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

Winkle, Lon J. Van; Ryznar, Rebecca

doi:10.3389/fcell.2019.00300

Cited by 40 publications

(69 citation statements)

References 45 publications

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“…Deficiency in B12 alters the levels of total homocysteine (tHcy), methionine, methylmalonic acid (MMA) and metabolites of 1C cycle including S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH), which is associated with various adverse pregnancy outcomes and cardiovascular complications 4 . Since epigenetic modifications play a major role on the pathogenesis of many disease states, recent research predicts that metabolites of 1C metabolism might have an intermediate effect in adverse metabolic outcomes 5 . Several observational and epidemiological studies have shown that low B12 is associated with high BMI 6 , insulin resistance (IR) 7 , increasing severity of glucose tolerance 8 and adverse lipid profiles in type 2 diabetes (T2D) 9 .…”

Section: Sdmentioning

confidence: 99%

Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia

Adaikalakoteswari

Wood

Mina

et al. 2020

Sci Rep

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Vitamin B12 (B12) is a micronutrient essential for one-carbon (1C) metabolism. B12 deficiency disturbs the 1C cycle and alters DNA methylation which is vital for most metabolic processes. Studies show that B12 deficiency may be associated with obesity, insulin resistance and gestational diabetes; and with obesity in child-bearing women. We therefore hypothesised that the associations between B12 deficiency, BMI and the metabolic risk could be mediated through altered 1C metabolites in early pregnancy. We explored these associations in two different early pregnancy cohorts in the UK (cohort 1; n = 244 and cohort 2; n = 60) with anthropometric data at 10-12 weeks and plasma/serum sampling at 16-18 weeks. B12, folate, total homocysteine (tHcy), methionine, MMA, metabolites of 1C metabolism (SAM, SAH) and anthropometry were measured. B12 deficiency (< 150 pmol/l) in early pregnancy was 23% in cohort 1 and 18% in cohort 2. Regression analysis after adjusting for likely confounders showed that B12 was independently and negatively associated with BMI (Cohort 1: β = − 0.260, 95% CI (− 0.440, − 0.079), p = 0.005, Cohort 2: (β = − 0.220, 95% CI (− 0.424, − 0.016), p = 0.036) and positively with HDL cholesterol (HDL-C) (β = 0.442, 95% CI (0.011,0.873), p = 0.045). We found that methionine (β = − 0.656, 95% CI (− 0.900, − 0.412), p < 0.0001) and SAH (β = 0.371, 95% CI (0.071, 0.672), p = 0.017) were independently associated with triglycerides. Low B12 status and alteration in metabolites in 1C metabolism are common in UK women in early pregnancy and are independently associated with maternal obesity and dyslipidaemia. Therefore, we suggest B12 monitoring in women during peri-conceptional period and future studies on the pathophysiological relationship between changes in 1C metabolites and its association with maternal and fetal outcomes on larger cohorts. This in turn may offer potential to reduce the metabolic risk in pregnant women and their offspring. Abbreviations 1CM One-carbon metabolism B12 Vitamin B12 GDM Gestational diabetes tHcy Total homocysteine IR Insulin resistance MMA Methylmalonic acid

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Section: Sdmentioning

confidence: 99%

Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia

Adaikalakoteswari

Wood

Mina

et al. 2020

Sci Rep

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“…Blastocysts developing in a medium containing essential amino acids also produce larger fetuses. While essential amino acids support growth and development as nutrients, they also foster signaling in early embryos [1,[4][5][6]. Amino acid transport proteins are needed in plasma membranes to regulate the concentrations of essential amino acids in conceptuses, but these transporters can be overwhelmed by altered amino acid availability.…”

Section: Introductionmentioning

confidence: 99%

Lysine Deprivation during Maternal Consumption of Low-Protein Diets Could Adversely Affect Early Embryo Development and Health in Adulthood

Winkle

Galat

Iannaccone

2020

IJERPH

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The conversion of lysine to glutamate is needed for signaling in all plants and animals. In mouse embryonic stem (mES) cells, and probably their progenitors, endogenous glutamate production and signaling help maintain cellular pluripotency and proliferation, although the source of glutamate is yet to be determined. If the source of glutamate is lysine, then lysine deprivation caused by maternal low-protein diets could alter early embryo development and, consequently, the health of the offspring in adulthood. For these reasons, we measured three pertinent variables in human embryonic stem (hES) cells as a model for the inner cell masses of human blastocysts. We found that RNA encoding the alpha-aminoadipic semialdehyde synthase enzyme, which regulates glutamate production from lysine, was highly expressed in hES cells. Moreover, the mean amount of lysine consumed by hES cells was 50% greater than the mean amount of glutamate they produced, indicating that lysine is likely converted to glutamate in these cells. Finally, hES cells expressed RNA encoding at least two glutamate receptors. Since this may also be the case for hES progenitor cells in blastocysts, further studies are warranted to verify the presence of this signaling process in hES cells and to determine whether lysine deprivation alters early mammalian embryo development.

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“…MES cells need threonine (Thr) metabolism to complete epigenetic histone modification. Thr is converted to glycine and acetyl coenzyme A, and glycine metabolism specifically regulates the trimethylation of lysine (Lys) residues in histone H3 (H3K4me3) (Van Winkle & Ryznar, 2019). In addition, we also found that the modification of L-lysine carbamylation in the old group was lower than that in the young group.…”

Section: Conclusion and Discussionmentioning

confidence: 77%

“…Carbamylation is an irreversible non-enzyme modification process. The process is the side chain reaction between the decomposition product of urea and the N-terminus of protein or lysine residue, which was previously reported to be related to the ageing of proteins (Van Winkle & Ryznar, 2019). L-lysine carbamylation can promote the coordination interaction of metal ions to specific enzyme activities.…”

Section: Conclusion and Discussionmentioning

confidence: 99%

Global chemical modifications comparison of human plasma proteomes from two different age groups

Liu

Zhao

Pan

et al. 2020

Preprint

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The chemical modification of proteins refers to the covalent group reaction involved in their amino acid residues or chain ends which, in turn, change the molecular structure and function of the proteins. There are many types of molecular modifications in the human plasma proteome, such as phosphorylation, methylation, and acetylation. In this study, two groups of human plasma proteome at different age groups (old and young) were used to perform a comparison of global chemical modifications, as determined by tandem mass spectrometry (MS/MS) combined with non-limiting modification identification algorithms. The sulfhydryl in the cysteine A total of 4 molecular modifications were found to have significant differences: the succinylation and phosphorylation modification of cysteine (Cys, C) and the modification of lysine (Lys, K) with threonine (Thr, T) were significantly higher in the old group than in the young group, while the carbamylation of lysine was lower in the young group. Cysteine residue is an important group for forming disulphide bonds and maintaining the structure of the protein. Differential cysteine-related sulfydryl modifications may cause structural and functional changes. Lysine is a basic amino acid, and the modification of its amino group will change the charge state of the protein, which may affect the structure and function of the protein. In summary, four types of protein chemical modifications and substitutes were found to be significantly different in the plasma proteome in different age groups and their probabilities of random generation are lower by passing random grouping test. We speculate that there is an increase in certain modified proteins in the blood of the old people which, in turn, changes the function of those proteins. This change may be one of the reasons why the old people are more likely than the young people to be at risk for age-related diseases, such as metabolic diseases, cerebral and cardiovascular diseases, and cancer.

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

Cited by 40 publications

References 45 publications

Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia

Vitamin B12 deficiency and altered one-carbon metabolites in early pregnancy is associated with maternal obesity and dyslipidaemia

Lysine Deprivation during Maternal Consumption of Low-Protein Diets Could Adversely Affect Early Embryo Development and Health in Adulthood

Global chemical modifications comparison of human plasma proteomes from two different age groups

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