bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒07‒10
seven papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine
  1. Impact of Exercise and Aging on Mitochondrial Homeostasis in Skeletal Muscle: Roles of ROS and Epigenetics.
  2. Characterization of histone lysine β-hydroxybutyrylation in bovine tissues, cells, and cumulus-oocyte complexes.
  3. Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver.
  4. Epigenetic modifications in metabolic memory: What are the memories, and can we erase them?
  5. Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells.
  6. Metabolic Labeling-Based Chemoproteomics Establishes Choline Metabolites as Protein Function Modulators.
  7. Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts.
  1. Cells. 2022 Jun 30. pii: 2086. [Epub ahead of print]11(13):
    Impact of Exercise and Aging on Mitochondrial Homeostasis in Skeletal Muscle: Roles of ROS and Epigenetics.
    Jialin Li, Zhe Wang, Can Li, Yu Song, Yan Wang, Hai Bo, Yong Zhang.
      Aging causes degenerative changes such as epigenetic changes and mitochondrial dysfunction in skeletal muscle. Exercise can upregulate muscle mitochondrial homeostasis and enhance antioxidant capacity and represents an effective treatment to prevent muscle aging. Epigenetic changes such as DNA methylation, histone posttranslational modifications, and microRNA expression are involved in the regulation of exercise-induced adaptive changes in muscle mitochondria. Reactive oxygen species (ROS) play an important role in signaling molecules in exercise-induced muscle mitochondrial health benefits, and strong evidence emphasizes that exercise-induced ROS can regulate gene expression via epigenetic mechanisms. The majority of mitochondrial proteins are imported into mitochondria from the cytosol, so mitochondrial homeostasis is regulated by nuclear epigenetic mechanisms. Exercise can reverse aging-induced changes in myokine expression by modulating epigenetic mechanisms. In this review, we provide an overview of the role of exercise-generated ROS in the regulation of mitochondrial homeostasis mediated by epigenetic mechanisms. In addition, the potential epigenetic mechanisms involved in exercise-induced myokine expression are reviewed.
    Keywords:  ROS; aging; epigenetics; exercise; mitochondrial; skeletal muscle
    DOI:  https://doi.org/10.3390/cells11132086
  2. Mol Reprod Dev. 2022 Jul 08.
    Characterization of histone lysine β-hydroxybutyrylation in bovine tissues, cells, and cumulus-oocyte complexes.
    Juliano R Sangalli, Ricardo Perecin Nociti, Maite Del Collado, Rafael Vilar Sampaio, Juliano C da Silveira, Felipe Perecin, Lawrence Charles Smith, Pablo J Ross, Flávio V Meirelles.
      Besides their canonical roles as energy sources, short-chain fatty acids act as metabolic regulators of gene expression through histone posttranslational modifications. Ketone body β-hydroxybutyrate (BHB) causes a novel epigenetic modification, histone lysine β-hydroxybutyrylation (Kbhb), which is associated with genes upregulated in starvation-responsive metabolic pathways. Dairy cows increase BHB in early lactation, and the effects of this increase on cellular epigenomes are unknown. We searched for and identified that Kbhb is present in bovine tissues in vivo and confirmed that this epigenetic mark is responsive to BHB in bovine and human fibroblasts cultured in vitro in a dose-dependent manner. Maturation of cumulus-oocyte complexes with high concentrations of BHB did not affect the competence to complete meiotic maturation or to develop until the blastocyst stage. BHB treatment strongly induced H3K9bhb in cumulus cells, but faintly in oocytes. RNA-seq analysis in cumulus cells indicated that BHB treatment altered the expression of 345 genes. The downregulated genes were mainly involved in glycolysis and ribosome assembly pathways, while the upregulated genes were involved in mitochondrial metabolism and oocyte development. The genes and pathways altered by BHB will provide entry points to carry out functional experiments aiming to mitigate metabolic disorders and improve fertility in cattle.
    Keywords:  beta-hydroxybutyrate; cumulus cells; dairy cows; histone lysine β-hydroxybutyrylation; reproduction
    DOI:  https://doi.org/10.1002/mrd.23630
  3. Nat Commun. 2022 Jul 04. 13(1): 3835
    Renal UTX-PHGDH-serine axis regulates metabolic disorders in the kidney and liver.
    Hong Chen, Chong Liu, Qian Wang, Mingrui Xiong, Xia Zeng, Dong Yang, Yunhao Xie, Hua Su, Yu Zhang, Yixue Huang, Yuchen Chen, Junqiu Yue, Chengyu Liu, Shun Wang, Kun Huang, Ling Zheng.
      Global obesity epidemics impacts human health and causes obesity-related illnesses, including the obesity-related kidney and liver diseases. UTX, a histone H3K27 demethylase, plays important roles in development and differentiation. Here we show that kidney-specific knockout Utx inhibits high-fat diet induced lipid accumulation in the kidney and liver via upregulating circulating serine levels. Mechanistically, UTX recruits E3 ligase RNF114 to ubiquitinate phosphoglycerate dehydrogenase, the rate limiting enzyme for de novo serine synthesis, at Lys310 and Lys330, which leads to its degradation, and thus suppresses renal and circulating serine levels. Consistently, phosphoglycerate dehydrogenase and serine levels are markedly downregulated in human subjects with diabetic kidney disease or obesity-related renal dysfunction. Notably, oral administration of serine ameliorates high-fat diet induced fatty liver and renal dysfunction, suggesting a potential approach against obesity related metabolic disorders. Together, our results reveal a metabolic homeostasis regulation mediated by a renal UTX-PHGDH-serine axis.
    DOI:  https://doi.org/10.1038/s41467-022-31476-0
  4. Am J Physiol Cell Physiol. 2022 Jul 04.
    Epigenetic modifications in metabolic memory: What are the memories, and can we erase them?
    Zhuo Chen, Rama Natarajan.
      Inherent and acquired abnormalities in gene regulation due to the influence of genetics and epigenetics (traits related to environment rather than genetic factors) underly many diseases including diabetes. Diabetes could lead to multiple complications including retinopathy, nephropathy and cardiovascular disease that greatly increase morbidity and mortality. Epigenetic changes have also been linked to diabetes-related complications. Genes associated with many pathophysiological features of these vascular complications (e.g., inflammation, fibrosis, and oxidative stress) can be regulated by epigenetic mechanisms involving histone posttranslational modifications, DNA methylation, changes in chromatin structure/remodeling and noncoding RNAs. Intriguingly, these epigenetic changes triggered during early periods of hyperglycemic exposure and uncontrolled diabetes are not immediately corrected even after restoration of normoglycemia and metabolic balance. This latency in effect across time and conditions is associated with persistent development of complications in diabetes with prior history of poor glycemic control, termed as metabolic memory or legacy effect. Epigenetic modifications are generally reversible and provide a window of therapeutic opportunity to ameliorate cellular dysfunction and mitigate or 'erase' metabolic memory. Notably, trained immunity and related epigenetic changes transmitted from hematopoietic stem cells to innate immune cells have also been implicated in metabolic memory. Hence, identification of epigenetic variations at candidate genes, or epigenetic signatures genome-wide by epigenome-wide association studies can aid in prompt diagnosis to prevent progression of complications and identification of much-needed new therapeutic targets. Herein, we provide a review of epigenetics and epigenomics in metabolic memory of diabetic complications covering the current basic research, clinical data, and translational implications.
    Keywords:  DNA methylation; Diabetic Complications; Epigenetics; Metabolic Memory
    DOI:  https://doi.org/10.1152/ajpcell.00201.2022
  5. JCI Insight. 2022 Jul 08. pii: e158457. [Epub ahead of print]7(13):
    Phenylbutyrate modulates polyamine acetylase and ameliorates Snyder-Robinson syndrome in a Drosophila model and patient cells.
    Xianzun Tao, Yi Zhu, Zoraida Diaz-Perez, Seok-Ho Yu, Jackson R Foley, Tracy Murray Stewart, Robert A Casero, Richard Steet, R Grace Zhai.
      Polyamine dysregulation plays key roles in a broad range of human diseases from cancer to neurodegeneration. Snyder-Robinson syndrome (SRS) is the first known genetic disorder of the polyamine pathway, caused by X-linked recessive loss-of-function mutations in spermine synthase. In the Drosophila SRS model, altered spermidine/spermine balance has been associated with increased generation of ROS and aldehydes, consistent with elevated spermidine catabolism. These toxic byproducts cause mitochondrial and lysosomal dysfunction, which are also observed in cells from SRS patients. No efficient therapy is available. We explored the biochemical mechanism and discovered acetyl-CoA reduction and altered protein acetylation as potentially novel pathomechanisms of SRS. We repurposed the FDA-approved drug phenylbutyrate (PBA) to treat SRS using an in vivo Drosophila model and patient fibroblast cell models. PBA treatment significantly restored the function of mitochondria and autolysosomes and extended life span in vivo in the Drosophila SRS model. Treating fibroblasts of patients with SRS with PBA ameliorated autolysosome dysfunction. We further explored the mechanism of drug action and found that PBA downregulates the first and rate-limiting spermidine catabolic enzyme spermidine/spermine N1-acetyltransferase 1 (SAT1), reduces the production of toxic metabolites, and inhibits the reduction of the substrate acetyl-CoA. Taken together, we revealed PBA as a potential modulator of SAT1 and acetyl-CoA levels and propose PBA as a therapy for SRS and potentially other polyamine dysregulation-related diseases.
    Keywords:  Genetic diseases; Genetics; Lysosomes; Polyamines; Therapeutics
    DOI:  https://doi.org/10.1172/jci.insight.158457
  6. ACS Chem Biol. 2022 Jul 08.
    Metabolic Labeling-Based Chemoproteomics Establishes Choline Metabolites as Protein Function Modulators.
    Aditi Dixit, Gregor P Jose, Chitra Shanbhag, Nitin Tagad, Jeet Kalia.
      Choline is an essential nutrient for mammalian cells. Our understanding of the cellular functions of choline and its metabolites, independent of their roles as choline lipid metabolism intermediates, remains limited. In addition to fundamental cellular physiology, this knowledge has implications for cancer biology because elevated choline metabolite levels are a hallmark of cancer. Here, we establish a mammalian choline metabolite-interacting proteome by utilizing a photocrosslinkable choline probe. To design this probe, we performed metabolic labeling experiments with structurally diverse choline analogues that resulted in the serendipitous discovery of a choline lipid headgroup remodeling mechanism involving sequential dealkylation and methylation steps. We demonstrate that phosphocholine inhibits the binding of one of the proteins identified, the attractive anticancer target p32, to its endogenous ligands and to the promising p32-targeting anticancer agent, Lyp-1. Our results reveal that choline metabolites play vital roles in cellular physiology by serving as modulators of protein function.
    DOI:  https://doi.org/10.1021/acschembio.2c00400
  7. Gut. 2022 Jul 08. pii: gutjnl-2022-326928. [Epub ahead of print]
    Methionine deficiency facilitates antitumour immunity by altering m6A methylation of immune checkpoint transcripts.
    Ting Li, Yue-Tao Tan, Yan-Xing Chen, Xiao-Jun Zheng, Wen Wang, Kun Liao, Hai-Yu Mo, Junzhong Lin, Wei Yang, Hai-Long Piao, Rui-Hua Xu, Huai-Qiang Ju.
      OBJECTIVE: Methionine metabolism is involved in a myriad of cellular functions, including methylation reactions and redox maintenance. Nevertheless, it remains unclear whether methionine metabolism, RNA methylation and antitumour immunity are molecularly intertwined.DESIGN: The antitumour immunity effect of methionine-restricted diet (MRD) feeding was assessed in murine models. The mechanisms of methionine and YTH domain-containing family protein 1 (YTHDF1) in tumour immune escape were determined in vitro and in vivo. The synergistic effects of MRD or YTHDF1 depletion with PD-1 blockade were also investigated.
    RESULTS: We found that dietary methionine restriction reduced tumour growth and enhanced antitumour immunity by increasing the number and cytotoxicity of tumour-infiltrating CD8+ T cells in different mouse models. Mechanistically, the S-adenosylmethionine derived from methionine metabolism promoted the N6-methyladenosine (m6A) methylation and translation of immune checkpoints, including PD-L1 and V-domain Ig suppressor of T cell activation (VISTA), in tumour cells. Furthermore, MRD or m6A-specific binding protein YTHDF1 depletion inhibited tumour growth by restoring the infiltration of CD8+ T cells, and synergised with PD-1 blockade for better tumour control. Clinically, YTHDF1 expression correlated with poor prognosis and immunotherapy outcomes for cancer patients.
    CONCLUSIONS: Methionine and YTHDF1 play a critical role in anticancer immunity through regulating the functions of T cells. Targeting methionine metabolism or YTHDF1 could be a potential new strategy for cancer immunotherapy.
    Keywords:  colorectal cancer; immunotherapy; methylation
    DOI:  https://doi.org/10.1136/gutjnl-2022-326928
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