Integrative analysis of independent transcriptome data for rare diseases

Zhang, Zhe; Hailat, Zeyad; Falk, Marni J.; Chen, Xue wen

doi:10.1016/j.ymeth.2014.06.003

Cited by 6 publications

(3 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We found that 329 mRNAs were significantly dysregulated in MELAS patients vs. controls. Interestingly, some of them were previously reported to be dysregulated in mitochondrial myopathy, including MYC, ATP2A2, ACTN3, AQP4, GLUL, TRIM63 and PFKFB3, which were partly consistent with transcriptome datasets from previous studies of mitochondrial genetic disorders 21 22 23 24 . This suggested that mitochondrial disease have disparate causes, and yet share common mechanistic themes 25 .…”

Section: Discussionsupporting

confidence: 84%

Identification of miRNA, lncRNA and mRNA-associated ceRNA networks and potential biomarker for MELAS with mitochondrial DNA A3243G mutation

Wang

Zhuang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

Researchers in the field of mitochondrial biology are increasingly unveiling of the complex mechanisms between mitochondrial dysfunction and noncoding RNAs (ncRNAs). However, roles of ncRNAs underlying mitochondrial myopathy remain unexplored. The aim of this study was to elucidate the regulating networks of dysregulated ncRNAs in Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes (MELAS) with mitochondrial DNA (mtDNA) A3243G mutation, which might make contributions to the unveiling of the complex mechanisms underlying mitochondrial myopathy and, possibly, new tools applicable to clinical practice. Through high-throughput technology followed by quantitative real-time polymerase chain reaction (qRT-PCR) and bioinformatics analyses, for the first time, we found that the dysregulated muscle miRNAs and lncRNAs between 20 MELAS patients with mtDNA A3243G mutation and 20 controls formed complex regulation networks and participated in immune system, signal transduction, translation, muscle contraction and other pathways in discovery and training phase. Then, selected ncRNAs were validated in muscle and serum in independent validation cohorts by qRT-PCR. Finally, ROC curve analysis indicated reduced serum miR-27b-3p had the better diagnosis value than lactate and might serve as a novel, noninvasive biomarker for MELAS. Follow-up investigation is warranted to better understand roles of ncRNAs in mitochondrial myopathy pathogenesis.

show abstract

Section: Discussionsupporting

confidence: 84%

Identification of miRNA, lncRNA and mRNA-associated ceRNA networks and potential biomarker for MELAS with mitochondrial DNA A3243G mutation

Wang

Zhuang

et al. 2017

Sci Rep

View full text Add to dashboard Cite

show abstract

“…Although efficacy, toxicity or optimal dose of these drugs have not been objectively assessed in human RC disease patients, they are often empirically prescribed in hopes of enhancing residual RC enzymatic function or quenching ‘toxic’ metabolites that are theorized to accumulate in RC dysfunction (Avula et al, 2014; Pfeffer et al, 2013). Provision of these therapies generally adopts a “one size fits all” approach, overtly ignoring inherent variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors such as the predominant downstream metabolic and signaling alterations (Zhang et al, 2014; Zhang et al, 2013).…”

Section: 1 Introductionmentioning

confidence: 99%

Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish

Byrnes

Ganetzky

Lightfoot

et al. 2018

Neurochemistry International

Self Cite

View full text Add to dashboard Cite

Mitochondrial respiratory chain (RC) disease is a heterogeneous and highly morbid group of energy deficiency disorders for which no proven effective therapies exist. Robust vertebrate animal models of primary RC dysfunction are needed to explore the effects of variation in RC disease subtypes, tissue-specific manifestations, and major pathogenic factors contributing to each disorder, as well as their pre-clinical response to therapeutic candidates. We have developed a series of zebrafish (Danio rerio) models that inhibit, to variable degrees, distinct aspects of RC function, and enable quantification of animal development, survival, behaviors, and organ-level treatment effects as well as effects on mitochondrial biochemistry and physiology. Here, we characterize four pharmacologic inhibitor models of mitochondrial RC dysfunction in early larval zebrafish, including rotenone (complex I inhibitor), azide (complex IV inhibitor), oligomycin (complex V inhibitor), and chloramphenicol (mitochondrial translation inhibitor that leads to multiple RC complex dysfunction). A range of concentrations and exposure times of each RC inhibitor were systematically evaluated on early larval development, animal survival, integrated behaviors (touch and startle responses), organ physiology (brain death, neurologic tone, heart rate), and fluorescence-based analyses of mitochondrial physiology in zebrafish skeletal muscle. Pharmacologic RC inhibitor effects were validated by spectrophotometric analysis of Complex I, II and IV enzyme activities, or relative quantitation of ATP levels in larvae. Outcomes were prioritized that utilize in vivo animal imaging and quantitative behavioral assessments, as may optimally inform the translational potential of pre-clinical drug screens for future clinical study in human mitochondrial disease subjects. The RC complex inhibitors each delayed early embryo development, with short-term exposures of these three agents or chloramphenicol from 5 to 7 days post fertilization also causing reduced larval survival and organ-specific defects ranging from brain death, behavioral and neurologic alterations, reduced mitochondrial membrane potential in skeletal muscle (rotenone), and/or cardiac edema with visible blood pooling (oligomycin). Remarkably, we demonstrate that treating animals with probucol, a nutrient-sensing signaling network modulating drug that has been shown to yield therapeutic effects in a range of other RC disease cellular and animal models, both prevented acute rotenone-induced brain death in zebrafish larvae, and significantly rescued early embryo developmental delay from either rotenone or oligomycin exposure. Overall, these zebrafish pharmacologic RC function inhibition models offer a unique opportunity to gain novel insights into diverse developmental, survival, organ-level, and behavioral defects of varying severity, as well as their individual response to candidate therapies, in a highly tractable and cost-effective vertebrate animal model system.

show abstract

“…Most of the studies investigating transcriptomic changes associated to mitochondrial dysfunction, however, have been carried out with microarray technologies. In fact, the only published systematic approach incorporated datasets from several organisms ( H. sapiens , M. musculus , D. melanogaster and C. elegans ) and various microarray platforms 31 .…”

Section: Discussionmentioning

confidence: 99%

An ATF4-centric regulatory network is required for the assembly and function of the OXPHOS system

Cagin,

Gómez,

Casajús-Pelegay

et al. 2023

Preprint

View full text Add to dashboard Cite

Identifying the factors that determine mammalian cell viability when oxidative phosphorylation (OXPHOS) function is impaired poses challenges due to the diverse cellular responses and limited clinical material availability. Moreover, animal models often fail to replicate human phenotypes. To address these challenges, this study conducted comprehensive analyses involving multiple defects and species by comparing the RNA-Seq expression profiles of human and murine cell lines with distinct nuclear backgrounds, representing both normal and OXPHOS-deficient models. To minimize species-specific variation, the study employed clustering techniques to group murine genes affected by OXPHOS dysfunction and identified crucial regulators like ATF4, UCP1, and SYVN1. ATF4 consistently displayed activation in response to OXPHOS defects, not only in murine but also in human cells, confirming its pivotal role in the cellular response to mitochondrial dysfunction. By integrating human and murine data, the study unveiled a conserved regulatory network encompassing genes related to the mTOR pathway and folate metabolism. Remarkably, the study uncovered an unexpected finding: the depletion of ATF4 in both mouse and human cells impairs OXPHOS assembly and supercomplex organization. This impairment primarily stems from a severe disruption in complex I assembly in the absence of ATF4, even under non-stress conditions.

show abstract

Integrative analysis of independent transcriptome data for rare diseases

Cited by 6 publications

References 50 publications

Identification of miRNA, lncRNA and mRNA-associated ceRNA networks and potential biomarker for MELAS with mitochondrial DNA A3243G mutation

Identification of miRNA, lncRNA and mRNA-associated ceRNA networks and potential biomarker for MELAS with mitochondrial DNA A3243G mutation

Pharmacologic modeling of primary mitochondrial respiratory chain dysfunction in zebrafish

An ATF4-centric regulatory network is required for the assembly and function of the OXPHOS system

Contact Info

Product

Resources

About