Abstract
Protein products of the regenerating islet-derived (REG) gene family are important regulators of many cellular processes. Here we functionally characterise a non-protein coding product of the family, the long noncoding RNA (lncRNA) REG1CP that is transcribed from a DNA fragment at the family locus previously thought to be a pseudogene. REG1CP forms an RNA–DNA triplex with a homopurine stretch at the distal promoter of the REG3A gene, through which the DNA helicase FANCJ is tethered to the core promoter of REG3A where it unwinds double stranded DNA and facilitates a permissive state for glucocorticoid receptor α (GRα)-mediated REG3A transcription. As such, REG1CP promotes cancer cell proliferation and tumorigenicity and its upregulation is associated with poor outcome of patients. REG1CP is also transcriptionally inducible by GRα, indicative of feedforward regulation. These results reveal the function and regulation of REG1CP and suggest that REG1CP may constitute a target for cancer treatment.
Highlights
Protein products of the regenerating islet-derived (REG) gene family are important regulators of many cellular processes
The results revealed that REG1CP was the most prominently upregulated long noncoding RNA (lncRNA) in colon cancer cells (Supplementary Table 2)
The increased REG3A expression is driven by feedforward regulation involving glucocorticoid receptor α (GRα) that is responsible for transcriptional activation of REG1CP and REG3A
Summary
Protein products of the regenerating islet-derived (REG) gene family are important regulators of many cellular processes. 5 Department of Molecular Biology, Department of Pathology, Shanxi Cancer Hospital and Regenerating islet-derived (REG) protein family members are involved in regulation of many cellular processes, including protection against cell death and promotion of cell proliferation[1]. As such, their dysregulation is associated with various pathological conditions such as inflammation and cancer[2]. One emerging mode of the regulation involves lncRNAs forming RNA–DNA triplex structures, acting as “local address codes” to target chromatinmodifying enzymes to specific DNA sequences[6] This in turn leads to alterations in chromatin structure and regulation of gene transcription as has been demonstrated for a number of lncRNAs such as Khps[1], MEG3 and PARTICLE7–9. We demonstrate the functional importance of this mechanism, showing that REG1CP promotes cancer cell proliferation and tumorigenicity through activation of REG3A
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