DNA methylation dynamics of a maternally methylated DMR in the mouse <i>Dlk1</i>–<i>Dio3</i> domain

Zeng, Tiebo; He, Hongbin; Han, Ze‐Guang; Zhang, Fengwei; Huang, Zhijun; Liu, Qi; Cui, Wei; Wu, Qiong

doi:10.1016/j.febslet.2014.10.038

Cited by 14 publications

(10 citation statements)

References 41 publications

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“…The loss of genomic imprinting (LOI) expression of DLK1-Dio3 miRNAs in acute promyelocytic leukemia (APL) and type 2 diabetes mellitus (T2DM) has been associated with altered DNA methylation at Gtl2 (MEG3)-DMR region [ 52 , 53 ]. In addition, a recent study reported a new maternally methylated DMR named CGI-2-DMR, which acquires differential methylation pattern during embryonic development [ 54 ]. However, the role of CGI-2 DMR in the regulation of imprinting DLK1-Dio3 gene expression has not been addressed in the report.…”

Section: Discussionmentioning

confidence: 99%

The Upregulation of Genomic Imprinted DLK1-Dio3 miRNAs in Murine Lupus Is Associated with Global DNA Hypomethylation

Dai

Ahmed

2016

PLoS ONE

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Epigenetic factors such as DNA methylation and microRNAs (miRNAs) are now increasingly recognized as vital contributors to lupus etiology. In this study, we investigated the potential interaction of these two epigenetic factors in lupus-prone MRL-lpr mice. We recently reported dysregulated expression of miRNAs in splenocytes of MRL-lpr mice. Here, we report that a majority of the upregulated miRNAs in MRL-lpr mice is located at the genomic imprinted DLK1-Dio3 domain. Further, we show a differential magnitude of upregulation of DLK1-Dio3 miRNA cluster in purified splenic CD4+ T, CD19+ B, and splenic CD4-CD19- cells from MRL-lpr lupus mice when compared to control MRL mice. MRL-lpr splenocytes (especially CD19+ and CD4-CD19- subsets) were hypomethylated compared to cells from control, MRL mice. We further show that deliberate demethylation of splenocytes from control MRL mice, but not from MRL-lpr lupus mice, with specific DNA methylation inhibitor 5-Aza-2’-deoxycytidine significantly augmented DLK1-Dio3 miRNAs expression. These findings strongly indicate that the upregulation of DLK1-Dio3 miRNAs in lupus splenic cell subsets is associated with reduced global DNA methylation levels in lupus cells. There was a differential upregulation of DLK-Dio3 miRNAs among various demethylated splenic cell subsets, which implies varied sensitivity of DLK1-Dio3 miRNA cluster in these cell subsets to DNA hypomethylation. Finally, inhibition of select DLK1-Dio3 miRNA such as miR-154, miR-379 and miR-300 with specific antagomirs significantly reduced the production of lupus-relevant IFNγ, IL-1β, IL-6, and IL-10 in lipopolysaccharide (LPS) activated splenocytes from MRL-lpr mice. Our study is the first to show that DNA methylation regulates genomic imprinted DLK1-Dio3 miRNAs in autoimmune lupus, which suggests a connection of DNA methylation, miRNA and genomic imprinting in lupus pathogenesis.

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Section: Discussionmentioning

confidence: 99%

The Upregulation of Genomic Imprinted DLK1-Dio3 miRNAs in Murine Lupus Is Associated with Global DNA Hypomethylation

Dai

Ahmed

2016

PLoS ONE

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“…The Dlk1/Dio3 imprinted domain contains three known differentially methylated regions (DMRs) that are paternally methylated: intergenic DMR (IG-DMR), maternally expressed 3-DMR (Gtl2-DMR), and Dlk1-DMR [16]. Previous studies suggest that the IG-DMR dictates the allelic methylation status of the Gtl2 promoter DMR, which then controls gene expression across the entire cluster [17].…”

Section: Introductionmentioning

confidence: 99%

Effect of Nano-SiO2 on Expression and Aberrant Methylation of Imprinted Genes in Lung and Testis

et al. 2018

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Nanotechnology has been developing rapidly and is now used in many cutting-edge medical therapeutics. However, there is increasing concern that exposure to nanoparticles (NPs) may induce different systemic diseases as epigenetic mechanisms are associated with more and more disease. The role of NP epigenomic modification is important to disease etiology. Our study aimed to determine the epigenetic mechanisms of damage in lung and testis cells by exposing cells to SiO2 NPs. We used male C57BL/6 mice to characterize the damaging effect of SiO2 NPs on lung and testis cells as well as the resulting methylation state at the imprinted Dlk1/Dio3 domain region. The A549 cells exposed to SiO2 NPs had cell apoptosis, and male mice exposed to SiO2 NPs had altered lung and testis tissues. The genes in the imprinted domains Dlk1/Dio3 region changed in both tissues; Dlk1, Rtl1, and Dio3 are upregulated in testis while Dlk1 and Dio3 are also upregulated in lung tissues. Bisulfite sequencing PCR of male adult lung and testis were mostly hypomethylated, with a few hypermethylated CpGs. These findings indicate that nanoparticles play an important role in DNA methylation of imprinted genes.Electronic supplementary materialThe online version of this article (10.1186/s11671-018-2673-4) contains supplementary material, which is available to authorized users.

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“…Although IG-DMR and Meg3/Gtl2-DMR are paternally methylated, a maternally methylated DMR upstream of the Rtl1 gene in mice has been reported (Zeng et al, 2014). Similarly, in humans, a maternally methylated DMR was identified in the second intron of the MEG8 noncoding RNA that acquires differential methylation postfertilization (Court et al, 2014).…”

Section: Meg8-dmrmentioning

confidence: 99%

Imprinted small nucleolar RNAs: Missing link in development and disease?

Gawade,

Raczynska

2023

WIREs RNA

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The 14q32.2 (DLK1‐DIO3) and 15q11‐q13 (SNURF‐SNRPN) imprinted gene loci harbor the largest known small nucleolar RNA clusters expressed from the respective maternal and paternal alleles. Recent studies have demonstrated significant roles for the 15q11‐q13 located SNORD115‐SNORD116 C/D box snoRNAs in Prader‐Willi syndrome (PWS), a neurodevelopmental disorder. Even though the effect of SNORD116 deletion is apparent in the PWS phenotype, similar effects of a SNORD113‐SNORD114 cluster deletion from the 14q32.2 locus in Kagami‐Ogata syndrome (KOS14) and upregulation in Temple syndrome (TS14) remain to be explored. Moreover, apart from their probable involvement in neurodevelopmental disorders, snoRNAs from the SNORD113‐SNORD114 cluster have been implicated in multiple biological processes, including pluripotency, development, cancers, and RNA modifications. Here we summarize the current understanding of the system to explore the possibility of a link between developmental disorders and C/D box snoRNA expression from the imprinted 14q32.2 locus.This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development RNA Processing > Processing of Small RNAs

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DNA methylation dynamics of a maternally methylated DMR in the mouse Dlk1–Dio3 domain

Cited by 14 publications

References 41 publications

The Upregulation of Genomic Imprinted DLK1-Dio3 miRNAs in Murine Lupus Is Associated with Global DNA Hypomethylation

The Upregulation of Genomic Imprinted DLK1-Dio3 miRNAs in Murine Lupus Is Associated with Global DNA Hypomethylation

Effect of Nano-SiO2 on Expression and Aberrant Methylation of Imprinted Genes in Lung and Testis

Imprinted small nucleolar RNAs: Missing link in development and disease?

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