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    • purchase Fmoc-O-Phospho-Tyr-OH To the best of our knowledge

    2018-10-29

    To the best of our knowledge, only three metabolites, L-threonine, butyrate, and vitamin C, have been identified so far that act as epigenetic modulators of ESC self-renewal and/or somatic cell reprogramming (Mali et al., 2010; Shyh-Chang et al., 2013; Wang et al., 2009). Interestingly, L-threonine, which is the only amino purchase Fmoc-O-Phospho-Tyr-OH among these metabolites, influences H3K4me3 by controlling the abundance of S-adenosylmethionine, leaving other lysine residues unaltered (Shyh-Chang et al., 2013). This intriguing specificity is also exerted by L-Pro that conversely influences the global level of trimethylation of lysines K9 and K36, which would likely exert a wider effect on gene expression. This is consistent with the extensive molecular and phenotypic variations induced by L-Pro on ESCs, as, for instance, the striking acquisition of motility and invasiveness. Most remarkably, L-Pro-induced global increase of H3K9 and H3K36 trimethylation preferentially occurs at noncoding intergenic regions and constitutive heterochromatin. Whereas H3K9me3 is a well-known repressive heterochromatic mark, the H3K36me3 deposition within heterochromatin domains has only recently emerged. H3K36me3 might thus contribute to the establishment of a transcriptionally unfavorable chromatin conformation by recruiting repressive complexes (Chantalat et al., 2011). Our data suggest that L-Pro can induce heterochromatization, increasing H3K9me3 and H3K36me3 especially at pericentromeric and gene desert regions, and imply that there is a hierarchy of target chromatin regions and associated noncoding elements that are more sensitive to the effect of L-Pro in ESCs. Thus, our findings add to the emerging evidence that metabolites are key mediators of epigenetic regulation of stem cell fate and strengthen the role of the amino acids in this process. Yet how metabolites control chromatin modifiers in space and time, translating a dynamic metabolic state into a histone code, is still a key unresolved question (Folmes et al., 2012; Phang et al., 2013; Sassone-Corsi, 2013; Zhang et al., 2012). Interestingly, it has been recently proposed that the concentration of metabolites and their biosynthetic enzymes may localize to chromatin subdomains promoting the clustering of relevant DNA and histone modifications at specific genomic loci (Katada et al., 2012). It is thus tempting to speculate that specific histone-modifying enzymes might sense the presence of L-Pro and eventually translate this signal into different histone maps. Interestingly, we have shown that vitamin C, which is a cofactor of the Jumonji-family histone demethylases, antagonizes the effect of L-Pro on H3K9me3 and H3K36me3 levels. Of note, knockdown of Jmjd1a (H3K9 demethylase) does not prevent vitamin C-induced PiC-to-ESC reversion. However, because many other vitamin C-regulated histone modifier enzymes might be involved in this process, further studies are needed to reveal its molecular nature. We believe that our findings have several implications for stem cell biology. First, it has been shown that the reprogramming process initiates through a mesenchymal-to-epithelial transition (MET) (Li et al., 2010; Samavarchi-Tehrani et al., 2010) and that vitamin C-dependent decrease of H3K9/H3K36 methylation levels promote somatic/pre-iPSC to iPSC transition (Chen et al., 2013; Wang et al., 2011). Thus L-Pro and vitamin C exert opposite effects on H3K9 and H3K36 methylation status, regulating antagonistic cellular processes relevant for cell reprogramming. Recently, it was reported that vitamin C also promotes Tet-mediated DNA demethylation (Blaschke et al., 2013). It will be thus interesting to investigate the effect of L-Pro on DNA methylation. Second, the L-Pro/vitamin C-regulated esMT-MesT switch is reminiscent of the transient EMT-MET switch that has been proposed as a driving force of metastasis, largely influenced by microenvironment (Brabletz et al., 2005). Indeed, it is proposed that induction of EMT confers migrating properties to cancer stem cell (Brabletz, 2012). How this occurs is still poorly defined. Interestingly, the ECM is mostly composed of collagen (80%) and is considered as a reservoir of mobilizable L-Pro (Phang et al., 2008). Here, we suggest that L-Pro, which is released from ECM degradation during tumor invasion, may act as environmental cue of the EMT to control tumor dissemination. Moreover, L-Pro metabolism is dysregulated in cancer (Liu et al., 2012; Phang et al., 2012) and L-Pro synthesis is associated with tumor progression and aggressiveness (Scott et al., 2011), yet the mechanisms remain largely unsolved. Although much work remains to be carried out to assess the in vivo relevance of L-Pro as signal molecule, our findings contribute to elucidating its role in regulating stem cell behavior and provide insights into the mechanisms by which metabolites control stem cell fate.