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Frequency of neural tube defects (NTDs) in Shmt1-deficient embryos on a 129/SvEv background as a function of embryonic Shmt1 genotype 1 Embryonic Shmt1 genotype 2
Source publication
Folic acid supplementation prevents the occurrence and recurrence of neural tube defects (NTDs), but the causal metabolic pathways underlying folic acid-responsive NTDs have not been established. Serine hydroxymethyltransferase (SHMT1) partitions folate-derived one-carbon units to thymidylate biosynthesis at the expense of cellular methylation, and...
Citations
... Strain-dependent variations in NTDs have been observed in various other mouse mutants, with 129 strains displaying higher disease susceptibility while B6 strains generally do not (12,13,61). To our knowledge, few studies have ventured into the exploration of modifier loci for these variations (62)(63)(64). Conventional gene knockout studies are frequently conducted in mice using congenic inbred strains, which may not adequately capture the complex genetic landscape associated with human NTDs. The stark disparity in NTD penetrance among different strains of Tet1 mutants we generated, thus offers a unique opportunity to identify the genetic factors that modify NTD susceptibility. ...
The etiology of neural tube defects (NTDs) involves complex gene-environmental interactions. Folate is the largest modifier of NTD risk, but mechanisms remain unclear. Here, we identify the DNA demethylase TET1 as a nexus of folate metabolism and genetic risk factors post-gastrulation. We observed cranial NTDs in Tet1 null embryos at contrasting penetrance in inbred versus genetically heterogenous strains. Furthermore, we identified a risk locus harboring a hotspot of genes co-regulated by a strain-dependent interaction between TET1 and developmental signaling pathways during neural induction. Adverse maternal dietary folic acid (FA) status interacts with the loss of TET1 to affect offspring DNA methylation primarily at neurogenesis loci. Conversely, excess FA in Tet1 null embryos drives promoter DNA hypermethylation and reduced expression of membrane solute transporters, associated with reduced FA intake and disruption of phospholipid metabolism. Overall, our study unravels interactions between modified maternal FA status, Tet1 gene dosage and genetic backgrounds that impact neurotransmitter functions, response to cell-extrinsic inputs, and individual susceptibility to congenital disorders.
... have found that the biosynthesis of thymidine and purine is abnormal in NTDs mouse models [8][9][10]. The lack of folic acid plays a certain role in the occurrence of NTDs, but the specific mechanism of NTDs in human is still unclear [11,12]. ...
Background
Neural tube defects (NTDs) are one of the most severe congenital abnormalities characterized by failures of the neural tube to close during early embryogenesis. Maternal folate deficiency could impact the occurrence of NTDs, however, the mechanisms involved in the cause of NTDs are poorly defined.
Results
Here, we report that histone H3 methyltransferase disruptor of telomeric silencing 1-like (DOT1L) expression was significantly downregulated, and low levels of H3K79me2 were found in the corresponding NTDs samples with their maternal serum folate under low levels. Using ChIP-seq assays, we found that a decrease of H3K79me2 downregulates the expression of Shh and Sufu in mouse embryonic stem cells (mESC) under folate deficiency. Interestingly, folate antagonist methotrexate treatment led to attenuation of H3K79me2 due to Dot1l, affecting Shh and Sufu genes regulation. Upon further analysis, we find that the genes Shh and Sufu are both downregulated in the brain tissues of mice and humans with NTDs. There was a positive correlation between the transcription levels of Shh, Sufu and the protein levels of DOT1L by Pearson correlation analysis.
Conclusion
Our results indicate that abnormal Shh and Sufu genes expression reduced by aberrant Dot1l-mediated H3K79me2 levels could be the cause of NTDs occurrence.
... The main biological effects of DNA damage are gene mutation and cell apoptosis. Studies have shown that DNA damage repair may contribute to the pathogenesis of NTDs [9][10][11][12]. Chemotherapeutic agents such as cyclophosphamide and methotrexate induce DNA damage and cell apoptosis, which is likely to be one of the mechanisms in the occurrence of NTDs [13][14][15][16][17][18][19]. ...
... These data indicate that folate deficiency could affect the ability of DNA repair and genomic stability [49,50]. Uracil misincorporation into DNA under folate deficiency might be causal in the development of folate-responsive NTDs [9,35]. Anti-cancer drugs such as antifolates (5-fluorouracil, methotrexate, and raltitrexed) reduced the de novo dTMP synthesis and increased the incorporation of uracil into DNA, resulting in the impairment of DNA synthesis [51][52][53]. ...
Neural tube defects (NTDs) are complex congenital malformations resulting from failure of neural tube closure during embryogenesis, which is affected by the interaction of genetic and environmental factors. It is well known that folate deficiency increases the incidence of NTDs; however, the underlying mechanism remains unclear. Folate deficiency not only causes DNA hypomethylation, but also blocks the synthesis of 2′-deoxythymidine-5′–monophosphate (dTMP) and increases uracil misincorporation, resulting in genomic instabilities such as base mismatch, DNA breakage, and even chromosome aberration. DNA repair pathways are essential for ensuring normal DNA synthesis, genomic stability and integrity during embryonic neural development. Genomic instability or lack of DNA repair has been implicated in risk of development of NTDs. Here, we reviewed the relationship between folate deficiency, DNA repair pathways and NTDs so as to reveal the role and significance of DNA repair system in the pathogenesis of NTDs and better understand the pathogenesis of NTDs.
... Neural tube closure requires complex reactions for various nucleotide biosynthesis and methylation. Deficient methylation and abnormal biosynthesis of purine base and thymidylate have been noticed in cases of NTDs [26]. ...
Neural tube defects (NTDs) are variety of defects which result from abnormal closure of the neural tube during embryogenesis. Various factors are implicated in the genesis of neural tube defects, with contributions from both genetic and environmental factors. The clear understanding of the causes which leads to NTDs is lacking, but several non-genetic risk factors have been identified which can be prevented by maternal folic acid supplementation. Multiple genetic causes and several critical biochemical reactions have been identified whose regulation is essential for the closure of neural tube. Preventive therapies can be developed by identifying potential risk factors in the genesis of NTDs.
... As a cofactor that mediates the transfer of one-carbon unit, folic acid plays a crucial role in nucleotide synthesis, DNA repair, and epigenetic modification [9,10]. Folic acid is involved in the biosynthesis of purines and thymine [11,12]. Deoxythymidine monophosphate (dTMP) is essential in DNA synthesis and normal cell division [13]. ...
Early life stage folate status may influence neurodevelopment in offspring. The developmental origin of health and disease highlights the importance of the period of the first 1000 days (from conception to 2 years) of life. This study aimed to evaluate the effect of early life stage folic acid deficiency on de novo telomere synthesis, neurobehavioral development, and the cognitive function of offspring rats. The rats were divided into three diet treatment groups: folate-deficient, folate-normal, and folate-supplemented. They were fed the corresponding diet from 5 weeks of age to the end of the lactation period. After weaning, the offspring rats were still fed with the corresponding diet for up to 100 days. Neurobehavioral tests, folic acid and homocysteine (Hcy) levels, relative telomere length in brain tissue, and uracil incorporation in telomere in offspring were measured at different time points. The results showed that folic acid deficiency decreased the level of folic acid, increased the level of Hcy of brain tissue in offspring, increased the wrong incorporation of uracil into telomeres, and hindered de novo telomere synthesis. However, folic acid supplementation increased the level of folic acid, reduced the level of Hcy of brain tissue in offspring, reduced the wrong incorporation of uracil into telomeres, and protected de novo telomere synthesis of offspring, which was beneficial to the development of early sensory-motor function, spatial learning, and memory in adolescence and adulthood. In conclusion, early life stage folic acid deficiency had long-term inhibiting effects on neurodevelopment and cognitive function in offspring.
... To confirm that the observed NADPH and fatty-acid labelling in liver is derived from cytosolic serine catabolism, we carried out [2,3,3-2 H]serine tracing in Shmt1 whole-body knock-out mice, which are viable, fertile and exhibit no major metabolic defects 51,54 (Extended Data Fig. 7b). As expected, these mice showed a complete loss of M+2 5-methyl-THF (Fig. 5c). ...
... Serine catabolism through one-carbon metabolism is important for organismal development, cancer cell growth and immune function [63][64][65][66] . The enzymes important for these functions are, however, mitochondrial (for example SHMT2, MTHFD2, and MTHFD1L) 50,52,54,67,68 , with the physiological function of cytosolic SHMT1 being a long-standing puzzle 54 . The present data show that, although most tissues generate one carbon units from serine via the mitochondrial pathway, the liver uniquely relies on cytosolic serine catabolism. ...
Carbohydrate can be converted into fat by de novo lipogenesis, a process upregulated in fatty liver disease. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor. The feedstocks used to generate acetyl-CoA and NADPH in lipogenic tissues remain, however, unclear. Here we show using stable isotope tracing in mice that de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH. The liver, in contrast, derives acetyl-CoA for lipogenesis from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway in liver running in the opposite direction to that observed in most tissues and tumours, with NADPH made by the SHMT1–MTHFD1–ALDH1L1 reaction sequence. SHMT inhibition decreases hepatic lipogenesis. Thus, liver folate metabolism is distinctively wired to support cytosolic NADPH production and lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are used, opening the door to tissue-specific pharmacological interventions. Liver and adipose tissue are shown to use different metabolic routes to generate NADPH for de novo lipogenesis, with the liver relying on a unique cytosolic serine catabolic pathway involving the enzyme SHMT1.
... To confirm that the observed NADPH and fatty acid labeling in liver is derived from cytosolic serine catabolism, we carried out [2,3,3-2 H]serine tracing in SHMT1 whole-body knock-out mice, which are viable, fertile, and exhibit no major metabolic defects 33,36 . These mice showed a complete loss of M+2 5methyl-THF (Fig. 4c), confirming functional ablation of SHMT1 enzymatic activity. ...
... One-carbon metabolism is important for organismal development and as a target for cancer therapy and autoimmune disease treatment 4,[41][42][43] . Genetic impairment of mitochondrial serine catabolism (e.g. via knockout of at SHMT2, MTHFD2, or MTHFD1L) results in developmental hallmarks of folate deficiency such as neural tube defects 36 . In cancer cells or T cells, loss of the mitochondrial 1C pathway impairs growth and proliferation 5,31,34,44 . ...
... In cancer cells or T cells, loss of the mitochondrial 1C pathway impairs growth and proliferation 5,31,34,44 . In contrast, SHMT1 loss is tolerated in both development and proliferating cells, rendering the physiological function of cytosolic serine catabolism a long-standing puzzle 36 . The present data show that, while most tissues generate 1C units from serine via the mitochondrial pathway, the liver uniquely relies on cytosolic serine catabolism. ...
Carbohydrate can be converted into fat by de novo lipogenesis. This process is known to occur in adipose and liver, and its activity is upregulated in fatty liver disease. Chemically, de novo lipogenesis involves polymerization and reduction of acetyl-CoA, using NADPH as the electron donor1. While regulation of the responsible enzymes has been extensively studied, the feedstocks used to generate acetyl-CoA and NADPH remain unclear. Here we show that, while de novo lipogenesis in adipose is supported by glucose and its catabolism via the pentose phosphate pathway to make NADPH, liver makes fat without relying on glucose. Instead, liver derives acetyl-CoA from acetate and lactate, and NADPH from folate-mediated serine catabolism. Such NADPH generation involves the cytosolic serine pathway running in liver in the opposite direction observed in most tissues and tumors, with NADPH made by the SHMT1-MTHFD1-ALDH1L1 reaction sequence. Thus, specifically in liver, folate metabolism is wired to support cytosolic NADPH production for lipogenesis. More generally, while the same enzymes are involved in fat synthesis in liver and adipose, different substrates are utilized, opening the door to tissue-specific pharmacological interventions.
... A lack of folate and choline in the maternal diet can cause a small proportion of fetuses to develop NTDs. [87] However, the response to maternal folic acid supplementation was only determined in a few of the 150 mouse models, [88] which exhibited NTDS, [89] and among those NTD models that responded to exogenous folic acid, only the Splotch mutation Body (Pax3Sp) shows impaired one-carbon metabolism. Homozygous Splotch embryos exhibit fully penetrating spina bifida and impaired new thymine biosynthesis. ...
One‐carbon metabolism is involved in varieties of physiological processes in mammals, including nucleic acid synthesis, amino acid homeostasis, epigenetic regulation, redox balance and neurodevelopment. The current evidence linking levels of one‐carbon nutrients during pregnancy to the development of oocytes, embryos, and placentas, as well as maternal and offspring health, is reviewed. The sources of mammalian one‐carbon units, the pathways active in mammalian one‐carbon metabolism, the maternal and fetal needs for one‐carbon units and their functions during pregnancy are described. The demand for one‐carbon metabolism is highest during pregnancy compared to the entire lifetime of a mammal. The primary types of one‐carbon metabolism in mammals are the folate cycle, methionine cycle and transsulfuration pathway, which varies at different pregnancy stages (e.g., methylation programming of embryo, neural development of fetus, fetal growth and placenta development). Therefore, an overall consideration of one‐carbon metabolism requirements for different pregnancy stages, is called for, specifically, the balance of all nutrients involved, not just one single nutrient in one‐carbon metabolism. Moreover, the establishment of an ideal one‐carbon metabolism requirement model is suggested according to the requirements for different pregnancy stages to support optimal pregnancy outcomes and maternal and offspring health.
... SHMT1 was an important supplier of carbon unit in the process of folate metabolism [25]. The SHMT1 hypermethylation could reduce the expression of SHMT1 [13] causing folic acid metabolism and Hcy remethylation pathways to be blocked [26]. Subsequently, excessive accumulation of Hcy caused to hyperhomocysteinemia [27], which led to stroke. ...
This study aimed to determine the correlation between serine hydroxymethyl transferase 1 (SHMT1) gene methylation and ischemic stroke. A total of 202 age- and sex-matched individuals were included. Quantitative methylation-specific polymerase chain reaction (qMSP-PCR) was used to analyze the DNA methylation level. The plasma homocysteine (Hcy) concentration was much higher in ischemic cases than in controls (p = 0.009), while the HDL levels in stroke cases were considerably lower than in controls (p = 0.005). A significantly higher level of SHMT1 methylation was observed in the ischemic strokes (58.82 ± 17.83 %) compared to that in the controls (42.59 ± 20.76 %, p < 0.001). The SHMT1 methylation level was strongly correlated with HDL concentration in the healthy controls (r = 0.517, p < 0.001), while the high plasma level of Hcy showed strong association with SHMT1 methylation in ischemic strokes (r = 0.346, p < 0.001). Receiver operating characteristic (ROC) analysis of curve indicated that SHMT1 methylation have been an acceptable indicator for ischemic stroke in female patients [all sexes, area under the curve (AUC) = 0.71, p < 0.001; male patients AUC = 0.62, p = 0.032; and female patients AUC = 0.79, p < 0.001] and in all ages (AUC = 0.71, p < 0.001). In our samples, DNA methylation levels of the STHMI gene were significantly correlated with ischemic stroke in Han Chinese. STHMI hypermethylation was significantly associated with the high Hcy concentration in ischemic stroke and had value as a potential indicator for female ischemic stroke.
... In this mouse model, overexpression of SHMT1 unexpectedly impaired the localization of SHMT1 and TYMS, and increased uracil content in hepatic nuclear DNA. Similarly, Shmt1 +/− and Shmt1 −/− mice exhibit elevated uracil in genomic DNA and develop folic acid-responsive NTDs (29,34). Taken together, these data suggest that impaired SHMT1 nuclear localization or impaired nuclear de novo dTMP complex formation may underlie the folic acid-responsive NTDs in mice (2). ...
Folate-mediated one-carbon metabolism (FOCM) is compartmentalized within human cells to the cytosol, nucleus, and mitochondria. The recent identifications of mitochondria-specific, folate-dependent thymidylate [deoxythymidine monophosphate (dTMP)] synthesis together with discoveries indicating the critical role of mitochondrial FOCM in cancer progression have renewed interest in understanding this metabolic pathway. The goal of this narrative review is to summarize recent advances in the field of one-carbon metabolism, with an emphasis on the biological importance of mitochondrial FOCM in maintaining mitochondrial DNA integrity and mitochondrial function, as well as the reprogramming of mitochondrial FOCM in cancer. Elucidation of the roles and regulation of mitochondrial FOCM will contribute to a better understanding of the mechanisms underlying folate-associated pathologies.
