bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2021‒10‒03
six papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Genes (Basel). 2021 Sep 21. pii: 1460. [Epub ahead of print]12(9):
      The modulation of dynamic histone acetylation states is key for organizing chromatin structure and modulating gene expression and is regulated by histone acetyltransferase (HAT) and histone deacetylase (HDAC) enzymes. The mammalian SIRT6 protein, a member of the Class III HDAC Sirtuin family of NAD+-dependent enzymes, plays pivotal roles in aging, metabolism, and cancer biology. Through its site-specific histone deacetylation activity, SIRT6 promotes chromatin silencing and transcriptional regulation of aging-associated, metabolic, and tumor suppressive gene expression programs. ATP citrate lyase (ACLY) is a nucleo-cytoplasmic enzyme that produces acetyl coenzyme A (acetyl-CoA), which is the required acetyl donor for lysine acetylation by HATs. In addition to playing a central role in generating cytosolic acetyl-CoA for de novo lipogenesis, a growing body of work indicates that ACLY also functions in the nucleus where it contributes to the nutrient-sensitive regulation of nuclear acetyl-CoA availability for histone acetylation in cancer cells. In this study, we have identified a novel function of SIRT6 in controlling nuclear levels of ACLY and ACLY-dependent tumor suppressive gene regulation. The inactivation of SIRT6 in cancer cells leads to the accumulation of nuclear ACLY protein and increases nuclear acetyl-CoA pools, which in turn drive locus-specific histone acetylation and the expression of cancer cell adhesion and migration genes that promote tumor invasiveness. Our findings uncover a novel mechanism of SIRT6 in suppressing invasive cancer cell phenotypes and identify acetyl-CoA responsive cell migration and adhesion genes as downstream targets of SIRT6.
    Keywords:  ACLY; SIRT6; Sirtuin; acetyl-CoA; cancer; chromatin; gene expression; histone acetylation
  2. Cells. 2021 Sep 07. pii: 2345. [Epub ahead of print]10(9):
      Isocitrate dehydrogenase (IDH) mutations are common genetic abnormalities in glioma, which result in the accumulation of an "oncometabolite", D-2-hydroxyglutarate (D-2-HG). Abnormally elevated D-2-HG levels result in a distinctive pattern in cancer biology, through competitively inhibiting α-ketoglutarate (α-KG)/Fe(II)-dependent dioxgenases (α-KGDDs). Recent studies have revealed that D-2-HG affects DNA/histone methylation, hypoxia signaling, DNA repair, and redox homeostasis, which impacts the oncogenesis of IDH-mutated cancers. In this review, we will discuss the current understanding of D-2-HG in cancer biology, as well as the emerging opportunities in therapeutics in IDH-mutated glioma.
    Keywords:  D-2-HG; DDR; IDH1/2mut; epigenetic; glioma; oncometabolites; redox
  3. Bioresour Technol. 2021 Sep 20. pii: S0960-8524(21)01320-1. [Epub ahead of print]342 125978
      Acetyl-CoA is a kind of important cofactor that is involved in many metabolic pathways. It serves as the precursor for many interesting commercial products, such as terpenes, flavonoids and anthraquinones. However, the insufficient supply of acetyl-CoA limits biosynthesis of its derived compounds in the intracellular. In this review, we outlined metabolic pathways involved in the catabolism and anabolism of acetyl-CoA, as well as some important derived products. We examined several strategies for the enhanced supply of acetyl-CoA, and provided insight into pathways that generate acetyl-CoA to balance metabolism, which can be harnessed to improve the titer, yield and productivities of interesting products in Saccharomyces cerevisiae and other eukaryotic microorganisms. We believe that peroxisomal fatty acid β-oxidation could be an attractive strategy for enhancing the supply of acetyl-CoA.
    Keywords:  Acetyl-CoA; Fatty acids; Saccharomyces cerevisiae; β-oxidation
  4. Nutrients. 2021 Sep 04. pii: 3111. [Epub ahead of print]13(9):
      Does the quality of our diet during early life impact our long-term mental health? Accumulating evidence suggests that nutrition interacts with our genes and that there is a strong association between the quality of diet and mental health throughout life. Environmental influences such as maternal diet during pregnancy or offspring diet have been shown to cause epigenetic changes during critical periods of development, such as chemical modifications of DNA or histones by methylation for the regulation of gene expression. One-carbon metabolism, which consists of the folate and methionine cycles, is influenced by the diet and generates S-Adenosylmethinoine (SAM), the main methyl donor for methylation reactions such as DNA and histone methylation. This review provides current knowledge on how the levels of one-carbon metabolism associated micronutrients such as choline, betaine, folate, methionine and B vitamins that play a role in brain function can impact our well-being and mental health across the lifespan. Micronutrients that act as methyl donors for SAM formation could affect global or gene methylation, altering gene expression and phenotype. Strategies should then be adopted to better understand how these nutrients work and their impact at different stages of development to provide individualized dietary recommendations for better mental health outcomes.
    Keywords:  brain; epigenetics; mental health; methyl donors; methylation; nutrition; one-carbon metabolism
  5. Cells. 2021 Aug 27. pii: 2224. [Epub ahead of print]10(9):
      Maternal high-fat diet (HFD) modulates vascular remodeling in adult offspring. Here, we investigated the impact of maternal HFD on abdominal aortic aneurysm (AAA) development. Female wild-type mice were fed an HFD or normal diet (ND). AAA was induced in eight-week-old pups using calcium chloride. Male offspring of HFD-fed dams (O-HFD) showed a significant enlargement in AAA compared with the offspring of ND-fed dams (O-ND). Positive-staining cells for tartrate-resistant acid phosphate (TRAP) and matrix metalloproteinase (MMP) activity were significantly increased in O-HFD. The pharmacological inhibition of osteoclastogenesis abolished the exaggerated AAA development in O-HFD. The in vitro tumor necrosis factor-α-induced osteoclast-like differentiation of bone marrow-derived macrophages showed a higher number of TRAP-positive cells and osteoclast-specific gene expressions in O-HFD. Consistent with an increased expression of nuclear factor of activated T cells 1 (NFATc1) in O-HFD, the nuclear protein expression of interferon regulatory factor 8 (IRF8), a transcriptional repressor, were much lower, with significantly increased H3K27me3 marks at the promoter region. The enhancer of zeste homolog 2 inhibitor treatment restored IRF8 expression, resulting in no difference in NFATc1 and TRAP expressions between the two groups. Our findings demonstrate that maternal HFD augments AAA expansion, accompanied by exaggerated osteoclast-like macrophage accumulation, suggesting the possibility of macrophage skewing via epigenetic reprogramming.
    Keywords:  EZH2; H3K27me3; IRF8; MMP; NFATc1; TRAP; abdominal aortic aneurysm; histone modification; maternal high-fat diet; osteoclast-like macrophages
  6. Leukemia. 2021 Oct 01.
      Little is known of hematopoietic stem (HSC) and progenitor (HPC) cell self-renewal. The role of Brahma (BRM), a chromatin remodeler, in HSC function is unknown. Bone marrow (BM) from Brm-/- mice manifested increased numbers of long- and short-term HSCs, GMPs, and increased numbers and cycling of functional HPCs. However, increased Brm-/- BM HSC numbers had decreased secondary and tertiary engraftment, suggesting BRM enhances HSC self-renewal. Valine was elevated in lineage negative Brm-/- BM cells, linking intracellular valine with Brm expression. Valine enhanced HPC colony formation, replating of human cord blood (CB) HPC-derived colonies, mouse BM and human CB HPC survival in vitro, and ex vivo expansion of normal mouse BM HSCs and HPCs. Valine increased oxygen consumption rates of WT cells. BRM through CD98 was linked to regulated import of branched chain amino acids, such as valine, in HPCs. Brm-/- LSK cells exhibited upregulated interferon response/cell cycle gene programs. Effects of BRM depletion are less apparent on isolated HSCs compared to HSCs in the presence of HPCs, suggesting cell extrinsic effects on HSCs. Thus, intracellular valine is regulated by BRM expression in HPCs, and the BRM/valine axis regulates HSC and HPC self-renewal, proliferation, and possibly differentiation fate decisions.