bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2020‒08‒30
six papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Biochim Biophys Acta Gene Regul Mech. 2020 Aug 19. pii: S1874-9399(20)30209-1. [Epub ahead of print] 194626
    Mutlu B, Puigserver P.
      General Control Non-repressed 5 protein (GCN5), encoded by the mammalian gene Kat2a, is the first histone acetyltransferase discovered to link histone acetylation to transcriptional activation [1]. The enzymatic activity of GCN5 is linked to cellular metabolic and energetic states regulating gene expression programs. GCN5 has a major impact on energy metabolism by i) sensing acetyl-CoA, a central metabolite and substrate of the GCN5 catalytic reaction, and ii) acetylating proteins such as PGC-1α, a transcriptional coactivator that controls genes linked to energy metabolism and mitochondrial biogenesis. PGC-1α is biochemically associated with the GCN5 protein complex during active metabolic reprogramming. In the first part of the review, we examine how metabolism can change GCN5-dependent histone acetylation to regulate gene expression to adapt cells. In the second part, we summarize the GCN5 function as a nutrient sensor, focusing on non-histone protein acetylation, mainly the metabolic role of PGC-1α acetylation across different tissues.
    Keywords:  GCN5; PGC-1α; acetyl-CoA; acetylation; glucose homeostasis; metabolism; mitochondria
  2. Nat Metab. 2020 Aug 24.
    Li L, Chen K, Wang T, Wu Y, Xing G, Chen M, Hao Z, Zhang C, Zhang J, Ma B, Liu Z, Yuan H, Liu Z, Long Q, Zhou Y, Qi J, Zhao D, Gao M, Pei D, Nie J, Ye D, Pan G, Liu X.
      Somatic cell reprogramming provides insight into basic principles of cell fate determination, which remain poorly understood. Here we show that the transcription factor Glis1 induces multi-level epigenetic and metabolic remodelling in stem cells that facilitates the induction of pluripotency. We find that Glis1 enables reprogramming of senescent cells into pluripotent cells and improves genome stability. During early phases of reprogramming, Glis1 directly binds to and opens chromatin at glycolytic genes, whereas it closes chromatin at somatic genes to upregulate glycolysis. Subsequently, higher glycolytic flux enhances cellular acetyl-CoA and lactate levels, thereby enhancing acetylation (H3K27Ac) and lactylation (H3K18la) at so-called 'second-wave' and pluripotency gene loci, opening them up to facilitate cellular reprogramming. Our work highlights Glis1 as a powerful reprogramming factor, and reveals an epigenome-metabolome-epigenome signalling cascade that involves the glycolysis-driven coordination of histone acetylation and lactylation in the context of cell fate determination.
  3. Front Physiol. 2020 ;11 949
    Tian H, Liu S, Ren J, Lee JKW, Wang R, Chen P.
      Skeletal muscle is the largest metabolic organ in the human body and is able to rapidly adapt to drastic changes during exercise. Histone acetyltransferases (HATs) and histone deacetylases (HDACs), which target histone and non-histone proteins, are two major enzyme families that control the biological process of histone acetylation and deacetylation. Balance between these two enzymes serves as an essential element for gene expression and metabolic and physiological function. Genetic KO/TG murine models reveal that HDACs possess pivotal roles in maintaining skeletal muscles' metabolic homeostasis, regulating skeletal muscles motor adaptation and exercise capacity. HDACs may be involved in mitochondrial remodeling, insulin sensitivity regulation, turn on/off of metabolic fuel switching and orchestrating physiological homeostasis of skeletal muscles from the process of myogenesis. Moreover, many myogenic factors and metabolic factors are modulated by HDACs. HDACs are considered as therapeutic targets in clinical research for treatment of cancer, inflammation, and neurological and metabolic-related diseases. This review will focus on physiological function of HDACs in skeletal muscles and provide new ideas for the treatment of metabolic diseases.
    Keywords:  exercise capacity; histone deacetylases; metabolism; muscle physiology; skeletal muscle
  4. Antioxid Redox Signal. 2020 Aug 26.
    Ludikhuize MC, Rodríguez Colman MJ.
      Significance Stem cell activation and differentiation occur along changes in cellular metabolism. Metabolic transitions translate into changes in redox balance, cell signalling and epigenetics, thereby regulating these processes. Metabolic transitions are key regulators of cell fate and exemplify the moonlighting nature of many metabolic enzymes and their associated metabolites. Recent advances Forkhead Box O transcription factors (FOXOs) are bona fide regulators of cellular homeostasis. FOXOs are multi-tasking proteins able to regulate cell cycle, cellular metabolism and redox state. Recent and ongoing research pose FOXOs as key factors in stem cell maintenance and differentiation in several tissues. Critical issues The multi-tasking nature of FOXOs and their tissue specific expression patterns hinders to disclose a possible conserved mechanism of regulation of stem cell maintenance and differentiation. Moreover, cellular metabolism, cell signalling and epigenetics establish complex regulatory interactions, which challenges the establishment of the causal-temporal nature of metabolic changes and stem cell activation and differentiation. Future directions The development of single cell technologies and in vitro models able to reproduce the dynamics of stem cell differentiation, are actively contributing to define the role of metabolism in this process. This knowledge is key to understanding and designing therapies for those pathologies where the balance between proliferation and differentiation is lost. Importantly, metabolic interventions could be applied to optimize stem cell cultures meant for therapeutical applications, such as transplantations to treat autoimmune and degenerative disorders.
  5. Front Cell Dev Biol. 2020 ;8 760
    Lai X, Li Q, Wu F, Lin J, Chen J, Zheng H, Guo L.
      Epithelial-mesenchymal transition (EMT) and its critical roles during cancer progression have long been recognized and extensively reviewed. Recent studies on the generation of induced pluripotent stem cells (iPSCs) have established the connections among EMT, energy metabolism, DNA methylation, and histone modification. Since energy metabolism, DNA methylation, and histone modification are important for cancer development and there are common characteristics between cancer cells and stem cells, it is reasonable to identify mechanisms that have been established during both reprogramming and cancer progression. In the current review, we start from a brief review on EMT and related processes during cancer progression, and then switch to the EMT during somatic cell reprogramming. We summarize the connection between EMT and metabolic switch during reprogramming, and further review the involvements of DNA methylation and cell proliferation. The connections between EMT and mesenchymal-epithelial transition (MET) and cellular aspects including DNA methylation, histone modification and energy metabolism may provide potential new targets for cancer diagnosis and treatment.
    Keywords:  EMT; OXPHOS; cancer; energy metabolism; glycolysis; reprogramming
  6. Cells. 2020 Aug 26. pii: E1968. [Epub ahead of print]9(9):
    Scumaci D, Olivo E, Fiumara CV, La Chimia M, De Angelis MT, Mauro S, Costa G, Ambrosio FA, Alcaro S, Agosti V, Costanzo FS, Cuda G.
      Enhanced glycolysis is a hallmark of breast cancer. In cancer cells, the high glycolytic flux induces carbonyl stress, a damaging condition in which the increase of reactive carbonyl species makes DNA, proteins, and lipids more susceptible to glycation. Together with glucose, methylglyoxal (MGO), a byproduct of glycolysis, is considered the main glycating agent. MGO is highly diffusible, enters the nucleus, and can react with easily accessible lysine- and arginine-rich tails of histones. Glycation adducts on histones undergo oxidization and further rearrange to form stable species known as advanced glycation end-products (AGEs). This modification alters nucleosomes stability and chromatin architecture deconstructing the histone code. Formation of AGEs has been associated with cancer, diabetes, and several age-related diseases. Recently, DJ-1, a cancer-associated protein that protects cells from oxidative stress, has been described as a deglycase enzyme. Although its role in cell survival results still controversial, in several human tumors, its expression, localization, oxidation, and phosphorylation were found altered. This work aimed to explore the molecular mechanism that triggers the peculiar cellular compartmentalization and the specific post-translational modifications (PTM) that, occurring in breast cancer cells, influences the DJ-1 dual role. Using a proteomic approach, we identified on DJ-1 a novel threonine phosphorylation (T125) that was found, by the in-silico tool scansite 4, as part of a putative Akt consensus. Notably, this threonine is in addition to histidine 126, a key residue involved in the formation of catalytic triade (glu18-Cys106-His126) inside the glioxalase active site of DJ. Interestingly, we found that pharmacological modulation of Akt pathway induces a functional tuning of DJ-1 proteoforms, as well as their shuttle from cytosol to nucleus, pointing out that pathway as critical in the development of DJ-1 pro-tumorigenic abilities. Deglycase activity of DJ-1 on histones proteins, investigated by coupling 2D tau gel with LC-MS/MS and 2D-TAU (Triton-Acid-Urea)-Western blot, was found correlated with its phosphorylation status that, in turn, depends from Akt activation. In normal conditions, DJ-1 acts as a redox-sensitive chaperone and as an oxidative stress sensor. In cancer cells, glycolytic rewiring, inducing increased reactive oxygen species (ROS) levels, enhances AGEs products. Alongside, the moderate increase of ROS enhances Akt signaling that induces DJ-1-phosphorylation. When phosphorylated DJ-1 increases its glyoxalase activity, the level of AGEs on histones decreases. Therefore, phospho-DJ-1 prevents glycation-induced histones misregulation and its Akt-related hyperactivity represents a way to preserve the epigenome landscape sustaining proliferation of cancer cells. Together, these results shed light on an interesting mechanism that cancer cells might execute to escape the metabolic induced epigenetic misregulation that otherwise could impair their malignant proliferative potential.
    Keywords:  2D TAU gel; AGEs; Akt; DJ-1; breast cancer; glycation; histones; metabolic rewiring