Abstract
Apoptosis is a form of regulated cell death that plays a critical role in survival and developmental homeostasis. There are numerous reports on regulation of apoptosis by protein-coding genes as well as small non-coding RNAs, such as microRNAs. However, there is no comprehensive investigation of circular RNAs (circRNA) that are differentially expressed under apoptotic conditions. We have performed a transcriptomics study in which we first triggered apoptosis in HeLa cells through treatment with four different agents, namely cisplatin, doxorubicin, TNF-α and anti-Fas mAb. Total RNAs isolated from control as well as treated cells were treated with RNAse R to eliminate the linear RNAs. The remaining RNAs were then subjected to deep-sequencing to identify differentially expressed circRNAs. Interestingly, some of the dys-regulated circRNAs were found to originate from protein-coding genes well-documented to regulate apoptosis. A number of candidate circRNAs were validated with qPCR with or without RNAse R treatment as well. We then took advantage of bioinformatics tools to investigate the coding potential of differentially expressed RNAs. Additionally, we examined the candidate circRNAs for the putative miRNA-binding sites and their putative target mRNAs. Our analyses point to a potential for circRNA-mediated sponging of miRNAs known to regulate apoptosis. In conclusion, this is the first transcriptomics study that provides a complete circRNA profile of apoptotic cells that might shed light onto the potential role of circRNAs in apoptosis.
Highlights
Apoptosis is a tightly regulated mechanism of type 1 programmed cell death that mediates balance between survival and cell death
Cisplatin and TNF-α caused the highest apoptotic rate (58%) while anti-Fas-treated population displayed a lower rate of apoptosis (27%) due to the desensitization of HeLa cells to FasR stimulation (Holmström et al, 1999)
Apoptosis is a highly regulated cellular process that is important for cell survival and cell death and it is involved in various physiological as well as pathological conditions
Summary
Apoptosis is a tightly regulated mechanism of type 1 programmed cell death that mediates balance between survival and cell death. Apoptosis mainly proceeds with the extrinsic death receptor pathway or the intrinsic mitochondrial dysfunction pathway (Vince and Silke, 2009; Fuchs and Steller, 2011). Functional apoptosis pathway is vital for tissue homeostasis and organ development. Dysregulation of apoptosis is associated with a wide range of diseases such as cancer, autoimmune diseases, neurodegenerative diseases, and acute pathologies (Favaloro et al, 2012). Much effort has been made to unravel molecular pathways that trigger and regulate apoptosis. A plethora of studies revealed that considerable amount of DNA called “dark matter of genome is transcribed but not translated” (Bertone et al, 2004). MicroRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are well-known examples of non-coding RNAs
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