Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE120089 | GEO | 2020/04/01
REPOSITORIES: GEO
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Project description:Background: Although modern advances in the treatment of heart disease have reduced mortality rates, long-term medical management is often associated with a progressive loss of function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, a.k.a. Nrf2) is a transcriptional regulator that provides the ischemic heart with transient cytoprotection following acute myocardial insult; however, its sustained activation paradoxically causes reductive stress, an emerging pathological phenomenon characterized by excessive antioxidant function and proteotoxic remodeling. Yet, the molecular mechanism by which chronic reductive stress produces heart failure remains elusive. Methods: Cardiac-specific constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing the transgene at low (TgL) and high (TgH) levels were employed in integrative mRNA and small RNA (miRNA) sequencing. Results and Conclusion: Here, we reveal several Nrf2 dose-responsive miRNA loci harboring putative upstream antioxidant response elements (AREs). Intriguingly, Nrf2-mediated miRNA responses were distinctly enriched for post-transcriptional regulation of cardiac-specific mRNAs. Altogether, these data reveal Nrf2 as a potent regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation into the relationship between myocardial redox status and pathophysiology.
2020-04-01 | GSE120087 | GEO
Project description:Background: Although modern advances in the treatment of heart disease have reduced mortality rates, long-term medical management is often associated with a progressive loss of function that manifests as heart failure. Nuclear factor, erythroid 2 like 2 (Nfe2l2, a.k.a. Nrf2) is a transcriptional regulator that provides the ischemic heart with transient cytoprotection following acute myocardial insult; however, its sustained activation paradoxically causes reductive stress, an emerging pathological phenomenon characterized by excessive antioxidant function and proteotoxic remodeling. Yet, the molecular mechanism by which chronic reductive stress produces heart failure remains elusive. Methods: Cardiac-specific constitutively active Nrf2 transgenic (caNrf2-Tg) mice expressing the transgene at low (TgL) and high (TgH) levels were employed in integrative mRNA and small RNA (miRNA) sequencing. Results and Conclusion: Here, we reveal several Nrf2 dose-responsive miRNA loci harboring putative upstream antioxidant response elements (AREs). Intriguingly, Nrf2-mediated miRNA responses were distinctly enriched for post-transcriptional regulation of cardiac-specific mRNAs. Altogether, these data reveal Nrf2 as a potent regulator of cardiac miRNA expression and provide novel candidates for future mechanistic investigation into the relationship between myocardial redox status and pathophysiology.
2020-04-01 | GSE120088 | GEO
Project description:Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression
| PRJNA491521 | ENA
Project description:Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [miRNA]
| PRJNA491523 | ENA
Project description:Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [mRNA]
| PRJNA491524 | ENA
Project description:Nuclear factor-erythroid 2-related factor 2 (Nrf2/NFE2L2), a redox-sensitive transcription factor plays a critical role in adaptation to cellular stress and affords cellular defense by initiating transcription of antioxidative and detoxification genes. While a protein can be regulated at multiple levels, control of Nrf2 has been largely studied at post-translational regulation points by Keap1. Importantly, post-transcriptional/translational based regulation of Nrf2 is less understood and to date there are no reports on such mechanisms in neuronal systems. In this context, studies involving the role of microRNAs (miRs) which are normally considered as fine tuning regulators of protein production through translation repression and/or post-transcriptional alterations, are in place. In the current study, based on in-silico analysis followed by immunoblotting and real time analysis, we have identified and validated for the first time that human NFE2L2 could be targeted by miR153/miR27a/miR142-5p/miR144 in neuronal, SH-SY5Y cells. Co-transfection studies with individual miR mimics along with either WT 3' UTR of human Nrf2 or mutated miRNA targeting seed sequence within Nrf2 3' UTR, demonstrated that Nrf2 is a direct regulatory target of these miRs. In addition, ectopic expression of miR153/miR27a/miR142-5p/miR144 affected Nrf2 mRNA abundance and nucleo-cytoplasmic concentration of Nrf2 in a Keap1 independent manner resulting in inefficient transactivating ability of Nrf2. Furthermore, forced expression of miRs diminished GCLC and GSR expression resulting in alteration of Nrf2 dependent redox homeostasis. Finally, bioinformatics based miRNA-disease network analysis (MDN) along with extended computational network analysis of Nrf2 associated pathologic processes suggests that if in a particular cellular scenario where any of these miR153/miR27a/miR142-5p/miR144 either individually or as a group is altered, it could affect Nrf2 thus triggering and/or determining the fate of wide range of disease outcomes.
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Project description:BACKGROUND:The work of the FANTOM5 Consortium has brought forth a new level of understanding of the regulation of gene transcription and the cellular processes involved in creating diversity of cell types. In this study, we extended the analysis of the FANTOM5 Cap Analysis of Gene Expression (CAGE) transcriptome data to focus on understanding the genetic regulators involved in mouse cerebellar development. RESULTS:We used the HeliScopeCAGE library sequencing on cerebellar samples over 8 embryonic and 4 early postnatal times. This study showcases temporal expression pattern changes during cerebellar development. Through a bioinformatics analysis that focused on transcription factors, their promoters and binding sites, we identified genes that appear as strong candidates for involvement in cerebellar development. We selected several candidate transcriptional regulators for validation experiments including qRT-PCR and shRNA transcript knockdown. We observed marked and reproducible developmental defects in Atf4, Rfx3, and Scrt2 knockdown embryos, which support the role of these genes in cerebellar development. CONCLUSIONS:The successful identification of these novel gene regulators in cerebellar development demonstrates that the FANTOM5 cerebellum time series is a high-quality transcriptome database for functional investigation of gene regulatory networks in cerebellar development.
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Project description:Motivation:Transcriptional regulators play a major role in most biological processes. Alterations in their activities are associated with a variety of diseases and in particular with tumor development and progression. Hence, it is important to assess the effects of deregulated regulators on pathological processes. Results:Here, we present REGulator-Gene Association Enrichment (REGGAE), a novel method for the identification of key transcriptional regulators that have a significant effect on the expression of a given set of genes, e.g. genes that are differentially expressed between two sample groups. REGGAE uses a Kolmogorov-Smirnov-like test statistic that implicitly combines associations between regulators and their target genes with an enrichment approach to prioritize the influence of transcriptional regulators. We evaluated our method in two different application scenarios, which demonstrate that REGGAE is well suited for uncovering the influence of transcriptional regulators and is a valuable tool for the elucidation of complex regulatory mechanisms. Availability and implementation:REGGAE is freely available at https://regulatortrail.bioinf.uni-sb.de. Supplementary information:Supplementary data are available at Bioinformatics online.
| S-EPMC6184769 | biostudies-literature
Project description:Every nucleosome across the genome must be disrupted and reformed when the replication fork passes, but how chromatin organization is re-established following replication is unknown. To address this problem, we have developed Mapping In vivo Nascent Chromatin with EdU and sequencing (MINCE-seq) to characterize the genome-wide location of nucleosomes and other chromatin proteins behind replication forks at high temporal and spatial resolution. We find that the characteristic chromatin landscape at Drosophila promoters and enhancers is lost upon replication. The most conspicuous changes are at promoters that have high levels of RNA polymerase II (RNAPII) stalling and DNA accessibility and show specific enrichment for the BRM remodeler. Enhancer chromatin is also disrupted during replication, suggesting a role for transcription factor (TF) competition in nucleosome re-establishment. Thus, the characteristic nucleosome landscape emerges from a uniformly packaged genome by the action of TFs, RNAPII, and remodelers minutes after replication fork passage.
| S-EPMC4855302 | biostudies-literature
Project description:The prognosis of cardiac arrest (CA) is dismal despite the ongoing progress in cardiopulmonary resuscitation (CPR). ginsenoside Rb1 (Gn-Rb1) has been verified to be cardioprotective in cardiac remodeling and cardiac ischemia/reperfusion (I/R) injury, but its role is less known in CA. After 15 min of potassium chloride-induced CA, male C57BL/6 mice were resuscitated. Gn-Rb1 was blindly randomized to mice after 20 s of CPR. We assessed the cardiac systolic function before CA and 3 h after CPR. Mortality rates, neurological outcome, mitochondrial homeostasis, and the levels of oxidative stress were evaluated. We found that Gn-Rb1 improved the long-term survival during the post-resuscitation period but did not affect the ROSC rate. Further mechanistic investigations revealed that Gn-Rb1 ameliorated CA/CPR-induced mitochondrial destabilization and oxidative stress, partially via the activation of Keap1/Nrf2 axis. Gn-Rb1 improved the neurological outcome after resuscitation partially by balancing the oxidative stress and suppressing apoptosis. In sum, Gn-Rb1 protects against post-CA myocardial stunning and cerebral outcomes via the induction of the Nrf2 signaling pathway, which may offer a new insight into therapeutic strategies for CA.
| S-EPMC10003120 | biostudies-literature