bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2020‒09‒20
four papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Sci Adv. 2020 Jul;pii: eabb2529. [Epub ahead of print]6(31):
      Mild mitochondrial stress experienced early in life can have beneficial effects on the life span of organisms through epigenetic regulations. Here, we report that acetyl-coenzyme A (CoA) represents a critical mitochondrial signal to regulate aging through the chromatin remodeling and histone deacetylase complex (NuRD) in Caenorhabditis elegans Upon mitochondrial stress, the impaired tricarboxylic acid cycle results in a decreased level of citrate, which accounts for reduced production of acetyl-CoA and consequently induces nuclear accumulation of the NuRD and a homeodomain-containing transcription factor DVE-1, thereby enabling decreased histone acetylation and chromatin reorganization. The metabolic stress response is thus established during early life and propagated into adulthood to allow transcriptional regulation for life-span extension. Furthermore, adding nutrients to restore acetyl-CoA production is sufficient to counteract the chromatin changes and diminish the longevity upon mitochondrial stress. Our findings uncover the molecular mechanism of the metabolite-mediated epigenome for the regulation of organismal aging.
  2. FEBS J. 2020 Sep 14.
      Pancreatic β-cells are critical mediators of glucose homeostasis in the body, and proper cellular nutrient metabolism is critical to β-cell function. Several interacting signaling networks that uniquely control β-cell metabolism produce essential substrates and co-factors for catalytic reactions, including reactions that modify chromatin. Chromatin modifications, in turn, regulate gene expression. The reactions that modify chromatin are therefore well-positioned to adjust gene expression programmes according to nutrient availability. It follows that dysregulation of nutrient metabolism in β-cells may impact chromatin state and gene expression through altering the availability of these substrates and co-factors. Metabolic disorders such as Type 2 diabetes (T2D) can significantly alter metabolite levels in cells. This suggests that a driver of β-cell dysfunction during T2D may be the altered availability of substrates or co-factors necessary to maintain β-cell chromatin state. Induced changes in the β-cell chromatin modifications then lead to dysregulation of gene expression, in turn contributing to the downward cascade of events that leads to the loss of functional β-cell mass, and loss of glucose homeostasis, that occurs in T2D.
    Keywords:  chromatin; diabetes; histone modification; metabolism; mitochondria; β-cell
  3. Int J Mol Sci. 2020 Sep 10. pii: E6622. [Epub ahead of print]21(18):
      Androgen receptor (AR)-mediated signaling is essential for the growth and differentiation of the normal prostate and is the primary target for androgen deprivation therapy in prostate cancer. Tat interactive protein 60 kDa (Tip60) is a histone acetyltransferase that is critical for AR activation. It is well known that cancer cells rewire their metabolic pathways in order to sustain aberrant proliferation. Growing evidence demonstrates that the AR and Tip60 modulate key metabolic processes to promote the survival of prostate cancer cells, in addition to their classical roles. AR activation enhances glucose metabolism, including glycolysis, tricarboxylic acid cycle and oxidative phosphorylation, as well as lipid metabolism in prostate cancer. The AR also interacts with other metabolic regulators, including calcium/calmodulin-dependent kinase kinase 2 and mammalian target of rapamycin. Several studies have revealed the roles of Tip60 in determining cell fate indirectly by modulating metabolic regulators, such as c-Myc, hypoxia inducible factor 1α (HIF-1α) and p53 in various cancer types. Furthermore, Tip60 has been shown to regulate the activity of key enzymes in gluconeogenesis and glycolysis directly through acetylation. Overall, both the AR and Tip60 are master metabolic regulators that mediate cellular energy metabolism in prostate cancer, providing a framework for the development of novel therapeutic targets in androgen-dependent prostate cancer.
    Keywords:  HIF-1α; Tip60; androgen receptor; c-Myc; metabolism; p53; prostate cancer
  4. Chin Neurosurg J. 2019 ;5 14
      Autophagy is an intracellular degenerative pathway which is responsible for neuronal survival. Under the condition of nutrient deprivation, autophagy can lead to dysfunction in memory consolidation. AMPK/mTOR pathway is currently the most studied autophagy mechanism, while recently researchers have proved ACSS2 can also affect autophagy. ACSS2 is phosphorylated at Ser659 by AMPK and then forms a translocation complex with Importin α5 to translocate into the nucleus. This process interacts with TFEB, resulting in upregulated expression of lysosomal and autophagosomal genes. These upregulations inhibit synaptic plasticity and hence memory functions. On the other hand, ACSS2 is also recognized as a regulator of histone acetylation. After recruiting CBP/p300 and activating CBP's HAT activity in the nucleus, ACSS2 maintains the level of localized histone acetylation by recapturing acetate from histone deacetylation to reform acetyl-CoA, providing substrates for HAT. The increase of histone acetylation locally enhanced immediate early gene transcription, including Egr2, Fos, Nr2f2, Sgk1, and Arc, to benefit neuronal plasticity and memory in many ways.
    Keywords:  ACSS2; Histone acetylation; Memory; TFEB