bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2022‒01‒30
eight papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Sex Dev. 2022 Jan 27. 1-16
      BACKGROUND: The germ cell lineage involves dynamic epigenetic changes during its formation and differentiation that are completely different from those of the somatic cell lineage. Metabolites and metabolic pathways have been reported as key factors related to the regulation of epigenetics as cofactors and substrates. However, our knowledge about the metabolic characteristics of germ cells, especially during the fetal stage, and their transition during differentiation is quite limited due to the rarity of the cells. Nevertheless, recent developments in omics technologies have made it possible to extract comprehensive metabolomic features of germ cells.SUMMARY: In this review, we present the latest researches on the metabolic properties of germ cells in 4 stages: primordial germ cell specification, fetal germ cell differentiation, spermatogenesis, and oogenesis. At every stage, extensive published data has been accumulated on energy metabolism, and it is possible to describe its changes during germ cell differentiation in detail. As pluripotent stem cells differentiate into germ cells, energy metabolism shifts from glycolysis to oxidative phosphorylation; however, in spermatogenesis, glycolytic pathways are also temporarily dominant in spermatogonial stem cells. Although the significance of metabolic pathways other than energy metabolism in germ cell differentiation is largely unknown, the relation of the pentose phosphate pathway and Ser-Gly-one-carbon metabolism with germ cell properties has been suggested at various stages. We further discuss the relationship between these characteristic metabolic pathways and epigenetic regulation during germ cell specification and differentiation. Finally, the relevance of dietary and supplemental interventions on germ cell function and epigenomic regulation is also discussed. Key Messages: Comprehensive elucidation of metabolic features and metabolism-epigenome crosstalk in germ cells is important to reveal how the characteristic metabolic pathways are involved in the germ cell regulation. The accumulation of such insights would lead to suggestions for optimal diets and supplements to maintain reproductive health through modulating metabolic and epigenetic status of germ cells.
    Keywords:  Development; Differentiation; Epigenome; Germ cells; Metabolism
  2. Nat Metab. 2022 Jan 24.
      The link between branched-chain amino acids (BCAAs) and obesity has been known for decades but the functional role of BCAA metabolism in white adipose tissue (WAT) of obese individuals remains vague. Here, we show that mice with adipose tissue knockout of Bcat2, which converts BCAAs to branched-chain keto acids (BCKAs), are resistant to high-fat diet-induced obesity due to increased inguinal WAT browning and thermogenesis. Mechanistically, acetyl-CoA derived from BCKA suppresses WAT browning by acetylation of PR domain-containing protein 16 (PRDM16) at K915, disrupting the interaction between PRDM16 and peroxisome proliferator-activated receptor-γ (PPARγ) to maintain WAT characteristics. Depletion of BCKA-derived acetyl-CoA robustly prompts WAT browning and energy expenditure. In contrast, BCKA supplementation re-establishes high-fat diet-induced obesity in Bcat2 knockout mice. Moreover, telmisartan, an anti-hypertension drug, significantly represses Bcat2 activity via direct binding, resulting in enhanced WAT browning and reduced adiposity. Strikingly, BCKA supplementation reverses the lean phenotype conferred by telmisartan. Thus, we uncover the critical role of the BCAA-BCKA axis in WAT browning.
  3. J Proteomics. 2022 Jan 19. pii: S1874-3919(22)00011-2. [Epub ahead of print] 104488
      Lysine crotonylation (Kcr) is a newly discovered post-translational modification, which is structurally and functionally different from the widely studied lysine acetylation. Kcr is found on histones and non-histone proteins, participating in many biological processes through the regulation of chromatin remodeling, metabolism, cell cycle and cellular organization. Among plants, Kcr in histones is not found in the same lysine residues but increases gene expression when it is co-localized with lysine acetylation. Kcr in non-histone proteins is mainly found in the chloroplast, which provides new insight into photosynthesis. In this review, we discuss recent findings on plant Kcr in histone and non-histone proteins, highlighting its biological implications. These findings not only point to new functions for Kcr, but also reveal the mechanisms by which crotonylation regulates cellular processes in plants and may even change the general direction of epigenome and plant regulation.
    Keywords:  Amino acids; Chloroplast; Epigenetic; Histones; Lysine modifications; Photosynthesis
  4. Front Med (Lausanne). 2021 ;8 770504
      Metabolic-associated fatty liver disease (MAFLD) is characterized by hepatic steatosis accompanied by one of three features: overweight or obesity, T2DM, or lean or normal weight with evidence of metabolic dysregulation. It is distinguished by excessive fat accumulation in hepatocytes, and a decrease in the liver's ability to oxidize fats, the accumulation of ectopic fat, and the activation of proinflammatory pathways. Chronic damage will keep this pathophysiologic cycle active causing progression from hepatic steatosis to cirrhosis and eventually, hepatocarcinoma. Epigenetics affecting gene expression without altering DNA sequence allows us to study MAFLD pathophysiology from a different perspective, in which DNA methylation processes, histone modifications, and miRNAs expression have been closely associated with MAFLD progression. However, these considerations also faced us with the circumstance that modifying those epigenetics patterns might lead to MAFLD regression. Currently, epigenetics is an area of great interest because it could provide new insights in therapeutic targets and non-invasive biomarkers. This review comprises an update on the role of epigenetic patterns, as well as innovative therapeutic targets and biomarkers in MAFLD.
    Keywords:  DNA methylation; MAFLD; NASH; histone modification; miRNAs
  5. Nutr Res Rev. 2022 Jan 24. 1-33
      Early-life malnutrition plays a critical role in fetal development and predispose to the appearance of metabolic diseases in later life, according to the concept of 'developmental programming'. Different types of early nutritional imbalances, including undernutrition, overnutrition or micronutrient deficiency have been related to long-term metabolic disorders. Accumulating evidence has demonstrated that disturbances in nutrition during the period of preconception, pregnancy and primary infancy can affect mitochondrial function and epigenetic mechanisms. Moreover, even though multiple mechanisms underlying non-alcoholic fatty liver disease (NAFLD) have been described, in the last years special attention has been given to mitochondrial dysfunction and epigenetic alterations. Mitochondria play a key role in cellular metabolic functions. Dysfunctional mitochondria contribute to oxidative stress, insulin resistance and inflammation. Epigenetic mechanisms have been related to alterations in genes involved in lipid metabolism, fibrogenesis, inflammation and tumorigenesis. In accordance, studies have reported that mitochondrial dysfunction and epigenetics linked to early-life nutrition can be important contributing factors in the pathogenesis of NAFLD. In this review, we summarize the current understanding of the interplay between mitochondrial dysfunction, epigenetics and nutrition during early life, which is relevant to developmental programming of NAFLD.
    Keywords:  Developmental programming; Early-life nutrition; Epigenetics; Mitochondria; NAFLD
  6. Proteomics. 2022 Jan 27. e2100175
      Protein O-GlcNAcylation is a specific form of protein glycosylation that targets a wide range of proteins with important functions. O-GlcNAcylation is known to be deregulated in cancer and has been linked to multiple aspects of cancer pathology. Despite its ubiquity and importance, the current understanding of the role of O-GlcNAcylation in the stress response remains limited. In this study, we performed a quantitative chemical proteomics-based open study of the O-GlcNAcome in HeLa cells, and identified 163 differentially-glycosylated proteins under starvation, involving multiple metabolic pathways. Among them, fatty acid metabolism was found to be targeted and subsequent analysis confirmed that fatty acid synthase (FASN) is O-GlcNAcylated. O-GlcNAcylation led to enhanced de novo fatty acid synthesis activity, and fatty acids contributed to the cytoprotective effects of O-GlcNAcylation under starvation. Moreover, dual inhibition of O-GlcNAcylation and FASN displayed a strong synergistic effect in vitro in inducing cell death in cancer cells. Together, the results from this study provide novel insights into the role of O-GlcNAcylation in the nutritional stress response and suggest the potential of combining inhibition of O-GlcNAcylation and fatty acid synthesis in cancer therapy. This article is protected by copyright. All rights reserved.
    Keywords:  FASN; LC-MS/MS; O-GlcNAc; iTRAQ; metabolic labelling
  7. Front Cell Dev Biol. 2021 ;9 805195
      B-cell non-Hodgkin lymphomas (B-NHLs) are highly heterogenous by genetic, phenotypic, and clinical appearance. Next-generation sequencing technologies and multi-dimensional data analyses have further refined the way these diseases can be more precisely classified by specific genomic, epigenomic, and transcriptomic characteristics. The molecular and genetic heterogeneity of B-NHLs may contribute to the poor outcome of some of these diseases, suggesting that more personalized precision-medicine approaches are needed for improved therapeutic efficacy. The germinal center (GC) B-cell like diffuse large B-cell lymphomas (GCB-DLBCLs) and follicular lymphomas (FLs) share specific epigenetic programs. These diseases often remain difficult to treat and surprisingly do not respond advanced immunotherapies, despite arising in secondary lymphoid organs at sites of antigen recognition. Epigenetic dysregulation is a hallmark of GCB-DLBCLs and FLs, with gain-of-function (GOF) mutations in the histone methyltransferase EZH2, loss-of-function (LOF) mutations in histone acetyl transferases CREBBP and EP300, and the histone methyltransferase KMT2D representing the most prevalent genetic lesions driving these diseases. These mutations have the common effect to disrupt the interactions between lymphoma cells and the immune microenvironment, via decreased antigen presentation and responsiveness to IFN-γ and CD40 signaling pathways. This indicates that immune evasion is a key step in GC B-cell lymphomagenesis. EZH2 inhibitors are now approved for the treatment of FL and selective HDAC3 inhibitors counteracting the effects of CREBBP LOF mutations are under development. These treatments can help restore the immune control of GCB lymphomas, and may represent optimal candidate agents for more effective combination with immunotherapies. Here, we review recent progress in understanding the impact of mutant chromatin modifiers on immune evasion in GCB lymphomas. We provide new insights on how the epigenetic program of these diseases may be regulated at the level of metabolism, discussing the role of metabolic intermediates as cofactors of epigenetic enzymes. In addition, lymphoma metabolic adaptation can negatively influence the immune microenvironment, further contributing to the development of immune cold tumors, poorly infiltrated by effector immune cells. Based on these findings, we discuss relevant candidate epigenetic/metabolic/immune targets for rational combination therapies to investigate as more effective precision-medicine approaches for GCB lymphomas.
    Keywords:  GCB-DLBCLs; combination therapies; epigenetics; immune microenvironment; metabolic intermediates
  8. J Neurophysiol. 2022 Jan 26.
      Biological principles sustain the inference that synaptic function is coupled to neural metabolism, but the precise relationship between these two activities is not known. For example, it is unclear whether all synaptic transmission events are uniformly dependent on metabolic flux. Most synapses utilize glutamate and the principal metabolic function of the brain is glucose oxidation, which starts with glycolysis. Thus, we asked how glutamatergic synaptic currents are modified by partial deficiency of the main glycolytic enzyme pyruvate dehydrogenase (PDH), which generates the intermediary metabolism product acetyl coenzyme A (acetyl-CoA). Using brain slices obtained from mice genetically modified to harbor a behaviorally relevant degree of PDH suppression, we also asked whether such impact is indeed metabolic via the bypassing of PDH with a glycolysis-independent acetyl-CoA substrate. We analyzed spontaneous synaptic currents under recording that minimize artificial metabolic augmentation. Principal component analysis identified synaptic charge transfer as the major difference between a subset of wild type and PDH-deficient (PDHD) postsynaptic currents. This was due to reduced charge transfer as well as diminished current rise and decay times. The alternate acetyl-CoA source acetate rapidly restored these features but only for events of large amplitude as revealed by correlational and kernel density analyses. Application of tetrodotoxin to block large-amplitude events evoked by action potentials removed synaptic event charge transfer and decay-time differences between wild type and PDHD neurons. These results suggest that glucose metabolic flux and excitatory transmission are intimately coupled for synaptic events characterized by large current amplitude.
    Keywords:  Inhibitory; Metabolism; Synapse