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.
Highlights
Human embryonic stem cells, derived from the inner cell mass of blastocysts, have the potency to self-renew and differentiate into cells representative of all three germ layers [1]
A network of core transcription factors (TFs) including OCT4, NANOG, KLF4, LIN28 and SOX2 promote the undifferentiated state of both Human embryonic stem cells (hESC) and human embryonal carcinoma cells via inducing and sustaining expression of stem cell related genes and simultaneously suppressing expression of somatic enriched genes. hEC are malignant tumor cells derived from teratocarcinomas and are considered the malignant counterparts of hESC
It has been shown that ACTIVIN A, one of the factors secreted by mouse embryonic fibroblasts (MEFs), is necessary for maintaining self-renewal and pluripotency in hESC [2,4]
Summary
Human embryonic stem cells (hESC), derived from the inner cell mass of blastocysts, have the potency to self-renew and differentiate into cells representative of all three germ layers [1]. A network of core transcription factors (TFs) including OCT4, NANOG, KLF4, LIN28 and SOX2 promote the undifferentiated state of both hESC and human embryonal carcinoma cells (hEC) via inducing and sustaining expression of stem cell related genes and simultaneously suppressing expression of somatic enriched genes. Like TGFß1 and NODAL, INHBA activates the SMAD2/3 branch of the TGFß signalling pathway which in turn activates pluripotency associated genes such as NANOG [2,5,6]. During differentiation, activated BMP4, binds its receptor, resulting in the activation of the SMAD1/5/8 branch of the TGFß-signalling pathway and expression of somatic enriched genes
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
