampsia pathophysiology.

122 SUPPRESSION OF EPIGENETIC MODIFIERS ALTERS THE BOVINE EMBRYONIC DEVELOPMENTAL PROGRAM DURING IN VITRO CULTURE

2014 ◽  
Vol 26 (1) ◽  
pp. 175 ◽  
Author(s):  
M. D. Snyder ◽  
J. H. Pryor ◽  
M. D. Peoples ◽  
G. L. Williamson ◽  
M. C. Golding ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Embryonic Development ◽  
Dna Methyltransferase ◽  
Test Statistic ◽  
Gene Target ◽  
Blastocyst Rate ◽  
Green Fluorescent ◽  
Fluorescent Dextran

During early bovine embryogenesis, the regular establishment of DNA methylation and histone modification patterns is essential for proper gene expression and continuation of embryonic development. Epigenome patterns established during this period, if improperly maintained, can lead to developmental anomalies and may partially explain the lower pregnancy rates of in vitro-produced embryos. We hypothesised that the suppression of translation of the genes euchromatic histone-lysine N-methyltransferase 2 (EHMT2), DNA methyltransferase 3A (DNMT3A), absent, small, or homeotic-like (ASH2L), and SET domain, bifurcated 1 (SETDB1) would provide insightful information on the importance of these genes during early embryonic development in an in vitro setting. In order to define the roles of these genes, small interfering RNA (siRNA) targeting the gene of interest were synthesised and target verified in bovine cell culture using quantitative real-time RT-PCR (RT-qPCR). We acquired matured bovine oocytes from commercial suppliers, followed by IVF by standard laboratory procedures. Eighteen hours post IVF, cumulus cells were removed and zygotes separated into 3 different treatment groups: non-injected controls (CNTL), non-targeting siRNA injected controls (siNULL), and injection with siRNA targeting the gene of interest (si “gene target”). Each siRNA was mixed with a green fluorescent dextran at a concentration of 20 μM and ~100 pL injected cytoplasmically. The green fluorescent dextran was used to give visual confirmation that zygotes were indeed injected. Post-injection, fluorescent embryos were separated and cultured in Bovine Evolve (Zentih Biotech) medium supplemented with 4 mg mL–1 of BSA (Probumin, Millipore). Cleavage rates were monitored on Day 2, and only cleaved embryos were cultured further. On Day 8 post-IVF, embryos were morphologically examined and numbers of blastocysts recorded. Mean development rates between siNULL and targeting siRNA were compared using a t-test statistic. Over the course of these experiments the mean blastocyst rate for CNTL zygotes was 34.5% ± 2.6 s.e.m. (n = 1647). None of the zygotes injected with siEHMT2 (n = 1184) or siSETDB1 (n = 361) reached the blastocyst stage and these rates differed from the siNULL rate (21.0% ± 2.5 s.e.m., n = 1587; P < 0.05). Morphologically, embryos from both groups developed to the morula stage before they exhibited fragmentation. Injection of siDNMT3A also resulted in significant loss of viability at the 8-cell stage and few zygotes injected (n = 1057) developed to blastocyst (2.1% ± 0.5 s.e.m.; P < 0.001). Inhibiting gene expression of ASH2L showed little variation in blastocyst rate from our siNULL embryos (31.3% ± 2.0 s.e.m., n = 466 v. 34.8% ± 1.9 s.e.m., n = 418, respectively, P > 0.2). It is unknown at this time if inhibition of ASH2L translation will have effects later in development. Ongoing experiments analysing DNA methylation and histone modifications through immunocytochemistry and global gene expression via RT-qPCR will further explore the establishment and maintenance of these genes in the embryonic epigenome.

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