MINDY1 Is a Downstream Target of the Polyamines and Promotes Embryonic Stem Cell Self-Renewal

Abstract

Embryonic stem cells have the ability to self-renew or differentiate and these processes are under tight control. We previously reported that the polyamine regulator AMD1 is critical for embryonic stem cell self-renewal. The polyamines putrescine, spermidine, and spermine are essential organic cations that play a role in a wide array of cellular processes. Here, we explore the essential role of the polyamines in the promotion of self-renewal and identify a new stem cell regulator that acts downstream of the polyamines: MINDY1. MINDY1 protein levels are high in embryonic stem cells (ESCs) and are dependent on high polyamine levels. Overexpression of MINDY1 can promote ESC self-renewal in the absence of the usually essential cytokine Leukemia Inhibitory Factor (LIF). MINDY1 protein is prenylated and this modification is required for its ability to promote self-renewal. We go on to show that Mindy1 RNA is targeted for repression by mir-710 during Neural Precursor cell differentiation. Taken together, these data demonstrate that high polyamine levels are required for ESC self-renewal and that they function, in part, through promotion of high MINDY1 levels. STEM CELLS 2018; 00:000-000 SIGNIFICANCE STATEMENTThis article shows that the polyamines, putrescine, spermidine, and spermine are essential for the maintenance of embryonic stem cell self-renewal. Inhibition of polyamine synthesis causes differentiation. This study identifies the MINDY1 protein as being a critical downstream target of the polyamines in driving self-renewal. MINDY1 functions to remove ubiquitin from target proteins this preventing their degradation. This study proposes that MINDY1 is a new critical regulator of stem cell self-renewal that functions to promote the stability of core self-renewal proteins.

microRNAs Regulating Human and Mouse Naïve Pluripotency

“…Other enzymes or metabolites in the polyamine pathway did not change, possibly because some enzymes are regulated at the translational level, not transcriptional level (e.g., AMD1) [67]. ODC1 has been shown to be essential for mouse ESC self-renewal [68], and high polyamine (e.g., spermidine) levels have been shown to promote mouse ESC self-renewal [69]. Our analysis suggests that ODC1 and spermidine may also promote human naïve pluripotency, and down-regulation of miR-218-5p may be important for maintaining high polyamine metabolism in naïve hESCs.…”

AMD1 upregulates hepatocellular carcinoma cells stemness by FTO mediated mRNA demethylation

“…This might stem from the difference of species and histologic type. 50 As mentioned, demethylation of N6-methyladenosine of mRNA of multiple pluripotency factors would increase the mRNA stability and then promote protein expression. 19,20 Therefore, we hypothesized that AMD1 also enhanced HCC cells stemness through regulating mRNA m6A levels.…”

MicroRNA-710 regulates multiple pathways of carcinogenesis in murine metastatic breast cancer

“…In addition, miR-710 is unique in its full array of targets within the murine and human transcriptome. For example, mmu-miR-710 has been shown to enhance the differentiation of murine embryonic stem cells [18]. Importantly, studies in growth hormone receptor knock out mice (GHR-KO), discovered that miR-710 is at the core of a three-dimensional lncRNA–mRNA–miRNA regulatory network that defines phenotype in the GHR-KO animals, which is characterized by resistance to cancer and enhanced longevity [19].…”