Activation of the methylation cycle in cells reprogrammed into a stem cell-like state

Fernández-Arroyo, Salvador; Cuyàs, Elisabet; Bosch-Barrera, Joaquim; Alarcón, Tomás; Joven, Jorge; Menendez, Javier A.

doi:10.18632/oncoscience.280

Cited by 30 publications

(10 citation statements)

References 51 publications

(35 reference statements)

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“…Homocysteine is nonprotein amino acid which behaves as both a substrate and product of methionine. Homocysteine has key role in methylation cycle, within which a methyl group is transferred to a different substrate (Fernández-Arroyo et al 2016). Formed homocysteine can be utilized in two ways: 1) homocysteine can be remethylated to methionine by catalytic activity of the enzyme N5, N10-methylenetetrahydrofolate reductase; 2) homocysteine can be converted to D r a f t transformed into S-adenosylhomocysteine (SAH).…”

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confidence: 99%

Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems

Djuric

Jakovljević

Živković

et al. 2018

Can. J. Physiol. Pharmacol.

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Homocysteine, an amino acid containing a sulfhydryl group, is an intermediate product during metabolism of the amino acids methionine and cysteine. Hyperhomocysteinemia is used as a predictive risk factor for cardiovascular disorders, the stroke progression, screening for inborn errors of methionine metabolism, and as a supplementary test for vitamin B deficiency. Two organic systems in which homocysteine has the most harmful effects are the cardiovascular and nervous system. The adverse effects of homocysteine are achieved by the action of several different mechanisms, such as overactivation of N-methyl-d-aspartate receptors, activation of Toll-like receptor 4, disturbance in Ca handling, increased activity of nicotinamide adenine dinucleotide phosphate-oxidase and subsequent increase of production of reactive oxygen species, increased activity of nitric oxide synthase and nitric oxide synthase uncoupling and consequent impairment in nitric oxide and reactive oxygen species synthesis. Increased production of reactive species during hyperhomocysteinemia is related with increased expression of several proinflammatory cytokines, including IL-1β, IL-6, TNF-α, MCP-1, and intracellular adhesion molecule-1. All these mechanisms contribute to the emergence of diseases like atherosclerosis and related complications such as myocardial infarction, stroke, aortic aneurysm, as well as Alzheimer disease and epilepsy. This review provides evidence that supports the causal role for hyperhomocysteinemia in the development of cardiovascular disease and nervous system disorders.

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confidence: 99%

Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems

Djuric

Jakovljević

Živković

et al. 2018

Can. J. Physiol. Pharmacol.

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“…The former hypothesis, formulated previously [ 75 ], was corroborated in our experiment by the tendency for greater mRNA abundance of MAT1A and PEMT ( P value < 0.10; Table 7 ) in MET calves. These genes, indeed, play an important role in hepatic phosphatidylcholine (PC) synthesis [ 76 – 78 ], which is known to participate in VLDL synthesis and help prevent fatty liver [ 79 , 80 ]. Endogenous synthesis of PC from supplemental Met [ 81 ] was already proposed to play a role in the ability of the cow liver to handle influx of FA produced from lipolysis after parturition [ 34 ].…”

Section: Discussionmentioning

confidence: 99%

Unique adaptations in neonatal hepatic transcriptome, nutrient signaling, and one-carbon metabolism in response to feeding ethyl cellulose rumen-protected methionine during late-gestation in Holstein cows

et al. 2021

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Background Methionine (Met) supply during late-pregnancy enhances fetal development in utero and leads to greater rates of growth during the neonatal period. Due to its central role in coordinating nutrient and one-carbon metabolism along with immune responses of the newborn, the liver could be a key target of the programming effects induced by dietary methyl donors such as Met. To address this hypothesis, liver biopsies from 4-day old calves (n = 6/group) born to Holstein cows fed a control or the control plus ethyl-cellulose rumen-protected Met for the last 28 days prepartum were used for DNA methylation, transcriptome, metabolome, proteome, and one-carbon metabolism enzyme activities. Results Although greater withers and hip height at birth in Met calves indicated better development in utero, there were no differences in plasma systemic physiological indicators. RNA-seq along with bioinformatics and transcription factor regulator analyses revealed broad alterations in ‘Glucose metabolism’, ‘Lipid metabolism, ‘Glutathione’, and ‘Immune System’ metabolism due to enhanced maternal Met supply. Greater insulin sensitivity assessed via proteomics, and efficiency of transsulfuration pathway activity suggested beneficial effects on nutrient metabolism and metabolic-related stress. Maternal Met supply contributed to greater phosphatidylcholine synthesis in calf liver, with a role in very low density lipoprotein secretion as a mechanism to balance metabolic fates of fatty acids arising from the diet or adipose-depot lipolysis. Despite a lack of effect on hepatic amino acid (AA) transport, a reduction in metabolism of essential AA within the liver indicated an AA ‘sparing effect’ induced by maternal Met. Conclusions Despite greater global DNA methylation, maternal Met supply resulted in distinct alterations of hepatic transcriptome, proteome, and metabolome profiles after birth. Data underscored an effect on maintenance of calf hepatic Met homeostasis, glutathione, phosphatidylcholine and taurine synthesis along with greater efficiency of nutrient metabolism and immune responses. Transcription regulators such as FOXO1, PPARG, E2F1, and CREB1 appeared central in the coordination of effects induced by maternal Met. Overall, maternal Met supply induced better immunometabolic status of the newborn liver, conferring the calf a physiologic advantage during a period of metabolic stress and suboptimal immunocompetence.

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“…IDH2 was more abundant in WT MEFs than in KO and is responsible for the production of NADPH, whereas NADPH is essential for the proliferation of both normal and tumor cells 52 . In addition, NADPH is needed to establish cancer-like glycolytic phenotypes, which is further required for establishing and maintaining a DNA methylation pattern in iPSCs resembling that of ESCs 53 . Recently, it was reported that primed human pluripotent stem cells require SIRT2 downregulation to maintain pluripotency via altering metabolic pathways toward aerobic glycolysis 24 .…”

Section: Discussionmentioning

confidence: 99%

SIRT2 is required for efficient reprogramming of mouse embryonic fibroblasts toward pluripotency

Kim

Lee

et al. 2018

Cell Death Dis

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The role of sirtuins (SIRTs) in cancer biology has been the focus of recent research. The similarities between underlying pathways involved in the induction of pluripotent stem cells and transformation of cancer cells revealed the role of SIRTs in cellular reprogramming. Seven SIRTs have been identified in mammals and downregulation of SIRT2 was found to facilitate the generation of primed pluripotent stem cells, such as human induced pluripotent stem cells. Herein, we evaluated the role of SIRT2 in naive pluripotent stem cell generation using murine cells. We found that absolute depletion of SIRT2 in mouse embryonic fibroblasts resulted in a notable reduction in reprogramming efficiency. SIRT2 depletion not only upregulated elements of the INK4/ARF locus, which in turn had an antiproliferative effect, but also significantly altered the expression of proteins related to the PI3K/Akt and Hippo pathways, which are important signaling pathways for stemness. Thus, this study demonstrated that SIRT2 is required for cellular reprogramming to naive states of pluripotency in contrast to primed pluripotency states.

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Activation of the methylation cycle in cells reprogrammed into a stem cell-like state

Abstract: Generation of induced pluripotent stem (iPS) cells and cancer biogenesis

Cited by 30 publications

References 51 publications

Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems

Homocysteine and homocysteine-related compounds: an overview of the roles in the pathology of the cardiovascular and nervous systems

Unique adaptations in neonatal hepatic transcriptome, nutrient signaling, and one-carbon metabolism in response to feeding ethyl cellulose rumen-protected methionine during late-gestation in Holstein cows

SIRT2 is required for efficient reprogramming of mouse embryonic fibroblasts toward pluripotency

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