bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒02‒14
eight papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine
  1. Physiological interrelationships between NADPH oxidases and Chromatin remodelling.
  2. BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells.
  3. The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.
  4. Sensing and Signaling of Methionine Metabolism.
  5. Aberrant gene expression induced by a high fat diet is linked to H3K9 acetylation in the promoter-proximal region.
  6. Metabolic Control of m6A RNA Modification.
  7. Dietary betaine prevents obesity through gut microbiota-drived microRNA-378a family.
  8. Sirt5 Deficiency Causes Posttranslational Protein Malonylation and Dysregulated Cellular Metabolism in Chondrocytes Under Obesity Conditions.
  1. Free Radic Biol Med. 2021 Feb 05. pii: S0891-5849(21)00069-1. [Epub ahead of print]
    Physiological interrelationships between NADPH oxidases and Chromatin remodelling.
    Alison C Brewer.
      The epigenetic landscape describes the chromatin structure of the eukaryotic genome and is therefore the major determinant of gene transcription and hence cellular phenotype. The molecular processes which act to shape the epigenetic landscape through cellular differentiation are thus central to cellular determination and specification. In addition, cellular adaptation to (patho)-physiological stress requires dynamic and reversible chromatin remodelling. It is becoming clear that redox-dependent molecular mechanisms are important determinants of this epigenetic regulation. NADPH oxidases generate reactive oxygen species (ROS) to activate redox-dependent signalling pathways in response to extracellular and intracellular environmental cues. This mini review aims to summarise the current knowledge of the role of NADPH oxidases in redox-dependent chromatin remodelling, and how epigenetic changes might feedback and impact upon the transcriptional expression of these ROS-producing enzymes themselves. The potential physiological significance of this relationship in the control of cellular differentiation and homeostasis by Nox4, specifically, is discussed.
    Keywords:  DNA methylation; Epigenetics; Histone acetylation; Histone methylation; Nox4; One-carbon metabolism; Redox regulation
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.01.052
  2. Nat Immunol. 2021 Feb 11.
    BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells.
    Chen Yao, Guohua Lou, Hong-Wei Sun, Ziang Zhu, Yi Sun, Zeyu Chen, Daniel Chauss, E Ashley Moseman, Jun Cheng, Marc A D'Antonio, Wangke Shi, Junwei Shi, Kohei Kometani, Tomohiro Kurosaki, E John Wherry, Behdad Afzali, Luca Gattinoni, Yuwen Zhu, Dorian B McGavern, John J O'Shea, Pamela L Schwartzberg, Tuoqi Wu.
      During chronic infection and cancer, a self-renewing CD8+ T cell subset maintains long-term immunity and is critical to the effectiveness of immunotherapy. These stem-like CD8+ T cells diverge from other CD8+ subsets early after chronic viral infection. However, pathways guarding stem-like CD8+ T cells against terminal exhaustion remain unclear. Here, we show that the gene encoding transcriptional repressor BACH2 is transcriptionally and epigenetically active in stem-like CD8+ T cells but not terminally exhausted cells early after infection. BACH2 overexpression enforced stem-like cell fate, whereas BACH2 deficiency impaired stem-like CD8+ T cell differentiation. Single-cell transcriptomic and epigenomic approaches revealed that BACH2 established the transcriptional and epigenetic programs of stem-like CD8+ T cells. In addition, BACH2 suppressed the molecular program driving terminal exhaustion through transcriptional repression and epigenetic silencing. Thus, our study reveals a new pathway that enforces commitment to stem-like CD8+ lineage and prevents an alternative terminally exhausted cell fate.
    DOI:  https://doi.org/10.1038/s41590-021-00868-7
  3. Nat Cancer. 2020 ;1 653-664
    The serine hydroxymethyltransferase-2 (SHMT2) initiates lymphoma development through epigenetic tumor suppressor silencing.
    Sara Parsa, Ana Ortega-Molina, Hsia-Yuan Ying, Man Jiang, Matt Teater, Jiahui Wang, Chunying Zhao, Ed Reznik, Joyce P Pasion, David Kuo, Prathibha Mohan, Shenqiu Wang, Jeannie M Camarillo, Paul M Thomas, Neeraj Jain, Javier Garcia-Bermudez, Byoung-Kyu Cho, Wayne Tam, Neil L Kelleher, Nicholas Socci, Ahmet Dogan, Elisa De Stanchina, Giovanni Ciriello, Michael R Green, Sheng Li, Kivanc Birsoy, Ari M Melnick, Hans-Guido Wendel.
      Cancer cells adapt their metabolic activities to support growth and proliferation. However, increased activity of metabolic enzymes is not usually considered an initiating event in the malignant process. Here, we investigate the possible role of the enzyme serine hydroxymethyltransferase-2 (SHMT2) in lymphoma initiation. SHMT2 localizes to the most frequent region of copy number gains at chromosome 12q14.1 in lymphoma. Elevated expression of SHMT2 cooperates with BCL2 in lymphoma development; loss or inhibition of SHMT2 impairs lymphoma cell survival. SHMT2 catalyzes the conversion of serine to glycine and produces an activated one-carbon unit that can be used to support S-adenosyl methionine synthesis. SHMT2 induces changes in DNA and histone methylation patterns leading to promoter silencing of previously uncharacterized mutational genes, such as SASH1 and PTPRM. Together, our findings reveal that amplification of SHMT2 in cooperation with BCL2 is sufficient in the initiation of lymphomagenesis through epigenetic tumor suppressor silencing.
    DOI:  https://doi.org/10.1038/s43018-020-0080-0
  4. Metabolites. 2021 Jan 31. pii: 83. [Epub ahead of print]11(2):
    Sensing and Signaling of Methionine Metabolism.
    Linda Lauinger, Peter Kaiser.
      Availability of the amino acid methionine shows remarkable effects on the physiology of individual cells and whole organisms. For example, most cancer cells, but not normal cells, are hyper dependent on high flux through metabolic pathways connected to methionine, and diets restricted for methionine increase healthy lifespan in model organisms. Methionine's impact on physiology goes beyond its role in initiation of translation and incorporation in proteins. Many of its metabolites have a major influence on cellular functions including epigenetic regulation, maintenance of redox balance, polyamine synthesis, and phospholipid homeostasis. As a central component of such essential pathways, cells require mechanisms to sense methionine availability. When methionine levels are low, cellular response programs induce transcriptional and signaling states to remodel metabolic programs and maintain methionine metabolism. In addition, an evolutionary conserved cell cycle arrest is induced to ensure cellular and genomic integrity during methionine starvation conditions. Methionine and its metabolites are critical for cell growth, proliferation, and development in all organisms. However, mechanisms of methionine perception are diverse. Here we review current knowledge about mechanisms of methionine sensing in yeast and mammalian cells, and will discuss the impact of methionine imbalance on cancer and aging.
    Keywords:  S-adenosylmethionine; aging; cancer; cell cycle; methionine; methionine/SAM sensing
    DOI:  https://doi.org/10.3390/metabo11020083
  5. Biochim Biophys Acta Gene Regul Mech. 2021 Feb 05. pii: S1874-9399(21)00008-0. [Epub ahead of print] 194691
    Aberrant gene expression induced by a high fat diet is linked to H3K9 acetylation in the promoter-proximal region.
    Núria Morral, Sheng Liu, Abass M Conteh, Xiaona Chu, Yue Wang, X Charlie Dong, Yunlong Liu, Amelia K Linnemann, Jun Wan.
      Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease, with an estimated global prevalence of 1 in 4 individuals. Aberrant transcriptional control of gene expression is central to the pathophysiology of metabolic diseases. However, the molecular mechanisms leading to gene dysregulation are not well understood. Histone modifications play important roles in the control of transcription. Acetylation of histone 3 at lysine 9 (H3K9ac) is associated with transcriptional activity and is implicated in transcript elongation by controlling RNA polymerase II (RNAPII) pause-release. Hence, changes in this histone modification may shed information on novel pathways linking transcription control and metabolic dysfunction. Here, we carried out genome-wide analysis of H3K9ac in the liver of mice fed a control or a high-fat diet (an animal model of NAFLD), and asked whether this histone mark associates with changes in gene expression. We found that over 70% of RNAPII peaks in promoter-proximal regions overlapped with H3K9ac, consistent with a role of H3K9ac in the regulation of transcription. When comparing high-fat with control diet, approximately 17% of the differentially expressed genes were associated with changes in H3K9ac in their promoters, showing a strong correlation between changes in H3K9ac signal and gene expression. Overall, our data indicate that in response to a high-fat diet, dysregulated gene expression of a subset of genes may be attributable to changes in transcription elongation driven by H3K9ac. Our results point at an added mechanism of gene regulation that may be important in the development of metabolic diseases.
    Keywords:  gene regulation; high-fat diet; histone acetylation; liver; non-alcoholic fatty liver disease
    DOI:  https://doi.org/10.1016/j.bbagrm.2021.194691
  6. Metabolites. 2021 Jan 30. pii: 80. [Epub ahead of print]11(2):
    Metabolic Control of m6A RNA Modification.
    Joohwan Kim, Gina Lee.
      Nutrients and metabolic pathways regulate cell growth and cell fate decisions via epigenetic modification of DNA and histones. Another key genetic material, RNA, also contains diverse chemical modifications. Among these, N6-methyladenosine (m6A) is the most prevalent and evolutionarily conserved RNA modification. It functions in various aspects of developmental and disease states, by controlling RNA metabolism, such as stability and translation. Similar to other epigenetic processes, m6A modification is regulated by specific enzymes, including writers (methyltransferases), erasers (demethylases), and readers (m6A-binding proteins). As this is a reversible enzymatic process, metabolites can directly influence the flux of this reaction by serving as substrates and/or allosteric regulators. In this review, we will discuss recent understanding of the regulation of m6A RNA modification by metabolites, nutrients, and cellular metabolic pathways.
    Keywords:  N6-methyladenosine; RNA chemical modification; RNA epitranscriptome; RNA methylation; m6A; metabolic pathways; metabolites; nutrient signaling
    DOI:  https://doi.org/10.3390/metabo11020080
  7. Gut Microbes. 2021 Jan-Dec;13(1):13(1): 1-19
    Dietary betaine prevents obesity through gut microbiota-drived microRNA-378a family.
    Jingjing Du, Peiwen Zhang, Jiang Luo, Linyuan Shen, Shunhua Zhang, Hao Gu, Jin He, Linghui Wang, Xue Zhao, Mailing Gan, Liu Yang, Lili Niu, Ye Zhao, Qianzi Tang, Guoqing Tang, Dongmei Jiang, Yanzhi Jiang, Mingzhou Li, Anan Jiang, Long Jin, Jideng Ma, Surong Shuai, Lin Bai, Jinyong Wang, Bo Zeng, De Wu, Xuewei Li, Li Zhu.
      Betaine is a natural compound present in commonly consumed foods and may have a potential role in the regulation of glucose and lipids metabolism. However, the underlying molecular mechanism of its action remains largely unknown. Here, we show that supplementation with betaine contributes to improved high-fat diet (HFD)-induced gut microbiota dysbiosis and increases anti-obesity strains such as Akkermansia muciniphila, Lactobacillus, and Bifidobacterium. In mice lacking gut microbiota, the functional role of betaine in preventing HFD-induced obesity, metabolic syndrome, and inactivation of brown adipose tissues are significantly reduced. Akkermansia muciniphila is an important regulator of betaine in improving microbiome ecology and increasing strains that produce short-chain fatty acids (SCFAs). Increasing two main members of SCFAs including acetate and butyrate can significantly regulate the levels of DNA methylation at host miR-378a promoter, thus preventing the development of obesity and glucose intolerance. However, these beneficial effects are partially abolished by Yin yang (YY1), a common target gene of the miR-378a family. Taken together, our findings demonstrate that betaine can improve obesity and associated MS via the gut microbiota-derived miR-378a/YY1 regulatory axis, and reveal a novel mechanism by which gut microbiota improve host health.
    Keywords:  Betaine; SCFA; gut microbiota; microRNA; obesity
    DOI:  https://doi.org/10.1080/19490976.2020.1862612
  8. Cartilage. 2021 Feb 11. 1947603521993209
    Sirt5 Deficiency Causes Posttranslational Protein Malonylation and Dysregulated Cellular Metabolism in Chondrocytes Under Obesity Conditions.
    Shouan Zhu, Albert Batushansky, Anita Jopkiewicz, Dawid Makosa, Kenneth M Humphries, Holly Van Remmen, Timothy M Griffin.
      OBJECTIVE: Obesity accelerates the development of osteoarthritis (OA) during aging and is associated with altered chondrocyte cellular metabolism. Protein lysine malonylation (MaK) is a posttranslational modification (PTM) that has been shown to play an important role during aging and obesity. The objective of this study was to investigate the role of sirtuin 5 (Sirt5) in regulating MaK and cellular metabolism in chondrocytes under obesity-related conditions.METHODS: MaK and SIRT5 were immunostained in knee articular cartilage of obese db/db mice and different aged C57BL6 mice with or without destabilization of the medial meniscus surgery to induce OA. Primary chondrocytes were isolated from 7-day-old WT and Sirt5-/- mice and treated with varying concentrations of glucose and insulin to mimic obesity. Sirt5-dependent effects on MaK and metabolism were evaluated by western blot, Seahorse Respirometry, and gas/chromatography-mass/spectrometry (GC-MS) metabolic profiling.
    RESULTS: MaK was significantly increased in cartilage of db/db mice and in chondrocytes treated with high concentrations of glucose and insulin (GluhiInshi). Sirt5 was increased in an age-dependent manner following joint injury, and Sirt5 deficient primary chondrocytes had increased MaK, decreased glycolysis rate, and reduced basal mitochondrial respiration. GC-MS identified 41 metabolites. Sirt5 deficiency altered 13 distinct metabolites under basal conditions and 18 metabolites under GluhiInshi treatment. Pathway analysis identified a wide range of Sirt5-dependent altered metabolic pathways that include amino acid metabolism, TCA cycle, and glycolysis.
    CONCLUSION: This study provides the first evidence that Sirt5 broadly regulates chondrocyte metabolism. We observed changes in SIRT5 and MaK levels in cartilage with obesity and joint injury, suggesting that the Sirt5-MaK pathway may contribute to altered chondrocyte metabolism that occurs during OA development.
    Keywords:  chondrocyte; lysine malonylation; metabolism; osteoarthritis; sirtuin 5
    DOI:  https://doi.org/10.1177/1947603521993209
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