bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒01‒03
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Free Radic Biol Med. 2020 Dec 24. pii: S0891-5849(20)31670-1. [Epub ahead of print]
      Biological redox signaling plays an important role in many diseases. Redox signaling involves reductive and oxidative mechanisms. Oxidative stress occurs when reductive mechanism overwhelms oxidative challenges. Cellular oxidative stress occurs when reactive oxygen/nitrogen species (RO/NS) exceed the cellular reductive/antioxidant capacity. Endogenously produced RO/NS from mitochondrial metabolic citric-acid-cycle coupled with electron-transport-chain or exogenous stimuli trigger cellular signaling events leading to homeostatic response or pathological damage. Recent evidence suggests that RO/NS also modulate epigenetic machinery driving gene expression. RO/NS affect DNA methylation/demethylation, histone acetylation/deacetylation or histone methylation/demethylation. Many health beneficial phytochemicals possess redox capability that counteract RO/NS either by directly scavenging the radicals or via inductive mechanism of cellular defense antioxidant/reductive enzymes. Amazingly, these phytochemicals also possess epigenetic modifying ability. This review summarizes the latest advances on the interactions between redox signaling, mitochondrial metabolism, epigenetics and redox active phytochemicals and the future challenges of integrating these events in human health.
    Keywords:  Citric acid cycle; Epigenetics; Metabolism; Oxidative stress; Redox; Redox active phytochemicals
  2. Cytometry A. 2020 Dec 16.
      CD8+ T cells, a fundamental part of the adaptive immune system, employ cytotoxic responses important for targeting pathogenic bacteria, viruses, and tumor cells. During early activation, CD8+ T cells undergo many changes in metabolism and gene expression. The bridge between epigenetic and metabolic influences on gene expression and cell fate has yet to be fully understood. Here, we investigated the importance of ATP citrate lyase (Acly), an enzyme involved in both metabolism and histone acetylation, for early stages of CD8+ T cell activation. We performed polyclonal activation of murine CD8+ T cells in vitro in the presence or absence of the Acly inhibitor BMS303141. We found that inhibiting Acly during early activation results in decreased expression of early activation markers. Consistent with impaired early activation, we found that inhibition also resulted in increased uptake of fatty acids and decreased glucose uptake without changing mitochondrial ATP levels. On an epigenetic and transcriptional level, early stage Acly inhibition specifically downregulated promoter histone H3 acetylation (H3ac) and expression of the key transcription factor IRF4; however, global levels of H3ac remained similar. Most importantly, the study was able to highlight the importance of Acly in early stages of CD8+ T cell activation and histone regulation.
    Keywords:  Acly; CD8+ T cells; IRF4
  3. Front Med. 2021 Jan 02.
      Cancer development is a complicated process controlled by the interplay of multiple signaling pathways and restrained by oxygen and nutrient accessibility in the tumor microenvironment. High plasticity in using diverse nutrients to adapt to metabolic stress is one of the hallmarks of cancer cells. To respond to nutrient stress and to meet the requirements for rapid cell proliferation, cancer cells reprogram metabolic pathways to take up more glucose and coordinate the production of energy and intermediates for biosynthesis. Such actions involve gene expression and activity regulation by the moonlighting function of oncoproteins and metabolic enzymes. The signal - moonlighting protein - metabolism axis facilitates the adaptation of tumor cells under varying environment conditions and can be therapeutically targeted for cancer treatment.
    Keywords:  epigenetics; moonlighting function; tumor metabolism