miR-27 Negatively Regulates Pluripotency-Associated Genes in Human Embryonal Carcinoma Cells

Abstract

Human embryonic stem cells and human embryonal carcinoma cells have been studied extensively with respect to the transcription factors (OCT4, SOX2 and NANOG), epigenetic modulators and associated signalling pathways that either promote self-renewal or induce differentiation in these cells. The ACTIVIN/NODAL axis (SMAD2/3) of the TGFß signalling pathway coupled with FGF signalling maintains self-renewal in these cells, whilst the BMP (SMAD1,5,8) axis promotes differentiation. Here we show that miR-27, a somatic-enriched miRNA, is activated upon RNAi-mediated suppression of OCT4 function in human embryonic stem cells. We further demonstrate that miR-27 negatively regulates the expression of the pluripotency-associated ACTIVIN/NODAL axis (SMAD2/3) of the TGFß signalling pathway by targeting ACVR2A, TGFßR1 and SMAD2. Additionally, we have identified a number of pluripotency-associated genes such as NANOG, LIN28, POLR3G and NR5A2 as novel miR-27 targets. Transcriptome analysis revealed that miR-27 over-expression in human embryonal carcinoma cells leads indeed to a significant up-regulation of genes involved in developmental pathways such as TGFß- and WNT-signalling.

miRNA‐23a/27a attenuates muscle atrophy and renal fibrosis through muscle‐kidney crosstalk

“…miR-23 targets TRIM63/MuRF1 and FBXO32/atrogin-1, PTEN, caspase-7, SMAD3, and RAS GTPase-activating protein SH3 domainbinding protein 2 (G3BP2), whereas miR-27 targets FoxO1, SMAD2, SMAD4, and myostatin. 18,20,[34][35][36] We found that miR-23a is lower in diabetic skeletal muscle, compared with controls. The decrease in miR-23a contributes to the welldocumented increase in expression of TRIM63/MuRF1 and FBXO32/atrogin-1 E3 ubiquitin ligases as well as dysfunctional insulin signalling (i.e., increased PTEN and decreased Akt phosphorylation).…”

“…In our study, delivery of the miR‐23a∼27a∼24‐2 precursor RNA by AAV produces both miR‐23a and miR‐27a, both of which target mRNAs that encode proteins which are relevant to the atrophy and fibrosis processes. miR‐23 targets TRIM63/MuRF1 and FBXO32/atrogin‐1, PTEN, caspase‐7, SMAD3, and RAS GTPase‐activating protein SH3 domain‐binding protein 2 (G3BP2), whereas miR‐27 targets FoxO1, SMAD2, SMAD4, and myostatin . We found that miR‐23a is lower in diabetic skeletal muscle, compared with controls.…”

Transcriptomic Profiling and H3K27me3 Distribution Reveal Both Demethylase-Dependent and Independent Regulation of Developmental Gene Transcription in Cell Differentiation

“…Although these cells are considered to be stem-like cancer cells with potentially ambiguous phenotypes, they constitute a robust and simplified means to analyze the differentiation and development during human embryogenesis [ 42 , 43 ]. Because RA-induced NCCIT differentiation has been widely in previous studies [ 44 , 45 ], we selected this carcinoma cell line as a cellular model. A whole transcriptomic analysis and the genome-wide mapping of a transcriptional suppressive markers identified a complex relationship between transcription activation and changes in the epigenetic landscape due to the enzymatic activity of histone demethylases.…”

Heterogeneity in cancer stem cells

“…On the contrary, when the Wnt or Notch signaling was downregulated, miR-27 was upregulated or cells were activated by BMP4, CSCs tend to differentiate to non-CSCs ( Fig. 2) [42,43]. All these findings indicated that the heterogeneity of CSCs was the consequences of interaction of intrinsic and extrinsic factors.…”