Sir2 is an NAD+-dependent histone deacetylase required to mediate transcriptional silencing and suppress rDNA recombination in budding yeast. We previously identified Tdh3, a glyceraldehyde 3-phosphate dehydrogenase (GAPDH), as a high expression suppressor of the lethality caused by Sir2 overexpression in yeast cells. Here we show that Tdh3 interacts with Sir2, localizes to silent chromatin in a Sir2-dependent manner, and promotes normal silencing at the telomere and rDNA. Characterization of specific TDH3 alleles suggests that Tdh3's influence on silencing requires nuclear localization but does not correlate with its catalytic activity. Interestingly, a genetic assay suggests that Tdh3, an NAD+-binding protein, influences nuclear NAD+ levels; we speculate that Tdh3 links nuclear Sir2 with NAD+ from the cytoplasm.

Human (h) and mouse (m) embryonic stem (ES) cells need specific amino acids to proliferate. mES cells require threonine (Thr) metabolism for epigenetic histone modifications. Thr is converted to glycine and acetyl CoA, and the glycine is metabolized specifically to regulate trimethylation of lysine (Lys) residue 4 in histone H3 (H3K4me3). DNA methylation and methylation of other H3 Lys residues remain unimpaired by Thr deprivation in mES cell culture medium. Similarly, hES cells require methionine (Met) to maintain the Met-SAM (S-adenosyl methionine) cycle of 1-carbon metabolism also for H3K4me3 formation. H3K4me3 is needed specifically to regulate and maintain both mES and hES cell proliferation and their pluripotent states. Better understanding of this regulation is essential since treatment of human diseases and disorders will increasingly involve hES cells. Furthermore, since ES cells are derived from their progenitor cells in preimplantation blastocysts, they serve as models of 1-carbon metabolism in these precursors of all mammalian tissues and organs. One-carbon metabolism challenges, such as a maternal low protein diet (LPD) during preimplantation blastocyst development, contribute to development of metabolic syndrome and related abnormalities in adults. These 1-carbon metabolism challenges result in altered epigenetic DNA and histone modifications in ES progenitor cells and the tissues and organs to which they develop. Moreover, the modified histones could have extracellular as well as intracellular effects, since histones are secreted in uterine fluid and influence early embryo development. Hence, the mechanisms and transgenerational implications of these altered epigenetic DNA and histone modifications warrant concerted further study.

Amino acids serve both to nourish and as signalling molecules in cells and, consequently, so do their biomembrane transporters. In fact, some of these transporters may initiate signalling while transporting an amino acid substrate rather than serving simply to transport a signalling molecule. Most amino acid transporters now appear to have been cloned, and virtually all the cloned transporters are listed in solute carrier tables for easy access online. The characteristics of the transporters as they are expressed normally in cells do not always correspond to the characteristics of cloned transporters, however, and their transport and signalling functions will likely continue to emerge long after all transporters have been identified. For example, amino acids are metabolised to products that regulate DNA and specific epigenetic histone modifications in embryonic stem cells in order to maintain their proliferation and pluripotency. Alterations in these histone modifications may be expressed in a transgenerational manner and include both intracellular and extracellular histone actions. Key Concepts At least 60 genes in 12 gene families encode amino acid transporters (see tables at http://slc.bioparadigms.org/ ). An amino acid may be listed as a substrate for a cloned transporter in these tables even though its transport has not been studied in detail. The characteristics of cloned amino acid transporters may not correspond to the ways they function in cellular physiology. Embryonic stem cells and their progenitors require specific environmental amino acids to remain undifferentiated. Metabolism of the required amino acids produce products that regulate DNA and specific epigenetic histone modifications needed to maintain stem cell proliferation and pluripotency. Mouse embryonic stem cells take up the threonine they require via at least three obligate exchange amino acid transporters. Human embryonic stem cells take up the methionine they need via amino acid transporter(s) that warrant full characterisation. A maternal low protein diet during pre‐ and peri‐implantation development of embryos likely alters epigenetic DNA and histone modifications in embryonic stem progenitor cells. These epigenetic DNA and histone alterations help to cause metabolic syndrome and related disorders, and they are likely transgenerational. Extracellular as well as intracellular histone actions may influence transgenerational phenotype.