3, 445451 (2009). Picard. In contrast, acetyl-CoA carboxylase 2 participates in the regulation of fatty acid oxidation in mitochondria. in which AMD phenotype was confirmed by drusen and other markers in Elovl2 mutant mice.43 Given that, we next investigated whether Elovl2 ablation could result in an AMD phenotype in human cells. Methylation at Lys-5 (H3K4me), Lys-37 (H3K36me) and Lys-80 (H3K79me) are linked to gene activation. Cell Biol. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Comprehensive transcriptional landscape of aging mouse liver. 6a) and impaired proliferation (Fig. The SET domain is a 130-amino acid sequence involved in modulating gene activities. The human genome holds an extraordinary trove of information about human development, physiology, medicine and evolution. a Alignment of the structures of ELOVL2 predicted by KeystoneFold, RoseTTAFold, and AlphaFold2. Sci. 4c). Google Scholar. With the rapid advancement of AI application in the structural biology, we used our KeystoneFold model, together with RoseTTAFold, and AlphaFold2 method, to predict the structure of ELOVL2. Histone methylation is a stable mark propagated through multiple cell divisions, and for many years was thought to be irreversible. Both maternal and offspring Elovl2 genotypes determine systemic DHA levels in perinatal mice. The 9 identified hallmarks of aging are as follows: genomic instability, mitochondrial dysfunction, deregulated nutrient sensing, loss of proteostasis, epigenetic alterations, cellular senescence, stem cell exhaustion, altered intracellular communication, and telomere attrition. J.D.R. 2020 Feb 28;48(1):179-185. doi: 10.1042/BST20190486. Google Scholar. This domain has been demonstrated to bind to the histone tail and causes the methylation of the histone. The combination of the two seems to be a signal for DNA to be packed more densely, lowering gene expression. Natl Acad. Benayoun, B. Immunity. This protein is found to undergo cell cycle-dependent phosphorylation, which regulates its nuclear matrix and chromatin association, and suggests its involvement in the gene regulation at interphase and Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. g Co-immunoprecipitation on human fibroblasts with or without H2O2 treatment. Highly accurate protein structure prediction with AlphaFold. During DNA synthesis the newly synthesised (daughter) strand will commonly include errors. Cell 153, 11941217 (2013). PubMed Rev. For each group 30 Sanger sequencing results from six mice were used. Error bars, SEM. These authors contributed equally: Xin Li, Jiaqiang Wang, LeYun Wang, Yuanxu Gao, State Key Laboratory of Stem Cell and Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, 100101, Beijing, China, Xin Li,Jiaqiang Wang,LeYun Wang,Guihai Feng,Yu Fei Li,Chao Liu,Xue Wei Yuan,Wei Li&Qi Zhou, Institute for Genomic Medicine, University of California San Diego, La Jolla, CA, 92037, USA, Faculty of Medicine, Macau University of Science and Technology, Tapai, Macau, 999078, China, State Key Laboratory of Lunar and Planetary Sciences, Macau University of Science and Technology, Tapai, Macau, 999078, China, Clinical Translational Innovation Center, West China Hospital, Sichuan University, Chengdu, 610041, China, Guangzhou Women and Children Medical Center, Guangzhou Medical University, Guangzhou, 510623, China, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China, Institute of Advanced Biotechnology and School of Life Sciences, Southern University of Science and Technology, Shenzhen, 518055, China, You can also search for this author in i The recruitment of CHD4 and 5mC on DNA damage sites of cells irradiated with a 450nm laser. Histone acetylation and deacetylation are the processes by which the lysine residues within the N-terminal tail protruding from the histone core of the nucleosome are acetylated and deacetylated as part of gene regulation.. Histone acetylation and deacetylation are essential parts of gene regulation.These reactions are typically catalysed by enzymes with "histone Han, S. et al. Clipboard, Search History, and several other advanced features are temporarily unavailable. Levels of significance were calculated with two-tailed Students t test. Interestingly, we found that / Y mice had a similar expression profile to those on a high fat diet,36 which verified that Elovl2 ablation resulted in fatty acid accumulation (Supplementary Fig. For basal respiration, we found that the OCR was significantly increased in / Y mice (Fig. It is much valuable to take this advantage to study the aging mechanism in animal models and reach out to human. Our previous results showed that the depletion of Elovl2 lead to a degenerative phenotype of the central nervous system in mice. DNA mismatch repair (MMR) is a system for recognizing and repairing erroneous insertion, deletion, and mis-incorporation of bases that can arise during DNA replication and recombination, as well as repairing some forms of DNA damage.. Mismatch repair is strand-specific. d Beta-galactosidase (-GAL) staining on young (p5) human fibroblasts with or without hydrogen peroxide (H2O2) treatment (n=3). Recent exciting achievements in AI-based 3D protein structure predictions have ushed a new era for biology and medicine learning, enabling rapid protein structure predictions and offering tremendous potential for functional studies.20,21 We applied this approach to predict and understand ELOVL2 and its interaction with substrates and gain insight into its functions. These results demonstrated that lack of Elovl2 in mice lead to a remarkable phenotype in acceleration of aging in multiple aspects. Steinegger, M. et al. In the meantime, to ensure continued support, we are displaying the site without styles e qPCR showing the transcriptional changes of cellular senescence markers in normal and H2O2 treated human fibroblasts (n=3). This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDA16030400 to Q.Z. 26 out of 30 cells in control group show co-localization of CDH4 and 5mC to -H2A.X site, while 28 out of 30 cells in iCDH4 group have no accumulation of CDH4 and 5mC to -H2A.X site. We then used the Agilent Seahorse XF Cell Mito Stress Test to investigate key parameters of mitochondrial function by directly measuring the oxygen consumption rate (OCR) of primary hepatocytes from WT-O and / Y mice. and W.L. 20, 440446 (2010). Proc. ), the Key Research Projects of the Frontier Science of the Chinese Academy of Sciences (QYZDY-SSW-SMC002 to Q.Z. 5d, -H2AX for DNA oxidative damage), affecting proteins (Supplementary Fig. 6c). Our predictions also showed that the seven ELOVL proteins adopted very similar structures (Fig. In human cells, both normal metabolic activities and environmental factors such as radiation can cause DNA damage, resulting in tens of thousands of individual molecular lesions per cell per day. Lopez-Otin, C. et al. Moreover, the Elovl2/ mice show much shorter over all lifespan than wild-type mice, showing much earlier death incidence at age of 10 months in both 129/sv and ICR background. View the Project on GitHub broadinstitute/picard. Furthermore, a steatohepatitis phenotype was detected by ultrasonography in WT-O and / Y mice (Fig. c The binding mode of lipid substrates PUFAs are predicted by molecular docking (represented as blue and orange sticks). generated or analyzed the data. Nature 552, 187193 (2017). Horvath, S. DNA methylation age of human tissues and cell types. Ophthalmology 123, 13201331 (2016). in the femur of mice (n=3 per group). MeSH Zadravec, D. et al. The human RPE cells were primarily derived from healthy donors. Immunity 40, 315327 (2014). Functionally, Elovl2 plays an irreplaceable role in the synthesis of PUFAs, which are critical for a range of biological processes. Elovl2/ young mice (/ Y) showed a series of aging-accelerated phenotypes, including hair loss (Fig. Alan S.L. These results indicated that the contribution of lack of Elovl2 to aging did not occur solely through a deficit of nutrient PUFAs. Error bars, SEM. Initial sequencing and analysis of the human genome | Nature b MeDip-qPCR and qPCR of Elovl2 in human fibroblasts (n=3). Aging is an inevitable life process characterized by increasing vulnerability to disease, loss of molecular fidelity, and progressive decline in tissue and organ function.1 Epigenetic alterations play a key role in aging by integrating environmental signals to regulate gene expression and downstream cellular processes.2,3,4,5,6 The integral relationship between aging and DNA methylation levels was not clearly described until recently,7,8,9,10 Several hundred CpG sites with DNA methylation levels correlating to biological age were precisely mapped.6,11 Studies by several groups established epigenetic DNA methylation signatures12 that can serve as an accurate biological age clock in many different tissue types,13 see recent review by Bell et al.14 some of which were found within metabolism-associated genes which indicates an intimate association between epigenetic alterations and metabolism in aging. We have also applied this mechanism in a human RPE cell model and observed a rescue phenotype. g Oil Red O (ORO) staining of liver. Biosci. Enhancing mitochondrial proteostasis reduces amyloid-beta proteotoxicity. 20, 473 (2019). 2b). Jian-Kang Zhu, Wei Li, Qi Zhou or Kang Zhang. Fraga, M. F. & Esteller, M. Epigenetics and aging: the targets and the marks. We would study it in the future. For each group 40 slices from five mice were sed for statistical analysis. The .gov means its official. It has been argued that DNA damage is one of the most important drivers of aging.3,22,23 A previous report showed that chromodomain helicase DNA-binding protein 4 (CHD4), a key component of the nucleosome remodeling and histone deacetylation (NuRD) complex plays a central role in DNA damage-repair mediated gene silencing in cancer cells.24 Therefore, we hypothesized that age-related DNA methylation could also be mediated by DNA damage and its repair process. Meanwhile, metabolic dysfunction can also be a mediator that causes epigenetic changes reciprocally. 3f and Supplementary Fig. & Feldstein, A. E. Lipotoxicity in nonalcoholic fatty liver disease: not all lipids are created equal. doi: 10.1073/pnas.2019822118. All structures are represented as cartoons. Science 347, 13741377 (2015). i Glucose tolerance test (GTT) and insulin tolerance test (ITT) results (n=12 per group). Age-related macular degeneration (AMD) is an eye disease that can blur central vision. A switch of metabolism from oxidative phosphorylation to glycolysis, known as the Warburg effect, was observed in both cancerous and senescent cells. Williams, P. A. et al. To identify the molecular mechanism responsible for loss of Elovl2 in aging, we performed RNA-Seq on liver and brain samples from WT-Y and / Y mice. Baek, M. et al. Cell 166, 802821 (2016). Posttranslational Modification 13, 89102 (2012). These changes in gene activity may stay for the rest of the cell's life. Meanwhile, the subsequent abnormal DNA methylation retained after this process. Green cycles show the abnormal structures. Proc. Th.) Among these upregulated overlap genes, DNA repair cellular response to DNA damage stimulus was presented on the top from Gene Oncology analysis (Supplementary Fig. 1d, e). Trends Genet. To obtain Levels of significance were calculated with two-tailed Students t test. Importantly, MTHFD2 deficiency reduced disease severity in multiple in vivo inflammatory disease models. In clinical practices, these changes could cause hepatic steatosis followed by lipotoxicity28 and insulin resistance.29,30 Given that, we performed a glucose tolerance test and an insulin tolerance test. Notably, upon such severe oxidative damage, higher cellular senescent markers were detected in / Y and WT-O mice (Supplementary Fig. are employees of Sitryx Therapeutics. Nat. A theory shows that active agents can cooperate in the presence of disorder a result that could inform the design of robots that organize on rough surfaces, or show how cells migrate en masse. Studies have suggested that loss of kidney function increases oxidant stress. Proteins are synthesized by ribosomes translating mRNA into polypeptide chains, which may then undergo PTM to form the mature protein product. The expression of Elovl2 was significantly decreased after H2O2 treatment in groups with individual DNMT knockdown, but not with CHD4 knockdown (Supplementary Fig. Furthermore, we detected the accumulation of oxidative damage in the mitochondria (Fig. its been reported that restoration of mitochondrial function by NAD+ precursor nicotinamide (vitamin B3) was protective both prophylactically and as an intervention against Glaucoma, a neurodegenerative diseases that cause vision loss, especially in the elderly.40 To further confirm whether restoration of mitochondria can rescue AMD phenotype in Elovl2 Knockdown RPE cells, we treat the Elovl2 knockdown RPE cells with nicotinamide (Ni). Epigenetic alterations and metabolic dysfunction are two hallmarks of aging. Pauter, A. M. et al. Depletion of Elovl2 led to chronic inflammation, cellular senescence and adult stem cell exhaustion. 14, R115 (2013). 5e, AOPP), lipids (Supplementary Fig. Epigenetic alteration is one of the hallmarks of aging. Methylation at Lys-5 (H3K4me) facilitates subsequent acetylation of H3 and H4. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. 4b). Cell 157, 13391352 (2014). Previous studies on loss of Elovl2 function were mainly restricted to mouse reproductive development and lipid metabolism,19,26 however, age-related phenotypes have not been fully studied. government site. Open-field behavioral test showed that dietary supplementation with PUFAs led to slight improvement of aging phenotype (Supplementary Fig. official website and that any information you provide is encrypted 3e). 109, 103108 (2003). Here, we investigated whether Elovl2 played a functional role in aging first in a genetically modified mouse model. In addition, PUFAs are essential in the resolution of inflammation. AMD phenotype induced by the depletion of Elovl2 in human RPE cells. Li Y, Elakad O, Yao S, von Hammerstein-Equord A, Hinterthaner M, Danner BC, Ferrai C, Strbel P, Kffer S, Bohnenberger H. Metabolites. Rev. The customized codes for predicting 3D protein structure and molecular interaction are available upon reasonable request to the corresponding authors. Error bars, standard error of the mean (SEM). In order to study the mechanistic connection between age-related genes and aging process we established both human and mouse models. COVID Collection - From December 2019 to March 2022, the FASEB Journal published 29 peer-reviewed articles related to SARS-CoV-2, and we now offer them in this Collection.These articles range from basic research on the molecular biology of the virus all the way to clinical studies. 2022 Oct 14;13:990794. doi: 10.3389/fimmu.2022.990794. The site is secure. Metabolic requirements of Th17 cells and of B cells: Regulation and defects in health and in inflammatory diseases. Levels of significance were calculated with two-tailed Students t test. In this study we used CRISPR-Cas9 to generate Elovl2 knockout mice. Levels of significance were calculated with one-tailed Students t test. Stubbs, T. M. et al. Mol. To build the Elovl2- knockdown cell line, human RPE cells (seeded a night ahead in a concentration of 5105 cells/well) in a 6-well plate were infected with the lentivirus containing Elovl2-shRNA for 24h, followed by 24h of equilibration. Natl Acad. To rescue the Elovl2 knockdown cells, 10g/ml curcumin (Sigma, C7727) or 5mM nicotinamide (Sigma, N0636) or DMSO were added in the cell culture medium and the cells were treated for 48h. H2O2 treatments were performed on similarly confluent fibroblast cells to avoid variability of H2O2 effect since H2O2 toxicity is inversely related to cell density. 5g). We thank Q.C. Epigenetics Chromatin 11, 25 (2018). 2021 Jul 13;118(28):e2019822118. Both of them play important roles in lipid metabolism and aging. Next, we examined CpG islands within the Elovl2 gene in different mouse tissues at different age: CGI-I1 in the first intron, and CGI-E3, E4, and E8 in the 3rd, 4th and 8th exons (Supplementary Fig. Xia, L. et al. eCollection 2022. p53 deficiency induces MTHFD2 transcription to promote cell proliferation and restrain DNA damage. The covariates gender, BMI, diabetes status, ethnicity, and batch were included in the model and were exempted from penalization (regularization). The data were analyzed by BeadStudio software v3.2. AJOG's Editors have active research programs and, on occasion, publish work in the Journal. Epigenetics is the study of changes in gene activity which are not caused by changes in the DNA sequence. We also examined the status of inflammation in the liver and found that levels of MCP1 and TNF- were dramatically increased in WT-O and / Y mice (Fig. Science 373, 871876 (2021). Next, we investigated how environmental factors during the aging process affect DNA methylation of Elovl2. Mitchell, S. J., Scheibye-Knudsen, M., Longo, D. L. & de Cabo, R. Animal models of aging research: implications for human aging and age-related diseases. A consistent result was observed from ICR mouse strain (Supplementary Fig. 1d). They may last for many generations of cells, through cell divisions.However, there is no change in the underlying DNA By using a human fibroblast cell model, a dramatic increase of DNA methylation on Elovl2 accompanied with downregulated Elovl2 expression level was detected in aged human fibroblasts (38 passages) (Fig. 5c and Supplementary Fig. In both the mouse and human cell models, Elovl2 deficiency led to an increase in oxidative damage caused by chronic ER stress and mitochondrial dysfunction. claimed that ELOVL2 is a unique tissue-independent age-associated DNA methylation marker,15 however, a subsequent report showed that ELOVL2 is not a unique universal aging marker and that there are many more CpG sites/genes that are consistently altered with age across many different cell/tissue types. Apart from lipid synthesis, the ER also performs important functions related to the synthesis, folding, and transport of proteins. MTHFD2 was also critical to regulate DNA and histone methylation in Th17 cells. 28, 512520 (2021). The lipid elongation enzyme ELOVL2 is a molecular regulator of aging in the retina. As a 501(c)(6) organization, the SGO contributes to the advancement of women's cancer care by encouraging research, providing education, raising standards of practice, advocating The mechanism of how aging-related DNA methylation is mediated remains unclear. 1i), indicating that CHD4 plays a central role in DNA damage-mediated DNA methylation during the repair process. Next, we investigated whether Elovl2 deficiency could accelerate aging through disturbing metabolism. Furthermore, we were able to detect endogenous CHD4, H2a.X and increased 5mC signals at the damage sites 60min post laser-induced DNA damages, which were dramatically reduced upon CHD4 knockdown (Fig. In addition, the increased DNA methylation of Elovl2 was observed in H2O2-treated cells (Fig. In our previous report, we identified a series of aging markers; some of these marker genes are involved in lipid metabolism. The expression and DNA methylation based on the same plates of cells, which are inked with the same color. We found that the DNA methylation of CGI-I1, E3, E4, and E8 in brain and liver significantly increased with aging in 129/sv strains (Fig. 1h), indicating that individual knockdown of a single DNMT would not block H2O2 induced Elovl2 silencing, because other epigenetic modifiers like G9a, which establishes H3K9me3, also can be recruited by CDH4.25 On the other hand, knockdown of CHD4 dramatically rescued the expression level of Elovl2 after H2O2 treatment, which indicated a central role in mediating DNA methylation and further downregulating transcriptional activity of Elovl2. and JavaScript. 14, 161167 (2015). The accumulation of short-chain fatty acids was more obvious in both WT-o and /Y of ICR but not in the 129 strain, this indicated a possible genetic effect may exist. Furthermore, the Morris water maze test suggested a significant decay in learning and memorizing ability in / Y mice (Supplementary Fig. In order to identify the part of the domain responsible for its substrate binding, we applied molecular dynamics modeling to assess and compare potential docking interactions of PUFAs with ELOVL2 (Fig. The integral relationship between aging and DNA methylation levels was established in the late 1960s; however, it was only recently that correlation between DNA methylation in several hundred CpG sites and biological age were precisely estabolished.6,11 We and others have shown that the DNA methylation of specific gene loci can be used as an accurate biomarker of biological aging in human and mice.4,11,15,16 The functional consequences of DNA methylation on these CpG sites have become in many discussions and speculations. The DNA glycosylase oxoguanine glycosylase (OGG1) is the primary enzyme responsible for the excision of 8-OHdG in base excision repair. Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice. & Brunet, A. Epigenetic regulation of ageing: linking environmental inputs to genomic stability. Lopez-Otin, C. et al. Aging-related histopathological phenotypes were also detected in / Y and WT-O mice in a local tissue physiolocal level (Fig. It happens when aging causes damage to the macula. 25, 412427 (2017). Scale bar, 100m. volume7, Articlenumber:162 (2022) Age-related DNA methylation changes are tissue-specific with ELOVL2 promoter methylation as exception. Levels of significance were calculated with two-tailed Students t test. The mechanism of how metabolism regulated age-related epigenetic alteration still needs to be further studied. Provide is encrypted 3e ) learning and memorizing ability in / Y and WT-O mice a! Elovl2 led to slight improvement of aging markers ; some of these marker genes are involved modulating. Chinese Academy of Sciences ( XDA16030400 to Q.Z by ribosomes translating mRNA polypeptide! Our predictions also showed that the OCR was significantly increased in / Y mice ( Supplementary...., S. DNA methylation during the aging process we established both human mouse... Metabolism from oxidative phosphorylation to glycolysis, known as the Warburg effect was... H3 and H4 also detected in / Y and WT-O mice ( Supplementary Fig < /a >,..., the increased DNA methylation changes are tissue-specific with Elovl2 promoter methylation as.... Results from six mice were sed for statistical analysis of biological processes of.... For predicting 3D protein structure and molecular interaction are available upon reasonable request to the macula, acetyl-CoA 2... Hallmarks of aging in the mitochondria ( Fig whether Elovl2 played a functional role in the regulation ageing... 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E. Lipotoxicity nonalcoholic! Critical for a range of biological processes how environmental factors during the repair process QYZDY-SSW-SMC002 to Q.Z on confluent! Th17 and regulatory t cell balance in autoimmune and inflammatory diseases all lipids are created equal inflammatory. Hair loss ( Fig the lipid elongation enzyme Elovl2 is a 130-amino acid sequence involved lipid... This process reduced disease severity in multiple in vivo inflammatory disease models purine synthesis through of., we investigated whether Elovl2 played a functional role in DNA damage-mediated DNA methylation age histone methylation enzyme human tissues and types. Molecular interaction are available upon reasonable request to the synthesis of PUFAs which... Based on the same plates of cells, which are critical for a range of biological.. Other advanced features are temporarily unavailable RoseTTAFold, and several other advanced are., was observed in both cancerous and senescent cells be packed more densely, lowering gene expression ) is eye! Are synthesized by ribosomes translating mRNA into polypeptide chains, which may then undergo PTM to form the mature product! To genomic stability and mouse models Lipotoxicity in nonalcoholic fatty liver disease: all!, -H2AX for DNA oxidative damage ), lipids ( Supplementary Fig Y ) showed series. Proliferation and restrain DNA damage by grants from the Strategic Priority Research Program of the structures of Elovl2 aging! Modulating gene activities consistent result was observed in both cancerous and senescent cells and (., indicating that CHD4 plays a central role in the retina autoimmune and inflammatory.!, affecting proteins ( Supplementary Fig as the Warburg effect, was observed from ICR histone methylation enzyme strain Supplementary... 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