bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒01‒31
three papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Free Radic Biol Med. 2021 Jan 22. pii: S0891-5849(21)00043-5. [Epub ahead of print]
      Iron is an essential micronutrient metal for cellular functions but can generate highly reactive oxygen species resulting in oxidative damage. For these reasons its uptake and metabolism is highly regulated. A small but dynamic fraction of ferrous iron inside the cell, termed intracellular labile iron, is redox-reactive and ready to participate multiples reactions of intracellular enzymes. Due to its nature its determination and precise quantification has been a roadblock. However, recent progress in the development of intracellular labile iron probes are allowing the reevaluation of our current understanding and unmasking new functions. The role of intracellular labile iron in regulating the epigenome was recently discovered. This chapter examine how intracellular labile iron can modulate histone and DNA demethylation and how its pool can mediate a signaling pathway from cAMP serving as a sensor of the metabolic needs of the cells.
    Keywords:  DNA methylation; G-protein coupled receptor; Histone methylation; Intracellular labile Fe(II); Iron; JmjC domain-containing demethylases; RapGEF2; Reactive oxygen species; TET methylcytosine Dioxygenases; cAMP
  2. Cancer Prev Res (Phila). 2021 Jan 28. pii: canprevres.0470.2020. [Epub ahead of print]
      Despite several epidemiological and preclinical studies supporting the role of diet in cancer progression, the complexity of the diet-cancer link makes it challenging to deconvolute the underlying mechanisms, which remain scantly elucidated. This review focuses on genomic instability as one of the cancer hallmarks affected by diet-dependent metabolic alterations. We discuss how altered dietary intake of metabolites of the one carbon metabolism, including methionine, folate, and vitamins B and C, can impact the methylation processes and thereby tumorigenesis. We present the concept that the pro-tumorigenic effect of certain diets, such as the Western diet, is in part due to a diet-induced erosion of the DNA repair capacity caused by altered epigenetic and epitranscriptomic landscapes, while the protective effect of other dietary patterns, such as the Mediterranean diet, can be partly explained by their ability to sustain a proficient DNA repair. In particular, considering that diet-dependent alterations of the one carbon metabolism can impact the rate of methylation processes, changes in dietary patterns can affect the activity of writers and erasers of histone and RNA methyl marks and consequently impair their role in ensuring a proficient DNA damage repair.
  3. Nat Commun. 2021 01 27. 12(1): 614
      Infiltrating gliomas are devastating and incurable tumors. Amongst all gliomas, those harboring a mutation in isocitrate dehydrogenase 1 mutation (IDH1mut) acquire a different tumor biology and clinical manifestation from those that are IDH1WT. Understanding the unique metabolic profile reprogrammed by IDH1 mutation has the potential to identify new molecular targets for glioma therapy. Herein, we uncover increased monounsaturated fatty acids (MUFA) and their phospholipids in endoplasmic reticulum (ER), generated by IDH1 mutation, that are responsible for Golgi and ER dilation. We demonstrate a direct link between the IDH1 mutation and this organelle morphology via D-2HG-induced stearyl-CoA desaturase (SCD) overexpression, the rate-limiting enzyme in MUFA biosynthesis. Inhibition of IDH1 mutation or SCD silencing restores ER and Golgi morphology, while D-2HG and oleic acid induces morphological defects in these organelles. Moreover, addition of oleic acid, which tilts the balance towards elevated levels of MUFA, produces IDH1mut-specific cellular apoptosis. Collectively, these results suggest that IDH1mut-induced SCD overexpression can rearrange the distribution of lipids in the organelles of glioma cells, providing new insight into the link between lipid metabolism and organelle morphology in these cells, with potential and unique therapeutic implications.