Abstract
BackgroundThe human chromosome 19 miRNA cluster (C19MC) of 43 genes is a primate-specific miRNA cluster that may have biological significance in the genetic complexity of the primate. Despite previous reports on individual C19MC miRNA expression in cancer and stem cells, systematic studies on C19MC miRNA expression and biological functions are lacking.ResultsCluster-wide C19MC miRNA expression profiling by microarray analysis showed wholesome C19MC activation in embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs). However, in multipotent adipose-derived mesenchymal stem cells (MSCs) and a unipotent human white pre-adipocyte cell line, only selected C19MC miRNAs were expressed. MiRNA copy number analysis also showed selective C19MC expression in cancer cells with expression patterns highly similar to those in MSCs, suggesting similar miRNA regulatory mechanisms in these cells. Selective miRNA expression also suggests complex transcriptional mechanism(s) regulating C19MC expression under specific cellular and pathological conditions. Bioinformatics analysis showed that sixteen of the C19MC miRNAs share the same “AAGUGC” seed sequence with members of the miR-302/-372 family, which are known cellular reprogramming factors. In particular, C19MC-AAGUGC-miRNAs with the nucleotides 2-7 canonical seed position as in miR-302/-372 miRNAs, may play similar roles as miR-302/-372 in induced pluripotency. A biased 3p-arm selection of the C19MC-AAGUGC-miRNAs was observed indicating that targets of the 3p species of these miRNAs may be biologically significant in regulating stemness. Furthermore, bioinformatics analysis of the putative targets of the C19MC-AAGUGC-miRNAs predicted significant involvement of signaling pathways in reprogramming, many of which contribute to promoting apoptosis by indirect activation of the pro-apoptotic proteins BAK/BAX via suppression of genes of the cell survival pathways, or by enhancing caspase-8 activation through targeting inhibitors of TRAIL-inducing apoptosis.ConclusionsThis work demonstrated selective C19MC expression in MSCs and cancer cells, and, through miRNA profiling and bioinformatics analysis, predicted C19MC modulation of apoptosis in induced pluripotency and tumorigenesis.
Highlights
The human chromosome 19 miRNA cluster (C19MC) of 43 genes is a primate-specific miRNA cluster that may have biological significance in the genetic complexity of the primate
Selective activation of C19MC miRNAs in mesenchymal stem cells We have previously reported genome-wide miRNA expression profiling of two Embryonic stem cells (ESC), two multipotent adiposederived MSCs, a unipotent human white pre-adipocyte (HWP) cell line, and the three Induced pluripotent stem cells (iPSC) lines derived from the MSCs and HWP [4]
The expression data of C19MC miRNAs in the MSCs and HWP, and the MSC- and HWP-derived iPSCs were extracted for further analysis
Summary
The human chromosome 19 miRNA cluster (C19MC) of 43 genes is a primate-specific miRNA cluster that may have biological significance in the genetic complexity of the primate. Selective maturation or co-existence of the 5p and 3p species is biologically important since they target different gene sets. MiRNAs form family groups defined by short homologous sequences, called the seed sequence, which is located at the 5’- end of the mature miRNAs. MiRNAs of the same family often form functionallyrelated groups that cross-regulate targets to ensure conservation of biological functions [3, 4]. Aberrant expression of miRNA affects crucial processes in the development and progression of tumors, including induction of anti-apoptosis, development of drug resistance and cancer invasion and metastasis [15,16,17,18,19,20,21,22]
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