Determinants of orofacial clefting II: Effects of 5-Aza-2′-deoxycytidine on gene methylation during development of the first branchial arch

Seelan, Ratnam S.; Mukhopadhyay, Partha; Warner, Dennis R.; Smolenkova, Irina; Pisano, M. Michele; Greene, Robert M.

doi:10.1016/j.reprotox.2016.11.020

Cited by 7 publications

(5 citation statements)

References 87 publications

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“…We did not find such a simple relationship between methylation and expression with the other genes. The fact depressed methylation of the respective gene promoter regions did not correlate with the upregulation of these, has already been described for both HMAs [ 57 , 58 ]. In addition, increased expression of the respective genes after AZA or DAC treatment can be explained by a decrease in the methylation of their promoter regions in only a small number of cases.…”

Section: Discussionmentioning

confidence: 64%

Changes in Apoptotic Pathways in MOLM-13 Cell Lines after Induction of Resistance to Hypomethylating Agents

Janotka

Messingerová

Šimoničová

et al. 2021

IJMS

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We established the following two variants of the MOLM-13 human acute myeloid leukemia (AML) cell line: (i) MOLM-13/DAC cells are resistant to 5-aza-2′-deoxycytidine (DAC), and (ii) MOLM-13/AZA are resistant to 5-azacytidine (AZA). Both cell variants were obtained through a six-month selection/adaptation procedure with a stepwise increase in the concentration of either DAC or AZA. MOLM-13/DAC cells are resistant to DAC, and MOLM-13/AZA cells are resistant to AZA (approximately 50-fold and 20-fold, respectively), but cross-resistance of MOLM-13/DAC to AZA and of MOLM-13/AZA to DAC was not detected. By measuring the cell retention of fluorescein-linked annexin V and propidium iodide, we showed an apoptotic mode of death for MOLM-13 cells after treatment with either DAC or AZA, for MOLM-13/DAC cells after treatment with AZA, and for MOLM-13/AZA cells after treatment with DAC. When cells progressed to apoptosis, via JC-1 (5,5′,6,6′-tetrachloro-1,1′,3,3′-tetraethyl-imidacarbocyanine iodide) assay, we detected a reduction in the mitochondrial membrane potential. Furthermore, we characterized promoter methylation levels for some genes encoding proteins regulating apoptosis and the relation of this methylation to the expression of the respective genes. In addition, we focused on determining the expression levels and activity of intrinsic and extrinsic apoptosis pathway proteins.

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Section: Discussionmentioning

confidence: 64%

Changes in Apoptotic Pathways in MOLM-13 Cell Lines after Induction of Resistance to Hypomethylating Agents

Janotka

Messingerová

Šimoničová

et al. 2021

IJMS

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“…To explore this idea more comprehensively, Methyl Capture-Seq was performed to assess the epigenome of 1-BAs exposed in utero for 12-hr to AzaD or vehicle. The results of this analysis are presented in a following study [94]. …”

Section: Discussionmentioning

confidence: 99%

“…Thus, to more comprehensively assess the demethylating effects of AzaD on the 1-BA epigenome, MethylCap-Seq (MCS) analysis was performed and the results of AzaD-treated 1-BAs were compared to that of vehicle-treated 1-BAs. Findings from this study are presented separately [94]. …”

Section: Discussionmentioning

confidence: 99%

Determinants of orofacial clefting I: Effects of 5-Aza-2′-deoxycytidine on cellular processes and gene expression during development of the first branchial arch

Mukhopadhyay

Seelan

Rezzoug

et al. 2017

Reproductive Toxicology

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In this study, we identify gene targets and cellular events mediating the teratogenic action(s) of 5-Aza-2′-deoxycytidine (AzaD), an inhibitor of DNA methylation, on secondary palate development. Exposure of pregnant mice (on gestation day (GD) 9.5) to AzaD for 12 hrs resulted in the complete penetrance of cleft palate (CP) in fetuses. Analysis of cells of the embryonic first branchial arch (1-BA), in fetuses exposed to AzaD, revealed: 1) significant alteration in expression of genes encoding several morphogenetic factors, cell cycle inhibitors and regulators of apoptosis; 2) a decrease in cell proliferation; and, 3) an increase in apoptosis. Pyrosequencing of selected genes, displaying pronounced differential expression in AzaD-exposed 1-BAs, failed to reveal significant alterations in CpG methylation levels in their putative promoters or gene bodies. CpG methylation analysis suggested that the effects of AzaD on gene expression were likely indirect.

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“…However, CpG methylation analysis of select genes revealed that these observed changes in gene expression were likely not due to direct methylation changes at their respective loci. This was confirmed in the companion study utilizing MethylCap‐Seq (MCS) analysis in a similar experimental design, although hypomethylation of genes associated with cleft palate was observed, including Axin2 , Efna5 , and Hic2 (Seelan et al, 2017). Interestingly, despite these findings, the latter study identified several differentially methylated regions (DMRs) within endogenous viral elements.…”

Section: Epigenetic Mechanisms Of Orofacial Cleftsmentioning

confidence: 68%

Role of epigenetics and miRNAs in orofacial clefts

Garland

Sun

Zhang

et al. 2020

Birth Defects Research

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Orofacial clefts (OFCs) have multiple etiologies and likely result from an interplay between genetic and environmental factors. Within the last decade, studies have implicated specific epigenetic modifications and noncoding RNAs as additional facets of OFC etiology. Altered gene expression through DNA methylation and histone modification offer novel insights into how specific genes contribute to distinct OFC subtypes. Epigenetics research has also provided further evidence that cleft lip only (CLO) is a cleft subtype with distinct etiology. Polymorphisms or misexpression of genes encoding microRNAs, as well as their targets, contribute to OFC risk. The ability to experimentally manipulate epigenetic changes and noncoding RNAs in animal models, such as zebrafish, Xenopus, mice, and rats, has offered novel insights into the mechanisms of various OFC subtypes. Although much remains to be understood, recent advancements in our understanding of OFC etiology may advise future strategies of research and preventive care.

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Determinants of orofacial clefting II: Effects of 5-Aza-2′-deoxycytidine on gene methylation during development of the first branchial arch

Cited by 7 publications

References 87 publications

Changes in Apoptotic Pathways in MOLM-13 Cell Lines after Induction of Resistance to Hypomethylating Agents

Changes in Apoptotic Pathways in MOLM-13 Cell Lines after Induction of Resistance to Hypomethylating Agents

Determinants of orofacial clefting I: Effects of 5-Aza-2′-deoxycytidine on cellular processes and gene expression during development of the first branchial arch

Role of epigenetics and miRNAs in orofacial clefts

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