A Hearty Dose of Noncoding RNAs: The Imprinted DLK1-DIO3 Locus in Cardiac Development and Disease

Dill, Tiffany L.; Naya, Francisco J.

doi:10.3390/jcdd5030037

Cited by 29 publications

(31 citation statements)

References 109 publications

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“…patients inherit two maternal copies of chromosome 14q32), and Kagami–Ogata syndrome (PatUPD14), caused by paternal uniparental disomy (reviewed in [36]). With that, miRNAs from this imprinting locus were found to be associated with the development of several diseases (reviewed in [37]), such as different types of cancer (reviewed in [36]), cardiovascular diseases [38], autoimmune diseases [39,40] and schizophrenia [41].…”

Section: Discussionmentioning

confidence: 99%

MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling

Baulina

Osmak

Kiselev

et al. 2019

Cells

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Relapsing-remitting multiple sclerosis (RRMS) is the most prevalent course of multiple sclerosis. It is an autoimmune inflammatory disease of the central nervous system. To investigate the gender-specific involvement of microRNAs (miRNAs) in RRMS pathogenesis, we compared miRNA profiles in peripheral blood mononuclear cells separately in men and women (eight RRMS patients versus four healthy controls of each gender) using high-throughput sequencing. In contrast to women, six downregulated and 26 upregulated miRNAs (padj < 0.05) were identified in men with RRMS. Genes encoding upregulated miRNAs are co-localized in DLK1-DIO3 imprinted locus on human chromosome 14q32. Reverse transcription quantitative polymerase chain reaction (RT-qPCR) analysis was performed in independent groups of men (16 RRMS patients and 10 healthy controls) and women (20 RRMS patients and 10 healthy controls). Increased expression of miR-431, miR-127-3p, miR-379, miR-376c, miR-381, miR-410 and miR-656 was again demonstrated in male (padj < 0.05), but not in female RRMS patients. At the same time, the expression levels of these miRNAs were lower in healthy men than in healthy women, whereas in RRMS men they increased and reached or exceeded levels in RRMS women. In general, we demonstrated that expression levels of these miRNAs depend both on “health–disease” status and gender. Network-based enrichment analysis identified that receptor tyrosine kinases-activated pathways were enriched with products of genes targeted by miRNAs from DLK1-DIO3 locus. These results suggest the male-specific involvement of these miRNAs in RRMS pathogenesis via regulation of PI3K/Akt signaling.

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Section: Discussionmentioning

confidence: 99%

MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling

Baulina

Osmak

Kiselev

et al. 2019

Cells

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“…The murine Delta-like homolog 1 (Dlk1)-type III iodothyronine deiodinase (Dio3) ncRNA locus is a mega-cluster (~1.000 kb) consisting of 3 protein coding genes, 61 miRNAs, and 3 lncRNAs [116,117]. The organization of the locus and most of its harboring ncRNAs are conserved between mammals [118]. It is not completely understood how expression of the numerous ncRNAs deriving from the Dlk1-Dio3 locus is controlled.…”

Section: Dlk1-dio3mentioning

confidence: 99%

Reviewing the Limitations of Adult Mammalian Cardiac Regeneration: Noncoding RNAs as Regulators of Cardiomyogenesis

2020

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The adult mammalian heart is incapable of regeneration following cardiac injury, leading to a decline in function and eventually heart failure. One of the most evident barriers limiting cardiac regeneration is the inability of cardiomyocytes to divide. It has recently become clear that the mammalian heart undergoes limited cardiomyocyte self-renewal throughout life and is even capable of modest regeneration early after birth. These exciting findings have awakened the goal to promote cardiomyogenesis of the human heart to repair cardiac injury or treat heart failure. We are still far from understanding why adult mammalian cardiomyocytes possess only a limited capacity to proliferate. Identifying the key regulators may help to progress towards such revolutionary therapy. Specific noncoding RNAs control cardiomyocyte division, including well explored microRNAs and more recently emerged long noncoding RNAs. Elucidating their function and molecular mechanisms during cardiomyogenesis is a prerequisite to advance towards therapeutic options for cardiac regeneration. In this review, we present an overview of the molecular basis of cardiac regeneration and describe current evidence implicating microRNAs and long noncoding RNAs in this process. Current limitations and future opportunities regarding how these regulatory mechanisms can be harnessed to study myocardial regeneration will be addressed.

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“…LncRNAs are expressed from the non-methylated maternal allele. In contrast, the paternal chromosome is methylated preventing the expression of the ncRNAs from this cluster [23].…”

Section: Dna Damaging Agents and Replication Stressors Regulate The Smentioning

confidence: 99%

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

Espinosa‐Díez¹,

Wilson²,

Mukherjee³

et al. 2018

Preprint

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Changes in gene expression are key for the cells to adapt and response to intrinsic and extrinsic stimulus. It has been shown that genotoxic stress induces global hypomethylation as a result of decreased expression of DNA methyl transferases (DNMT). We hypothesized that DNA damage suppresses long non-coding RNA expression in the vasculature via DNA methylation leading to more robust DNA repair/survival or cellular senescence/death cell fate decisions. We show here that ionizing radiation reduces the expression of DNMTs in the vascular endothelium and this leads to increased expression of the anti-apoptotic lncRNA MEG9. MEG9 is a lncRNA from the DLK1-DIO3 ncRNA cluster. Loss-of-function studies using RNA gapmers indicate that MEG9 protects endothelial cells from DNA damage induced cell death. Consistent with this phenotype, knockdown of MEG9 decreases growth factor dependent angiogenesis in a 3D fibrin gel angiogenesis assay. Mechanistically, we observed that MEG9 knockdown decreased the expression of cell survival genes including survivin and induced the expression of pro-apoptotic genes such as Bad/Bax. Taken together, our findings illustrate how DNA methylation at selective lncRNA loci can regulate their expression and drive endothelial cell fate decisions.

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A Hearty Dose of Noncoding RNAs: The Imprinted DLK1-DIO3 Locus in Cardiac Development and Disease

Cited by 29 publications

References 109 publications

MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling

MiRNAs from DLK1-DIO3 Imprinted Locus at 14q32 are Associated with Multiple Sclerosis: Gender-Specific Expression and Regulation of Receptor Tyrosine Kinases Signaling

Reviewing the Limitations of Adult Mammalian Cardiac Regeneration: Noncoding RNAs as Regulators of Cardiomyogenesis

DNA damage dependent hypomethylation regulates the pro-angiogenic LncRNA MEG9

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