Abstract
ES cells can propagate indefinitely, maintain self-renewal, and differentiate into almost any cell type of the body. These properties make them valuable in the research of embryonic development, regenerative medicine, and organ transplantation. MicroRNAs (miRNAs) are considered to have essential functions in the maintenance and differentiation of embryonic stem cells (ES cells). It was reported that, strong external stimuli, such as a transient low-pH and hypoxia stress, were conducive to the formation of induced pluripotent stem cells (iPS cells). AICA ribonucleotide (AICAR) is an AMP-activated protein kinase activator, which can let cells in the state of energy stress. We have demonstrated that AICAR can maintain the pluripotency of J1 mouse ES cells through modulating protein expression in our previous research, but its effects on ES cell miRNA expression remain unknown. In this study, we conducted small RNA high-throughput sequencing to investigate AICAR influence on J1 mouse ES cells by comparing the miRNA expression patterns of the AICAR-treated cells and those without treatment. The result showed that AICAR can significantly modulate the expression of multiple miRNAs, including those have crucial functions in ES cell development. Some differentially expressed miRNAs were selected and confirmed by real-time PCR. For the differently expressed miRNAs identified, further study was conducted regarding the pluripotency and differentiation associated miRNAs with their targets. Moreover, miR-134 was significantly down-regulated after AICAR treatment, and this was suggested to be directly associated with the up-regulated pluripotency markers, Nanog and Sox2. Lastly, Myc was significantly down-regulated after AICAR treatment; therefore, we predicted miRNAs that may target Myc and identified that AICAR induced up-regulation of miR-34a, 34b, and 34c can repress Myc expression in J1 mouse ES cells. Taken together, our study provide a new mechanism for AICAR in ES cells pluripotency maintenance and give insight for its usage in iPS cells generation.
Highlights
Embryonic stem cells (ES cells) are blastocyst inner cell massderived cells that are pluripotent and capable of self-renewal and immortalization [1]
The small RNA tags were mapped into the genome by short oligonucleotide alignment program (SOAP), which can analyze the expression and distribution of the clean reads in the genome
This finding revealed that approximately 64.38% (12,147,800) clean reads of dimethyl sulfoxide (DMSO) and 56.79% (11,978,538) clean reads of AICA ribonucleotide (AICAR) can be mapped into the genome
Summary
Embryonic stem cells (ES cells) are blastocyst inner cell massderived cells that are pluripotent and capable of self-renewal and immortalization [1]. The core transcription network composed of Nanog, Oct, Klf, and Sox is known to be essential for ES cell self-renewal and pluripotency maintenance [2]. Other signal pathways, including Wnt, TGF-b, LIF/JAK-STAT, and MEK/ERK signal pathway, have crucial functions in ES cells [3,4,5,6]. This homeostasis is influenced by the regulation of epigenetic modifications as well. As an important mechanism of epigenetic regulation, microRNAs (miRNAs) play crucial roles in the regulation of ES cell fate decision [7]
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