One-Carbon Metabolism Regulates Embryonic Stem Cell Fate Through Epigenetic DNA and Histone Modifications: Implications for Transgenerational Metabolic Disorders in Adults.

Lon J Van Winkle,Rebecca Ryznar

doi:10.3389/fcell.2019.00300

Abstract

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.

Highlights

Both sperm and egg cells contain DNA and histones that contribute to the genetic and epigenetic complements of mammalian conceptuses
The epigenetic complements of these gametes and early embryos are altered by environmental challenges to their one-carbon amino acid metabolism (Fleming et al, 2018; Clare et al, 2019; Goyal et al, 2019; Velazquez et al, 2019)
Such challenges increase the prevalence of metabolic syndrome and related disorders in offspring that develop from the embryonic stem (ES) progenitor cells in these early conceptuses (Van Winkle and Ryznar, 2018)

Summary

INTRODUCTION

Both sperm and egg cells contain DNA and histones that contribute to the genetic and epigenetic complements of mammalian conceptuses. An excess of Thr in the culture medium does, rescue hES proliferation from 3-HNV inhibition These findings support the theory that Thr fosters hES and mES cell proliferation through signaling, such as that requiring intact lipid rafts, that is separate from (and in addition to) regulation of epigenetic DNA and histone modifications by 1-carbon metabolites of Thr in mES cells (Van Winkle et al, 2014). The trophectoderm exhibits more proliferation, motility during penetration of the uterine epithelium, and endocytic sequestration of uterine fluid proteins (reviewed by Fleming et al, 2018) These proteins are likely hydrolyzed to supply Thr to mES progenitor cells (Van Winkle and Ryznar, 2019), so increased accumulation of the proteins should result in delivery of more Thr to these pluripotent cells. Transgenerational obesity amplification was not observed in F3 mice, owing to methyl donor supplementation beginning in the F0 generation (Waterland et al, 2008)

Other Sources of Extracellular Histones in the Reproductive Tract

CONCLUSION