Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

Arnaiz, Esther; Miar, Ana; Dias, Antônio Gregorio; Prasad, Naveen; Schulze, Ulrike; Waithe, Dominic; Rehwinkel, Jan; Harris, Ann

doi:10.3389/fonc.2021.779739

Cited by 13 publications

(13 citation statements)

References 54 publications

(72 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…3 C, Table 2), and confirmed that these effects were most pronounced for mitochondrial transcripts. The downregulation of mitochondrial genes such as MT-ND2, MT-ATP8, and MT-ND by hypoxic stimulation is already well known (Arnaiz et al 2021) validating our data. It has also been reported (Zhang et al 2008) that mitochondrial autophagy is commonly induced in response to hypoxia and that this process requires hypoxia-dependent factor-1-dependent BNIP3 expression, which also supports our results.…”

Section: Discussionsupporting

confidence: 91%

Exploratory Meta-Analysis of Hypoxic Transcriptomes Using Precise Transcript Reference Sequence Set

Ono

Bono

2022

Preprint

View full text Add to dashboard Cite

Gene expression studies are intrinsically biased with many being influenced by concomitant information such as the gene-disease association. However, this can be overcome using a data-driven analysis approach, which can provide insights without relying on ancillary information. This is exemplified by the FANTOM CAGE Associated Transcriptome (FANTOM-CAT) project, which provides a comprehensive meta-assembly of the human transcriptome using coding and non-coding genes. Various studies have shown that hypoxia has a significant effect on gene expression, with several of these reports suggesting that non-coding RNA (ncRNA) metabolism is downregulated in response to hypoxic stimuli. We aimed to interrogate the differential response of various transcripts to hypoxia by determining their hypoxia responsiveness score. We performed these evaluations using enrichment analysis, which revealed that several genes associated with ncRNA metabolism, especially those involved in ribosomal RNA processing, were significantly downregulated in response to hypoxia. Then, we used previously published information from the FANTOM-CAT project to create a novel reference file suitable for the meta-analysis of transcriptome sequencing data from both coding and ncRNAs and used this to evaluate the hypoxia responsiveness of target transcripts, while also evaluating the relationship between sense-antisense transcripts from the same locus. These evaluations revealed that these transcript pairs often exhibit similar regulatory patterns, but that this is largely reliant on their specific function. We believe that this study will facilitate the functional annotation of various transcripts including ncRNAs, allowing for both sense and antisense and coding and non-coding evaluations.

show abstract

Section: Discussionsupporting

confidence: 91%

Exploratory Meta-Analysis of Hypoxic Transcriptomes Using Precise Transcript Reference Sequence Set

Ono

Bono

2022

Preprint

View full text Add to dashboard Cite

show abstract

“…Visualization of this patterning then revealed likely regulation of gene expression by chromosome ( Fig 4B and Table 2 ) and confirmed that these effects were most pronounced for mitochondrial transcripts. The down-regulation of mitochondrial genes such as MT-ND2 , MT-ATP8 , and MT-ND by hypoxic stimulation is already well known ( Arnaiz et al, 2021 ), validating our data. It has also been reported ( Zhang et al, 2008 ) that mitochondrial autophagy is commonly induced in response to hypoxia and that this process requires hypoxia-dependent factor-1–dependent BNIP3 expression, which also supports our results.…”

Section: Discussionsupporting

confidence: 90%

Exploratory meta-analysis of hypoxic transcriptomes using a precise transcript reference sequence set

Ono

Bono

2022

Life Sci. Alliance

View full text Add to dashboard Cite

Gene expression studies are intrinsically biased, with many studies influenced by concomitant information such as gene–disease associations. This limitation can be overcome using a data-driven analysis approach without relying on ancillary information. The FANTOM CAGE–Associated Transcriptome project provides a comprehensive meta-assembly of the human transcriptome using coding and noncoding genes. Hypoxia strongly influences gene expression; in addition, noncoding RNA (ncRNA) metabolism is down-regulated in response to hypoxic stimuli. We evaluated the differential response of various transcripts to hypoxia by determining their hypoxia responsiveness scores. Enrichment analysis revealed that several genes associated with ncRNA metabolism, particularly those involved in ribosomal RNA processing, were down-regulated in response to hypoxia. Previously published information from the FANTOM CAGE–Associated Transcriptome project was suitable for meta-analysis of the transcriptome sequencing data from both coding and ncRNAs and to evaluate the hypoxia responsiveness of target transcripts and relationship between sense–antisense transcripts from the same locus. Our results may facilitate functional annotation of various transcripts including ncRNAs, allowing for both sense and antisense and coding and noncoding evaluations.

show abstract

“…Causative factors contributing to dsRNA formation in bladder ischemia may involve redox, a common phenomenon in ischemia that is strongly linked to the production of dsRNA. 27 Our data imply concomitant upregulation of Alu RNA transcription and dsRNA formation in bladder ischemia ( Figure 3 ). Alu RNA represents a family of repetitive sequences, and their sense and antisense transcripts are usually induced prior to dsRNA formation.…”

Section: Resultssupporting

confidence: 52%

Formation of Double Stranded RNA Provokes Smooth Muscle Contractions and Structural Modifications in Bladder Ischemia

Yang¹,

Zhao²,

Niu³

et al. 2022

RRU

View full text Add to dashboard Cite

Purpose Growing evidence suggests that ischemia provokes detrusor overactivity and degenerative responses in the bladder. Underlying mechanisms appear to involve modification of smooth muscle contractile rudiments by hypoxia, redox, cellular stress and cell survival signaling. Downstream pathways of cellular stress and stress response molecules eliciting bladder dysfunction in ischemia remain largely elusive. Our goal was to define the role of double stranded RNA (dsRNA), a stress response molecule provoked by redox, in ischemia mediated bladder dysfunction. Methods A rat model of pelvic ischemia along with a cell culture hypoxia model were used to investigate the expression levels, functional consequences, structural aspects, and regulatory mechanisms of dsRNA in the bladder. Gene and protein expression were examined by reverse transcription polymerase chain reaction (RT-PCR), dot blot, and Western blotting, respectively. Tissue structure and function were assessed using histological staining and organ bath. Regulatory mechanisms were analyzed in cultured bladder smooth muscle cells. Results The data presented here provide the first evidence of the formation of dsRNA in the overactive bladder. dsRNA is a cellular stress response molecule that sensitizes smooth muscle and regulates inflammatory and degenerative rejoinders. Our data suggest that the production of dsRNA in the bladder is provoked by ischemia. Formation of dsRNA appears to augment bladder smooth muscle contractions and provoke fibrotic and apoptotic responses. Downstream actions of dsRNA in the bladder may involve upregulation of dsRNA-activated protein kinase R (PKR) and caspase-3, the executioner of apoptosis. Conclusion Activation of dsRNA/PKR pathway may play a role in sensitization of bladder smooth muscle cells to contractile stimuli, whereas dsRNA and caspase-3 crosstalk appear to modulate cellular stress and instigate degenerative responses in bladder ischemia. These observations suggest the role of dsRNA in bladder dysfunction and may open new perspectives to overcome overactive smooth muscle contractions and structural damage in the bladder.

show abstract

Hypoxia Regulates Endogenous Double-Stranded RNA Production via Reduced Mitochondrial DNA Transcription

Cited by 13 publications

References 54 publications

Exploratory Meta-Analysis of Hypoxic Transcriptomes Using Precise Transcript Reference Sequence Set

Exploratory Meta-Analysis of Hypoxic Transcriptomes Using Precise Transcript Reference Sequence Set

Exploratory meta-analysis of hypoxic transcriptomes using a precise transcript reference sequence set

Formation of Double Stranded RNA Provokes Smooth Muscle Contractions and Structural Modifications in Bladder Ischemia

Contact Info

Product

Resources

About