Cell survival is dicey without Dicer

Adams, Clare M.; Eischen, Christine M.

doi:10.4161/23723548.2014.961825

Cited by 4 publications

(6 citation statements)

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“…All of the donors were first clinically assessed by professionals for PTSD. Participants were evaluated by the psychometric properties of the PTSD Checklist (PCL) 50 and the PTSD diagnosis was validated by the Clinician Administered PTSD Scale 51 and the Diagnostic and Statistical Manual of Mental Disorder (DSM-V) 4 . (Demographics of the PTSD patients included for the microarray and RNA-Seq analyses is provided in Table 1 ).…”

Section: Subjects Materials and Methodsmentioning

confidence: 99%

“…The values indicate mean and the values in parentheses for age, depression, anxiety and PTSD score indicates standard deviation. Depression, anxiety and PTSD scores were determined as per PCL, CAPS and DSM criteria 4 50 51 . * African American; **Caucasian; ***Hispanic.…”

Section: Figurementioning

confidence: 99%

“…PTSD is a serious psychiatric disorder with a poor understanding of its etiology, especially at the molecular level. Symptoms of PTSD include hyperarousal, intrusive thoughts, flashbacks, nightmares, numbing of feelings, insomnia, fear, avoidance of reminders, irritability, hypervigilance, heightened startle response and distress when exposed to reminders 4 . It is believed that numerous molecular factors determine the risk and subsequent development of PTSD 5 and such studies are now at the forefront of molecular psychiatry research.…”

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confidence: 99%

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Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation

Bam

Yang

Zumbrun

et al. 2016

Sci Rep

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Post-traumatic stress disorder patients experience chronic systemic inflammation. However, the molecular pathways involved and mechanisms regulating the expression of genes involved in inflammatory pathways in PTSD are reported inadequately. Through RNA sequencing and miRNA microarray, we identified 326 genes and 190 miRNAs that were significantly different in their expression levels in the PBMCs of PTSD patients. Expression pairing of the differentially expressed genes and miRNAs indicated an inverse relationship in their expression. Functional analysis of the differentially expressed genes indicated their involvement in the canonical pathways specific to immune system biology. DNA methylation analysis of differentially expressed genes also showed a gradual trend towards differences between control and PTSD patients, again indicating a possible role of this epigenetic mechanism in PTSD inflammation. Overall, combining data from the three techniques provided a holistic view of several pathways in which the differentially expressed genes were impacted through epigenetic mechanisms, in PTSD. Thus, analysis combining data from RNA-Seq, miRNA array and DNA methylation, can provide key evidence about dysregulated pathways and the controlling mechanism in PTSD. Most importantly, the present study provides further evidence that inflammation in PTSD could be epigenetically regulated.

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Section: Subjects Materials and Methodsmentioning

confidence: 99%

Section: Figurementioning

confidence: 99%

mentioning

confidence: 99%

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Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation

Bam

Yang

Zumbrun

et al. 2016

Sci Rep

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“…Prior to studies on the specific miRNAs, we first asked if miRNAs are involved in cycling quiescence of TMZ resistant GBM cells. This was addressed by knockdown of Dicer, which is a type III RNase and a key enzyme in the maturation of miRNAs (Adams and Eischen, 2014; van den Beucken et al, 2014). We established resistant GBM cells in which Dicer 1 was knocked down, as previously described (Munoz et al, 2014a).…”

Section: Resultsmentioning

confidence: 99%

Cycling Quiescence in Temozolomide Resistant Glioblastoma Cells Is Partly Explained by microRNA-93 and -193-Mediated Decrease of Cyclin D

et al. 2019

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Glioblastoma multiforme (GBM) is a fatal malignancy of the central nervous system, commonly associated with chemoresistance. The alkylating agent Temozolomide (TMZ) is the front-line chemotherapeutic agent and has undergone intense studies on resistance. These studies reported on mismatch repair gene upregulation, ABC-targeted drug efflux, and cell cycle alterations. The mechanism by which TMZ induces cell cycle arrest has not been well-established. TMZ-resistant GBM cells have been linked to microRNA (miRNA) and exosomes. A cell cycle miRNA array identified distinct miRNAs only in exosomes from TMZ-resistant GBM cell lines and primary spheres. We narrowed the miRs to miR-93 and -193 and showed in computational analyses that they could target Cyclin D1. Since Cyclin D1 is a major regulator of cell cycle progression, we performed cause-effect studies and showed a blunting effects of miR-93 and -193 in Cyclin D1 expression. These two miRs also decreased cell cycling quiescence and induced resistance to TMZ. Taken together, our data provide a mechanism by which GBM cells can exhibit TMZ-induced resistance through miRNA targeting of Cyclin D1. The data provide a number of therapeutic approaches to reverse chemoresistance at the miRNA, exosomal and cell cycle points.

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“…In this context, deficiency in DCR1, the enzyme responsible for the generation of mature miRNA by cleaving pre-miRNA to ~22 nucleotide mature miRNAs, is known to result in deficient miRNA biogenesis and can lead to lowered abundance of mature miRNAs. 14 , 15 , 16 Remarkably, a recent report showed that the expression of Dicer1 was decreased in PTSD, and this was linked to the lowered expression of miR-3130-5p. 17 Interestingly, the authors reported only miR-3130-5p as significantly downregulated but did not show any link between the downregulated miRNA and any physiological changes in PTSD.…”

Section: Introductionmentioning

confidence: 99%

Decreased AGO2 and DCR1 in PBMCs from War Veterans with PTSD leads to diminished miRNA resulting in elevated inflammation

et al. 2017

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Chronic inflammation is a characteristic of post-traumatic stress disorder (PTSD). The initiation of inflammation and molecules involved are not yet clearly understood. Here, we provide compelling evidence that the inflammation seen in PTSD may result from the dysregulated miRNA processing pathway. Using microarray analysis with a discovery group of peripheral blood mononuclear cell (PBMC) samples from War Veterans with PTSD, we found 183 significantly downregulated miRNAs, several of which target numerous genes categorized to be pro-inflammatory in nature. This observation was further confirmed in a replicate group by including more samples. Furthermore, employing RNA-sequencing, quantitative real time PCR (qRT-PCR) and in vitro experiments, we found that Argonaute 2 (AGO2) and Dicer1 (DCR1) were downregulated in PTSD and provided convincing evidence that their downregulation affects mature miRNA generation. In addition, we noted that STAT3 transcript was reduced in PTSD and this was possibly responsible for reduced AGO2 and DCR1, which in turn affected miRNA synthesis. Furthermore, we observed that activation of CD4+ T cells or monocytes led to reduced mature miRNA availability. Finally, the inflammation seen in PTSD was associated with downregulated miRNA profile. Altogether, the current study demonstrates that the chronic inflammation seen in PTSD may be a result of dysregulated miRNA biogenesis pathway due to diminished expression of the key molecules like AGO2, DCR1 and STAT3.

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Cell survival is dicey without Dicer

Cited by 4 publications

References 10 publications

Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation

Dysregulated immune system networks in war veterans with PTSD is an outcome of altered miRNA expression and DNA methylation

Cycling Quiescence in Temozolomide Resistant Glioblastoma Cells Is Partly Explained by microRNA-93 and -193-Mediated Decrease of Cyclin D

Decreased AGO2 and DCR1 in PBMCs from War Veterans with PTSD leads to diminished miRNA resulting in elevated inflammation

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