Protein-coding circular RNAs - mechanism, detection, and their role in cancer and neurodegenerative diseases.

Circular RNAs (circRNAs) are a unique class of non-coding RNAs and were originally thought to have no protein-coding potential due to their lack of a 5' cap and 3' poly(A) tail. However, recent studies have challenged this notion and revealed that some circRNAs have protein-coding potential. They have emerged as a key area of interest in cancer and neurodegeneration research as recent studies have identified several circRNAs that can produce functional proteins with important roles in cancer progression. The protein-coding potential of circRNAs is determined by the presence of an open reading frame (ORF) within the circular structure that can encode a protein. In some cases, the ORF can be translated into a functional protein despite the lack of traditional mRNA features. While the protein-coding potential of most circRNAs remains unclear, several studies have identified specific circRNAs that can produce functional proteins. Understanding the protein-coding potential of circRNAs is important for unravelling their biological functions and potential roles in disease. Our review provides comprehensive coverage of recent advances in the field of circRNA protein-coding capacity and its impact on cancer and neurodegenerative diseases pathogenesis and progression.

A unique circular RNA expression pattern in the peripheral blood of myalgic encephalomyelitis/chronic fatigue syndrome patients.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disease with obscure aetiology. The underdiagnosis rate of ME/CFS is high due to the lack of diagnostic criteria based on objective markers. In recent years, circRNAs have emerged as potential genetic biomarkers for neurological diseases, including Parkinson's disease and Alzheimer's disease, making them likely to have the same prospect of being biomarkers in ME/CFS. However, despite the extensive amount of research that has been performed on the transcriptomes of ME/CFS patients, all of them are solely focused on linear RNAs, and the profiling of circRNAs in ME/CFS has been completely omitted. In this study, we investigated the expression profiles of circRNAs, comparing ME/CFS patients and controls before and after two sessions of cardiopulmonary exercise longitudinally. In patients with ME/CFS, the number of detected circRNAs was higher compared to healthy controls, indicating potential differences in circRNA expression associated with the disease. Additionally, healthy controls showed an increase in the number of circRNAs following exercise testing, while no similar pattern was evident in ME/CFS patients, further highlighting physiological differences between the two groups. A lack of correlation was observed between differentially expressed circRNAs and their corresponding coding genes in terms of expression and function, suggesting the potential of circRNAs as independent biomarkers in ME/CFS. Specifically, 14 circRNAs were highly expressed in ME/CFS patients but absent in controls throughout the exercise study, indicating a unique molecular signature specific to ME/CFS patients and providing potential diagnostic biomarkers for the disease. Significant enrichment of protein and gene regulative pathways were detected in relation to five of these 14 circRNAs based on their predicted miRNA target genes. Overall, this is the first study to describe the circRNA expression profile in peripheral blood of ME/CFS patients, providing valuable insights into the molecular mechanisms underlying the disease.

Investigation of circular RNA transcriptome in obesity-related endometrial cancer.

The present study has investigated the circular RNA (circRNA) transcriptome of twenty obese and postmenopausal women, recruited in Australia, with endometrial cancer (EC). This paper expands on previous findings which evaluated the circRNA transcriptome of a similar cohort of six women recruited in the United States of America. EC is the most common gynaecological malignancy and the fifth most common cancer in women worldwide with obesity as one of its major risk factors. CircRNAs, a class of non-coding RNAs, are involved in many human diseases including cancer. As such the objective of this study was to investigate the circRNA transcriptome of these twenty women and identify circRNAs of interest. We obtained paired samples (EC and adjacent normal tissue) from the cohort of twenty women. Samples were subjected to ribosomal RNA depletion and sequencing performed using Illumina sequencing technology. CircRNAs were identified through CIRI2 and CIRCexplorer2 and common circRNAs extracted for differential expression with edgeR which met the criteria of counts per million > 0.1 and expressed in ≥ 10. We found that the overall abundance of circRNAs was lower in EC compared to adjacent non-cancerous endometrial tissue. We also identified hotspot genes, genes expressing over 10 distinct circRNA isoforms. There were 82 hotspot genes in normal tissue and 23 hotspot genes in EC. There were 174 significantly differentially expressed circRNAs, of which 172 were down-regulated and 2 were up-regulated in EC. The circRNAs identified from this study may act as diagnostic or prognostic biomarkers for EC in obese women. While the circRNA transcriptome of obesity-related EC has been investigated further work is required to determine their functional significance.

Investigation of Transcriptome Patterns in Endometrial Cancers from Obese and Lean Women.

Endometrial cancer is the most common gynaecological malignancy in developed countries. One of the largest risk factors for endometrial cancer is obesity. The aim of this study was to determine whether there are differences in the transcriptome of endometrial cancers from obese vs. lean women. Here we investigate the transcriptome of endometrial cancer between obese and lean postmenopausal women using rRNA-depleted RNA-Seq data from endometrial cancer tissues and matched adjacent non-cancerous endometrial tissues. Differential expression analysis identified 12,484 genes (6370 up-regulated and 6114 down-regulated) in endometrial cancer tissues from obese women, and 6219 genes (3196 up-regulated and 3023 down-regulated) in endometrial cancer tissues from lean women (adjusted p-value < 0.1). A gene ontology enrichment analysis revealed that the top 1000 up-regulated genes (by adjusted p-value) were enriched for growth and proliferation pathways while the top 1000 down-regulated genes were enriched for cytoskeleton restructure networks in both obese and lean endometrial cancer tissues. In this study, we also show perturbations in the expression of protein coding genes (HIST1H2BL, HIST1H3F, HIST1H2BH, HIST1H1B, TTK, PTCHD1, ASPN, PRELP, and CDH13) and the lncRNA MBNL1-AS1 in endometrial cancer tissues. Overall, this study has identified gene expression changes that are similar and also unique to endometrial cancers from obese vs. lean women. Furthermore, some of these genes may serve as prognostic biomarkers or, possibly, therapeutic targets for endometrial cancer.

Analysis of the Circular Transcriptome in the Synaptosomes of Aged Mice.

Recently, circular RNAs (circRNAs) have been revealed to be an important non-coding element of the transcriptome. The brain contains the most abundant and widespread expression of circRNA. There are also indications that the circular transcriptome undergoes dynamic changes as a result of brain ageing. Diminished cognitive function with increased age reflects the dysregulation of synaptic function and ineffective neurotransmission through alterations of the synaptic proteome. Here, we present changes in the circular transcriptome in ageing synapses using a mouse model. Specifically, we observed an accumulation of uniquely expressed circular transcripts in the synaptosomes of aged mice compared to young mice. Individual circRNA expression patterns were characterized by an increased abundance in the synaptosomes of young or aged mice, whereas the opposite expression was observed for the parental gene linear transcripts. These changes in expression were validated by RT-qPCR. We provide the first comprehensive survey of the circular transcriptome in mammalian synapses, thereby paving the way for future studies. Additionally, we present 16 genes that express solely circRNAs, without linear RNAs co-expression, exclusively in young and aged synaptosomes, suggesting a synaptic gene network that functions along canonical splicing activity.

Analysis of the circular RNA transcriptome in endometrial cancer.

Circular RNAs (circRNAs) are a naturally occurring family of non-coding RNA that may regulate gene expression in mammals. circRNAs are more stable than messenger RNAs due to their resistance to RNA exonuclease. A growing body of evidence has shown that the expression of circRNAs is regulated during development in a tissue-specific manner. CircRNAs have been implicated in a number of cancers; however, their role in endometrial cancer (EC) is completely unknown. Here, we report the circular transcriptome specific for EC as determined by RNA sequencing. We found that the overall abundance of circRNAs is lower in EC than in normal endometrium. Further, there are numerous 'hotspot' genes from which circRNAs are transcribed that may account for alterations in circRNA expression between the normal and malignant endometrium. Most importantly, we have also identified circRNAs that are differentially expressed between malignant and normal endometrial tissue. The functional significance of these circRNAs in cancer remains to be determined, but they may serve as potential biomarkers for the diagnosis of EC or monitoring of EC progression.

Transcriptome landscape of long intergenic non-coding RNAs in endometrial cancer.

Endometrial cancer is the most common gynecological malignancy in the developed world. It is the fifth most common cancer and accounts for 4.8% of all cancers in women. Long intergenic non-coding RNAs (lincRNAs), a subclass of long non-coding RNAs, are pervasively transcribed throughout the human genome. OBJECTIVE: LincRNA expression patterns in endometrial cancer compared to normal healthy tissue are poorly characterised. In this study, the lincRNA transcriptome of endometrial cancers and adjacent normal endometrium from the same patients was sequenced and compared with transcriptomes of other gynaecologic malignancies including ovarian and cervical cancers. METHODS: RNA was isolated from malignant and adjacent non-affected endometrial tissue from 6 patients with low grade and stage Type I endometrial cancer. Subsequently, Illumina paired-end RNA sequencing was performed, followed by bioinformatics analysis, to determine differential transcriptome expression patterns. RESULTS: LINC00958 was upregulated in all three cancers, and four lincRNAs including LINC01480, LINC00645, LINC00891 and LINC00702 demonstrated exquisite specificity for malignant endometrium compared to normal endometrium while also distinguishing endometrial cancer from ovarian and cervical cancers. Furthermore, LINC01480 has features required to express a micropeptide. CONCLUSIONS: The lincRNAs, characterised in this study, represent high priority genes to be tested for functional significance in the pathogenesis and/or progression of endometrial cancer. Furthermore, lincRNAs have potential to be released into the bloodstream and therefore the four lincRNAs identified here may represent biomarkers for early detection of endometrial cancer without biopsy.

RNA sequencing reveals pronounced changes in the noncoding transcriptome of aging synaptosomes.

Normal aging is associated with impairments in cognitive functions. These alterations are caused by diminutive changes in the biology of synapses, and ineffective neurotransmission, rather than loss of neurons. Hitherto, only a few studies, exploring molecular mechanisms of healthy brain aging in higher vertebrates, utilized synaptosomal fractions to survey local changes in aging-related transcriptome dynamics. Here we present, for the first time, a comparative analysis of the synaptosomes transcriptome in the aging mouse brain using RNA sequencing. Our results show changes in the expression of genes contributing to biological pathways related to neurite guidance, synaptosomal physiology, and RNA splicing. More intriguingly, we also discovered alterations in the expression of thousands of novel, unannotated lincRNAs during aging. Further, detailed characterization of the cleavage and polyadenylation factor I subunit 1 (Clp1) mRNA and protein expression indicates its increased expression in neuronal processes of hippocampal stratum radiatum in aging mice. Together, our study uncovers a new layer of transcriptional regulation which is targeted by aging within the local environment of interconnecting neuronal cells.

The emerging role of long non-coding RNAs in endometrial cancer.

The human genome is pervasively transcribed and approximately 98% of the genome is non-coding. Long non-coding RNAs (lncRNAs) are a heterogeneous group of RNA transcripts that are >200 nucleotides in length with minimal to no protein-coding potential. Similar to proteins, lncRNAs have important biological functions in both normal cells and disease states including many types of cancer. This review summarizes recent advances in our understanding of lncRNAs in cancer biology and highlights the potential for lncRNA as diagnostic biomarkers and therapeutics. Herein we focus on the poorly understood role of lncRNAs in endometrial cancer, the most common gynecologic malignancy in the developed world.

Characterization of circular RNAs landscape in multiple system atrophy brain.

Circular RNAs (circRNAs) have been recently identified as a naturally occurring family of widespread and diverse endogenous non-coding RNAs that may regulate gene expression in mammals. They are unusually stable RNA molecules with cell type- or developmental stage-specific expression patterns. However, the role of circRNAs in pathology of complex disease is entirely unknown. Here, we report the specific circular transcriptome in the multiple system atrophy (MSA) brain as determined by RNA sequencing. Five circRNAs, namely IQCK, MAP4K3, EFCAB11, DTNA, and MCTP1, were identified and validated as specifically over-expressed in MSA frontal cortex. The expression levels of linear transcripts were not significantly altered and thus did not follow the pattern of their circular counterparts. Further analysis of expression of five MSA-specific circRNAs revealed their over-expression in the white matter of the MSA cortical tissue. Together, this is the first report describing perturbation of circular transcriptome in α-synucleinopathies.