bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2023‒05‒21
nine papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Nature. 2023 May 17.
      Cancer cells rewire metabolism to favour the generation of specialized metabolites that support tumour growth and reshape the tumour microenvironment1,2. Lysine functions as a biosynthetic molecule, energy source and antioxidant3-5, but little is known about its pathological role in cancer. Here we show that glioblastoma stem cells (GSCs) reprogram lysine catabolism through the upregulation of lysine transporter SLC7A2 and crotonyl-coenzyme A (crotonyl-CoA)-producing enzyme glutaryl-CoA dehydrogenase (GCDH) with downregulation of the crotonyl-CoA hydratase enoyl-CoA hydratase short chain 1 (ECHS1), leading to accumulation of intracellular crotonyl-CoA and histone H4 lysine crotonylation. A reduction in histone lysine crotonylation by either genetic manipulation or lysine restriction impaired tumour growth. In the nucleus, GCDH interacts with the crotonyltransferase CBP to promote histone lysine crotonylation. Loss of histone lysine crotonylation promotes immunogenic cytosolic double-stranded RNA (dsRNA) and dsDNA generation through enhanced H3K27ac, which stimulates the RNA sensor MDA5 and DNA sensor cyclic GMP-AMP synthase (cGAS) to boost type I interferon signalling, leading to compromised GSC tumorigenic potential and elevated CD8+ T cell infiltration. A lysine-restricted diet synergized with MYC inhibition or anti-PD-1 therapy to slow tumour growth. Collectively, GSCs co-opt lysine uptake and degradation to shunt the production of crotonyl-CoA, remodelling the chromatin landscape to evade interferon-induced intrinsic effects on GSC maintenance and extrinsic effects on immune response.
  2. Mol Cell. 2023 May 18. pii: S1097-2765(23)00284-8. [Epub ahead of print]83(10): 1549-1551
      Cell cycle and metabolism are intimately intertwined, but how metabolites directly regulate cell-cycle machinery remains elusive. Liu et al.1 reveal that glycolysis end-product lactate directly binds and inhibits the SUMO protease SENP1 to govern the E3 ligase activity of the anaphase-promoting complex, leading to efficient mitotic exit in proliferative cells.
  3. Endocr Relat Cancer. 2023 May 01. pii: ERC-22-0344. [Epub ahead of print]
      Anaplastic thyroid cancer (ATC) is a rare but fatal cancer with BRAF mutation ranging from 30%-50%. Histone lysine lactylation represents a novel epigenetic mark that translates cellular metabolic signals into transcriptional regulation. It is not clear whether the Warburg effect can promote the proliferation of ATC with BRAFV600E mutation via metabolite-mediated histone lactylation. Our study aimed at illustrating how BRAFV600E restructures cellular protein lactylation landscape to boost ATC proliferation, and determining whether blockade of protein lactylation can sensitize mutant ATC to BRAFV600E inhibitors. Western blotting was used to evaluate lactylation status. Aerobic glycolysis was intervened by adding cell-permeable ethyl lactate or using metabolic inhibitors. Chromatin immunoprecipitation and RT-QPCR were applied to analyze the expression of growth-related genes. Different chemical inhibitors were used to inhibit BRAFV600E and other enzymes. ATC cell line derived xenograft model was employed to examine the efficacy of mono and combinatorial therapies. The results showed that aerobic glycolysis in ATC increased global protein lactylation via improving cellular lactate availability. In particular, lactylation on Histone 4 Lysine 12 residue (H4K12La) activated the expression of multiple genes essential for ATC proliferation. Furthermore, oncogenic BRAFV600E boosted glycolytic flux to restructure the cellular lactylation landscape, leading to H4K12La-driven gene transcription and cell cycle deregulation. Accordingly, blockade of cellular lactylation machinery synergized with BRAFV600E inhibitor to impair ATC progression both in vitro and in vivo. Our results demonstrated an extra beneficial effect of aerobic glycolysis on ATC, revealing a novel metabolism-epigenetics axis suitable for combinatorial therapy with BRAFV600E inhibition.
  4. Liver Int. 2023 May 15.
      BACKGROUND AND AIMS: Steatosis is the early pathological change in alcohol-associated liver disease. However, its precise mechanism is still unclear. The present study is aimed to explore the role and mechanism of acetyl-CoA synthetase 2 (ACSS2) in acute alcohol-induced lipogenesis.METHODS: The increase in ACSS2 nuclear import and histone H3 acetylation were observed in mice after intraperitoneally injected with 2 g/kg ethanol or oral administration of 5 g/kg ethanol and also validated in hepatocytes stimulated with ethanol or acetate. The role of ACSS2 was further explored in liver-specific ACSS2 knockdown mice fed with ethanol-containing diet.
    RESULTS: Alcohol challenge induced hepatic lipid deposition and upregulated lipogenic genes in mice. It also promoted ACSS2 nuclear import and increased histone H3 acetylation. In hepatocytes, ethanol induced similar phenomena whereas ACSS2 knockdown blocked histone acetylation and lipogenic gene induction. P300/CBP associated factor (PCAF), but not general control nonderepressible 5, CREB-binding protein (CBP) and p300, facilitated H3K9 acetylation responding to ethanol challenge. CUT&RUN assay showed the enrichment of acetylated histone H3K9 surrounding Fasn and Acaca promoters. These results indicated that ethanol metabolism promoted ACSS2 nuclear import to support lipogenesis via H3K9 acetylation. In alcohol-feeding mice, liver-specific ACSS2 knockdown blocked the interaction between PCAF and H3K9 and suppressed lipogenic gene induction in the liver, demonstrating the critical role of ACSS2 in lipogenesis.
    CONCLUSIONS: Our study demonstrated that alcohol metabolism generated acetyl-CoA in the nucleus dependently on nuclear ACSS2, contributing to epigenetic regulation of lipogenesis in hepatic steatosis. Targeting ACSS2 may be a potential therapeutical strategy for acute alcoholic liver steatosis.
    Keywords:  ACSS2; PCAF; alcoholic liver steatosis; histone acetylation; lipogenesis
  5. Curr Protoc. 2023 May;3(5): e738
      Protein lysine acetylation refers to the covalent transfer of an acetyl moiety from acetyl coenzyme A to the epsilon-amino group of a lysine residue and is critical for regulating protein functions in almost all living cells or organisms. Studies in the past decade have demonstrated the unexpected finding that acetylation-like acylation, such as succinylation, propionylation, butyrylation, crotonylation, and lactylation, is also present in histones and many non-histone proteins. Acetylation and acetylation-like acylation serve as reversible on/off switches for regulating protein function while interplaying with other post-translational modifications (such as phosphorylation and methylation) in a codified manner. Lysine acetylation and acetylation-like acylation are important for regulating different cellular and developmental processes in normal and pathological states. Thus, the detection of such modifications is important for related basic research and molecular diagnostics. Traditionally, lysine acetylation is detected by autoradiography, but recent decades have seen great improvement in the quality of site-specific antibodies against acetylation (or acetylation-like acylation), thereby providing competitive alternatives to the use of radioactive acetate and acetyl-coenzyme A for in vivo and in vitro labeling, respectively. This article describes protocols for the detection of lysine acetylation and acetylation-like acylation with site-specific antibodies to complement extant autoradiography-based methods (Pelletier et al., 2017). © 2023 Wiley Periodicals LLC. Basic Protocol 1: Acylation assays in vitro Basic Protocol 2: Determination of in vivo acylation.
    Keywords:  acetyltransferase; acylation; acyltransferase; butyrylation; crotonylation; lactylation; lysine acetylation; propionylation; succinylation
  6. Nat Struct Mol Biol. 2023 May 18.
      The transmission and maintenance of genetic information in eukaryotic cells relies on the faithful duplication of the entire genome. In each round of division, excessive replication origins are licensed, with only a fraction activated to give rise to bi-directional replication forks in the context of chromatin. However, it remains elusive how eukaryotic replication origins are selectively activated. Here we demonstrate that O-GlcNAc transferase (OGT) enhances replication initiation by catalyzing H4S47 O-GlcNAcylation. Mutation of H4S47 impairs DBF4-dependent protein kinase (DDK) recruitment on chromatin, causing reduced phosphorylation of the replicative helicase mini-chromosome maintenance (MCM) complex and compromised DNA unwinding. Our short nascent-strand sequencing results further confirm the importance of H4S47 O-GlcNAcylation in origin activation. We propose that H4S47 O-GlcNAcylation directs origin activation through facilitating MCM phosphorylation, and this may shed light on the control of replication efficiency by chromatin environment.
  7. Epigenomics. 2023 May 17.
    Keywords:  DNA methylation; cancer epigenetics; environmental epigenomics; epigenetic effects; epigenetic gene regulation; epigenetics and disease; gene expression; molecular epigenetics
  8. J Trace Elem Med Biol. 2023 May 15. pii: S0946-672X(23)00079-2. [Epub ahead of print]78 127203
      Iron deficiency is a common micronutrient deficiency associated with metabolic changes in the levels of iron regulatory proteins, hepcidin and ferroportin. Studies have associated dysregulation of iron homeostasis to other secondary and life-threatening diseases including anaemia, neurodegeneration and metabolic diseases. Iron deficiency plays a critical role in epigenetic regulation by affecting the Fe2+/α-ketoglutarate-dependent demethylating enzymes, Ten Eleven Translocase 1-3 (TET 1-3) and Jumonji-C (JmjC) histone demethylase, which are involved in epigenetic erasure of the methylation marks on both DNA and histone tails, respectively. In this review, studies involving epigenetic effects of iron deficiency associated with dysregulation of TET 1-3 and JmjC histone demethylase enzyme activities on hepcidin/ferroportin axis are discussed.
    Keywords:  Epigenetics; Ferroportin; Hepcidin; Iron deficiency; Iron homeostasis; JmjC histone demethylase; Ten eleven translocase