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Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression

ABSTRACT: Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression

PROVIDER: PRJNA491521 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7866980.fastq.gz	Fastqsanger.gz
	SRR7867190.fastq.gz	Fastqsanger.gz
	SRR7866981.fastq.gz	Fastqsanger.gz
	SRR7867181.fastq.gz	Fastqsanger.gz
	SRR7866982.fastq.gz	Fastqsanger.gz

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Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [miRNA]

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

Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [mRNA]

2020-04-01 | GSE120087 | GEO

Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [miRNA]

Project description:Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [miRNA]

| PRJNA491523 | ENA

Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [mRNA]

Project description:Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression [mRNA]

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Cardiac ReductomiRs: Identification of Novel Nrf2-Dependent microRNAs as Post-Transcriptional Regulators of Myocardial Gene Expression

Project description:This SuperSeries is composed of the SubSeries listed below.

2020-04-01 | GSE120089 | GEO

Molecular characterization of BRSK2 and BRSK1 kinases as negative regulators of the NRF2 transcription factor

Project description:NFE2L2/NRF2 is a transcription factor and master regulator of the cellular antioxidant response. Aberrantly high NRF2-dependent transcription is recurrent in human cancer, resulting in increased cellular fitness, chemo-radiation resistance, metabolic reprogramming and immune evasion. NRF2 protein levels and activity is governed primarily by the KEAP1/CUL3 ubiquitin ligase and subsequent proteasomal degradation. To what extent parallel signaling pathways and protein classes impact NRF2 activity remains to be fully explored. Also, because NRF2-directed therapies remain in the discovery and early development stages, continued identification and validation of NRF2 regulators is of potential clinical value. Here we used a gain-of-function genetic screen of the kinome to identify druggable activators and inhibitors of NRF2 signaling. We found that the understudied Brain Selective Kinase 1 and 2 (BRSK1/2) proteins suppress NRF2-dependent transcription and NRF2 protein levels in a kinase-dependent fashion. Integrative phospho-proteomic screens, RNAseq profiling and follow-up validation studies revealed BRSK1/2-driven activation of AMPK and suppression of MTOR signaling. BRSK2 over-expression suppressed global protein synthesis and decreased ribosome-RNA associations, which results in decreased NRF2 protein levels. Overall, our data establish the BRSK1 and BRSK2 kinases as negative regulators of NRF2 via the AMPK/MTOR signaling axis. Strategies which exploit these relationships may prove useful for therapeutically targeting NRF2 in cancer.

2020-06-24 | PXD015884 | Pride

Protein-like Polymers Targeting Keap1/Nrf2 as Therapeutics for Myocardial Infarction

Project description:Myocardial infarction (MI) results in oxidative stress to the myocardium and frequently leads to heart failure (HF). There is a need to therapeutically treat the inflammatory stress response and thus prevent negative left ventricular remodeling. Thus, we specifically target the protein-protein interaction between Nrf2 and Keap1, as Nrf2 activation is known to mitigate MI. We further leverage Nrf2 activation using a proteomimetic platform to inhibit the Keap1-Nrf2 axis via protein-like polymers (PLPs), given its stability in vivo, prolonged circulatory half-life, potent intracellular bioactivity, and multivalency. We employed in vitro and in vivo assays to probe cellular activity and MI therapeutic utility. These Keap1-inhibiting PLPs (Keap1i-PLPs) exhibit primary cardiomyocyte cytoprotection from oxidative stress via Nrf2 activation at sub-nanomolar concentrations. Single-digit mg/kg, single-dose, intravenous PLP treatment significantly improves cardiac function in rats post-MI through immunomodulatory, anti-apoptotic, and angiogenic mechanisms. Thus Keap1i-PLPs disrupt key intracellular PPIs following intravenous, systemic administration in vivo. These results have broad implications not only for MI, but also for other oxidative stress diseases.

2025-05-28 | GSE273545 | GEO

Comparative Characterization of Cardiac Development Specific microRNAs: Fetal Regulators for Future

Project description:MicroRNAs (miRNAs) are small, conserved RNAs known to regulate several biological processes by influencing gene expression in eukaryotes. The implication of miRNAs as another player of regulatory layers during heart development and diseases has recently been explored. The present study was designed to identify the microRNAs implicated in heart development using next generation sequencing, bioinformatics and experimental approaches. We sequenced six small RNA libraries prepared from different developmental stages of the heart using chicken as a model system to produce millions of short sequence reads. We detected 353 known and 703 novel miRNAs involved in heart development. Out of total 1056 microRNAs identified, 32.7% of total dataset of known microRNAs displayed differential expression whereas seven well studied microRNAs namely let-7, miR-140, miR-181, miR-30, miR-205, miR-103 and miR-22 were found to be conserved throughout the heart development. The 3'UTR sequences of genes were screened from Gallus gallus genome for potential microRNA targets. The target mRNAs were appeared to be enriched with genes related to cell cycle, apoptosis, signalling pathways, extracellular remodelling, metabolic, chromatin remodelling and transcriptional regulators. The study presents the first comprehensive overview of microRNA profiling during heart development and prediction of possible cardiac specific targets and has a big potential in future to develop microRNA based therapeutics against cardiac pathologies where fetal gene re-expression is witnessed in adult heart. 6 samples (CHL1, CHL2, CHL3, CHL4, CHL5, CHL6)

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microRNAs are negative and positive post-transcriptional regulators of BRAF-X1 mRNA

Project description:microRNAs are negative and positive post-transcriptional regulators of BRAF-X1 mRNA

| PRJNA482818 | ENA

Comparative Characterization of Cardiac Development Specific microRNAs: Fetal Regulators for Future

2015-06-09 | GSE69663 | GEO