IU Indianapolis ScholarWorks :: Browsing by Subject "MicroRNA"

Browsing by Subject "MicroRNA"

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Dynamic Alterations to Hepatic MicroRNA-29a in Response to Long-Term High-Fat Diet and EtOH Feeding
(MDPI, 2023-09-26) Liang, Tiebing; Kota, Janaiah; Williams, Kent E.; Saxena, Romil; Gawrieh, Samer; Zhong, Xiaoling; Zimmers, Teresa A.; Chalasani, Naga; Surgery, School of Medicine
MicroRNA-29a (miR-29a) is a well characterized fibro-inflammatory molecule and its aberrant expression is linked to a variety of pathological liver conditions. The long-term effects of a high-fat diet (HFD) in combination with different levels of EtOH consumption on miR-29a expression and liver pathobiology are unknown. Mice at 8 weeks of age were divided into five groups (calorie-matched diet plus water (CMD) as a control group, HFD plus water (HFD) as a liver disease group, HFD plus 2% EtOH (HFD + 2% E), HFD + 10% E, and HFD + 20% E as intervention groups) and fed for 4, 13, 26, or 39 weeks. At each time point, analyses were performed for liver weight/body weight (BW) ratio, AST/ALT ratio, as well as liver histology assessments, which included inflammation, estimated fat deposition, lipid area, and fibrosis. Hepatic miR-29a was measured and correlations with phenotypic traits were determined. Four-week feeding produced no differences between the groups on all collected phenotypic traits or miR-29a expression, while significant effects were observed after 13 weeks, with EtOH concentration-specific induction of miR-29a. A turning point for most of the collected traits was apparent at 26 weeks, and miR-29a was significantly down-regulated with increasing liver injury. Overall, miR-29a up-regulation was associated with a lower liver/BW ratio, fat deposition, inflammation, and fibrosis, suggesting a protective role of miR-29a against liver disease progression. A HFD plus increasing concentrations of EtOH produces progressive adverse effects on the liver, with no evidence of beneficial effects of low-dose EtOH consumption. Moreover, miR-29a up-regulation is associated with less severe liver injury.
Epigenetic Regulation of Nanog by MiR-302 Cluster-MBD2 Completes Induced Pluripotent Stem Cell Reprogramming
(Oxford University Press, 2013) Lee, Man Ryul; Prasain, Nutan; Chae, Hee-Don; Kim, Young-June; Mantel, Charlie; Yoder, Mervin C.; Broxmeyer, Hal E.; Microbiology and Immunology, School of Medicine
While most somatic cells undergoing induced pluripotent stem (iPS) cell reprogramming with Yamanaka factors accumulate at stable partially reprogrammed stages, the molecular mechanisms required to achieve full reprogramming are unknown. MicroRNAs (miRNAs) fine-tune mRNA translation and are implicated in reprogramming, but miRNA functional targets critical for complete iPS cell reprogramming remain elusive. We identified methyl-DNA binding domain protein 2 (MBD2) as an epigenetic suppressor, blocking full reprogramming of somatic to iPS cells through direct binding to NANOG promoter elements preventing transcriptional activation. When we overexpressed miR-302 cluster we observed a significant increase in conversion of partial to fully reprogrammed iPS cells by suppressing MBD2 expression, thereby increasing NANOG expression. Thus, expression of exogenous miR-302 cluster (without miR-367) is efficient in attaining a fully reprogrammed iPS state in partially reprogrammed cells by relieving MBD2-mediated inhibition of NANOG expression. Our studies provide a direct molecular mechanism involved in generating complete human iPS cell reprogramming to study disease pathogenesis, drug screening, and for potential cell-based therapies.
Functional microRNAs in Alzheimer’s disease and cancer: differential regulation of common mechanisms and pathways
(Frontiers Media, 2013-01-17) Holohan, Kelly N.; Lahiri, Debomoy K.; Schneider, Bryan P.; Foroud, Tatiana; Saykin, Andrew J.; Medical and Molecular Genetics, School of Medicine
Two of the main research priorities in the United States are cancer and neurodegenerative diseases, which are attributed to abnormal patterns of cellular behavior. MicroRNAs (miRNA) have been implicated as regulators of cellular metabolism, and thus are an active topic of investigation in both disease areas. There is presently a more extensive body of work on the role of miRNAs in cancer compared to neurodegenerative diseases, and therefore it may be useful to examine whether there is any concordance between the functional roles of miRNAs in these diseases. As a case study, the roles of miRNAs in Alzheimer's disease (AD) and their functions in various cancers will be compared. A number of miRNA expression patterns are altered in individuals with AD compared with healthy older adults. Among these, some have also been shown to correlate with neuropathological changes including plaque and tangle accumulation, as well as expression levels of other molecules known to be involved in disease pathology. Importantly, these miRNAs have also been shown to have differential expression and or functional roles in various types of cancer. To examine possible intersections between miRNA functions in cancer and AD, we review the current literature on these miRNAs in cancer and AD, focusing on their roles in known biological pathways. We propose a pathway-driven model in which some molecular processes show an inverse relationship between cancer and neurodegenerative disease (e.g., proliferation and apoptosis) whereas others are more parallel in their activity (e.g., immune activation and inflammation). A critical review of these and other molecular mechanisms in cancer may shed light on the pathophysiology of AD, and highlight key areas for future research. Conclusions from this work may be extended to other neurodegenerative diseases for which some molecular pathways have been identified but which have not yet been extensively researched for miRNA involvement.
Genetic Regulation of Human isomiR Biogenesis
(MDPI, 2023-09-04) Jiang, Guanglong; Reiter, Jill L.; Dong, Chuanpeng; Wang, Yue; Fang, Fang; Jiang, Zhaoyang; Liu, Yunlong; BioHealth Informatics, School of Informatics and Computing
MicroRNAs play a critical role in regulating gene expression post-transcriptionally. Variations in mature microRNA sequences, known as isomiRs, arise from imprecise cleavage and nucleotide substitution or addition. These isomiRs can target different mRNAs or compete with their canonical counterparts, thereby expanding the scope of miRNA post-transcriptional regulation. Our study investigated the relationship between cis-acting single-nucleotide polymorphisms (SNPs) in precursor miRNA regions and isomiR composition, represented by the ratio of a specific 5'-isomiR subtype to all isomiRs identified for a particular mature miRNA. Significant associations between 95 SNP-isomiR pairs were identified. Of note, rs6505162 was significantly associated with both the 5'-extension of hsa-miR-423-3p and the 5'-trimming of hsa-miR-423-5p. Comparison of breast cancer and normal samples revealed that the expression of both isomiRs was significantly higher in tumors than in normal tissues. This study sheds light on the genetic regulation of isomiR maturation and advances our understanding of post-transcriptional regulation by microRNAs.
In silico identification of microRNAs predicted to regulate the drug metabolizing cytochrome P450 genes
(Bentham Science, 2011-04) Ramamoorthy, Anuradha; Skaar, Todd C.; Department of Medicine, IU School of Medicine
OBJECTIVE: Cytochrome P450 (CYP) enzymes exhibit high interindividual variability that is not completely explained by known environmental and genetic factors. To further understand this variability, we hypothesized that microRNAs (miRNAs) may regulate CYP expression. METHODS: MiRNA identification algorithms were used to identify the miRNAs that are predicted to regulate twelve major drug metabolizing CYPs and to identify polymorphisms in CYP mRNA 3'-UTRs that are predicted to interfere with normal mRNA-miRNA interactions. RESULTS: All twelve CYPs were predicted to be targets of miRNAs. Additionally, 38 SNPs in CYP mRNA 3'-UTRs were predicted to interfere with miRNA targeting of mRNAs. These predicted miRNAs and SNPs are candidates for future in vitro studies focused on understanding the molecular regulation of these CYP genes. CONCLUSION: These in silico results provide strong support for a role of miRNA in the regulation and variability of CYP expression.
Inflammation-associated microRNA changes in circulating exosomes of heart failure patients
(BMC, 2017-12-19) Beg, Faheemullah; Wang, Ruizhong; Saeed, Zeb; Devaraj, Srikant; Masoor, Kamalesh; Nakshatri, Harikrishna; Surgery, School of Medicine
Objective MiR-486 and miR-146a are cardiomyocyte-enriched microRNAs that control cell survival and self-regulation of inflammation. These microRNAs are released into circulation and are detected in plasma or in circulating exosomes. Little is known whether heart failure affects their release into circulation, which this study investigated. Results Total and exosome-specific microRNAs in plasma of 40 heart failure patients and 20 controls were prepared using the miRVana Kit. We measured exosomal and total plasma microRNAs separately because exosomes serve as cargos that transfer biological materials and alter signaling in distant organs, whereas microRNAs in plasma indicate the level of tissue damage and are mostly derived from dead cells. qRT-PCR was used to quantify miR-486, miR-146a, and miR-16. Heart failure did not significantly affect plasma miR-486/miR-16 and miR-146a/miR-16 ratio, although miR-146a/miR-16 showed a trend of elevated expression (2.3 ± 0.79, p = 0.27). By contrast, circulating exosomal miR-146a/miR-16 ratio was higher in heart failure patients (2.46 ± 0.51, p = 0.05). miR-146a is induced in response to inflammation as a part of inflammation attenuation circuitry. Indeed, Tnfα and Gm-csf increased miR-146a but not miR-486 in the cardiomyocyte cell line H9C2. These results, if confirmed in a larger study, may help to develop circulating exosomal miR-146a as a biomarker of heart failure.
Mesenchymal Stem Cell-Derived Exosomal microRNAs in Cardiac Regeneration
(MDPI, 2023-12-11) Bhaskara, Meghana; Anjorin, Olufisayo; Wang, Meijing; Surgery, School of Medicine
Mesenchymal stem cell (MSC)-based therapy is one of the most promising modalities for cardiac repair. Accumulated evidence suggests that the therapeutic value of MSCs is mainly attributable to exosomes. MSC-derived exosomes (MSC-Exos) replicate the beneficial effects of MSCs by regulating various cellular responses and signaling pathways implicated in cardiac regeneration and repair. miRNAs constitute an important fraction of exosome content and are key contributors to the biological function of MSC-Exo. MSC-Exo carrying specific miRNAs provides anti-apoptotic, anti-inflammatory, anti-fibrotic, and angiogenic effects within the infarcted heart. Studying exosomal miRNAs will provide an important insight into the molecular mechanisms of MSC-Exo in cardiac regeneration and repair. This significant information can help optimize cell-free treatment and overcome the challenges associated with MSC-Exo therapeutic application. In this review, we summarize the characteristics and the potential mechanisms of MSC-derived exosomal miRNAs in cardiac repair and regeneration.
Methods of MicroRNA Promoter Prediction and Transcription Factor Mediated Regulatory Network
(Hindawi, 2017) Zhao, Yuming; Wang, Fang; Chen, Su; Wan, Jun; Wang, Guohua; Medical and Molecular Genetics, School of Medicine
MicroRNAs (miRNAs) are short (~22 nucleotides) noncoding RNAs and disseminated throughout the genome, either in the intergenic regions or in the intronic sequences of protein-coding genes. MiRNAs have been proved to play important roles in regulating gene expression. Hence, understanding the transcriptional mechanism of miRNA genes is a very critical step to uncover the whole regulatory network. A number of miRNA promoter prediction models have been proposed in the past decade. This review summarized several most popular miRNA promoter prediction models which used genome sequence features, or other features, for example, histone markers, RNA Pol II binding sites, and nucleosome-free regions, achieved by high-throughput sequencing data. Some databases were described as resources for miRNA promoter information. We then performed comprehensive discussion on prediction and identification of transcription factor mediated microRNA regulatory networks.
Microrna 21 targets B Cell Lymphoma 2 (Bcl2) Mrna to increase beta cell apoptosis and exosomal Microrna 21 could serve as a biomarker of developing Type 1 Diabetes Mellitus
(2018) Sims, Emily K.
The role of beta cell miR-21 in Type 1 Diabetes (T1D) pathophysiology has been controversial. Here, we sought to define the context of beta cell miR-21 upregulation in T1D and the phenotype of beta cell miR-21 overexpression through target identification. Furthermore, we sought to identify whether circulating extracellular vesicle (EV) beta cell-derived miR-21 may reflect inflammatory stress within the islet during T1D development.. Results suggest that beta cell miR-21 is increased in in-vivo models of T1D and cytokine-treated cells/islets. miR-21 overexpression decreased cell count and viability, and increased cleaved caspase-3 levels, suggesting increased cell death. In silico prediction tools identified the anti-apoptotic mRNA B Cell Lymphoma 2 (BCL2) as a conserved miR-21 target. Consistent with this, miR-21 overexpression decreased BCL2 transcript and protein expression, while miR-21 inhibition increased BCL2 protein levels and reduced cleaved caspase-3 levels following cytokine-treatment. miR-21-mediated cell death was abrogated in 828/33 cells, which constitutively overexpress BCL-2. Luciferase assays suggested a direct interaction between miR-21 and the BCL2 3’untranslated region. With miR-21 overexpression, PRP revealed a shift of BCL-2 message toward monosome-associated fractions, indicating inhibition of BCL2 translation. Finally, overexpression in dispersed human islets confirmed a reduction in BCL2 transcripts and increased cleaved caspase 3 production. Analysis of EVs from human beta cells and islets exposed to cytokines revealed a 3-5-fold increase in miR-21. Nanoparticle tracking analysis showed no changes in EV quantity in response to cytokines, implicating specific changes within EV cargo as responsible for the miR-21 increase. Circulating EVs from diabetic non-obese diabetic (NOD) mice displayed progressive increases in miR-21 that preceded diabetes onset. To validate relevance to human T1D, we assayed serum samples collected from 19 pediatric T1D subjects at the time of diagnosis and 16 healthy controls. Consistent with our NOD data, EV miR-21 was increased 5-fold in T1D samples. In conclusion, in contrast to the pro-survival role reported in other systems, our results demonstrate that miR-21 increases beta cell death via BCL2 transcript degradation and inhibition of BCL2 translation. Furthermore, we propose that EV miR-21 may be a promising marker of developing T1D.
MicroRNA 362-3p Reduces hERG-related Current and Inhibits Breast Cancer Cells Proliferation
(International Institute of Anticancer Research, 2019-12) Assiri, Abdullah A.; Mourad, Noha; Shao, Minghai; Kiel, Patrick; Liu, Wanqing; Skaar, Todd C.; Overholser, Brian R.; Pharmacology and Toxicology, School of Medicine
Background/Aim: hERG potassium channels enhance tumor invasiveness and breast cancer proliferation. MicroRNA (miRNA) dysregulation during cancer controls gene regulation. The objective of this study was to identify miRNAs that regulate hERG expression in breast cancer. Materials and Methods: Putative miRNAs targeting hERG were identified by bioinformatic approaches and screened using a 3’UTR luciferase assay. Functional assessments of endogenous hERG regulation were made using whole-cell electrophysiology, proliferation assays, and cell-cycle analyses following miRNA, hERG siRNA, or control transfection. Results: miR-362-3p targeted hERG 3’UTR and was associated with higher survival rates in patients with breast cancer (HR=0.39, 95%CI=0.18-0.82). Enhanced miR-362-3p expression reduced hERG expression, peak current, and cell proliferation in cultured breast cancer cells (p<0.05). Conclusion: miR-362-3p mediates the transcriptional regulation of hERG and is associated with survival in breast cancer. The potential for miR-362-3p to serve as a biomarker and inform therapeutic strategies warrants further investigation.

Browsing by Subject "MicroRNA"

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