bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2023‒01‒08
four papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

  1. Reprod Fertil Dev. 2022 Dec;35(2): 84-97
      Metabolism and epigenetics, which reciprocally regulate each other in different cell types, are fundamental aspects of cellular adaptation to the environment. Evidence in cancer and stem cells has shown that the metabolic status modifies the epigenome while epigenetic mechanisms regulate the expression of genes involved in metabolic processes, thereby altering the metabolome. This crosstalk occurs as many metabolites serve as substrates or cofactors of chromatin-modifying enzymes. If we consider the intense metabolic dynamic and the epigenetic remodelling of the embryo, the comprehension of these regulatory networks will be important not only for understanding early embryonic development, but also to determine in vitro culture conditions that support embryo development and may insert positive regulatory marks that may persist until adult life. In this review, we focus on how metabolism may affect epigenetic reprogramming of the early stages of development, in particular acetylation and methylation of histone and DNA. We also present other metabolic modifications in bovine embryos, such as lactylation, highlighting the promising epigenetic and metabolic targets to improve conditions for in vitro embryo development.
  2. Nat Metab. 2023 Jan 02.
      Enhanced glycolysis and accumulation of lactate is a common feature in various types of cancer. Intracellular lactate drives a recently described type of posttranslational modification, lysine lactylation (Kla), on core histones. However, the impact of lactylation on biological processes of tumour cells remains largely unknown. Here we show a global lactylome profiling on a prospectively collected hepatitis B virus-related hepatocellular carcinoma (HCC) cohort. Integrative lactylome and proteome analysis of the tumours and adjacent livers identifies 9,275 Kla sites, with 9,256 sites on non-histone proteins, indicating that Kla is a prevalent modification beyond histone proteins and transcriptional regulation. Notably, Kla preferentially affects enzymes involved in metabolic pathways, including the tricarboxylic acid cycle, and carbohydrate, amino acid, fatty acid and nucleotide metabolism. We further verify that lactylation at K28 inhibits the function of adenylate kinase 2, facilitating the proliferation and metastasis of HCC cells. Our study therefore reveals that Kla plays an important role in regulating cellular metabolism and may contribute to HCC progression.
  3. Biochem Cell Biol. 2023 Jan 04.
      Diffuse large B-cell lymphoma (DLBCL) often develops resistance and/or relapses in response to immunochemotherapy. Epigenetic modifiers are frequently mutated in DLBCL, i.e. the lysine (histone) acetyltransferases CREBBP and EP300. Mutations in CBP/p300 can prevent the proper acetylation and activation of 1) enhancer sequences of genes required for essential functions (e.g., germinal center exit and differentiation) and 2) the tumor suppressor p53. Based on evidence that omega-3 fatty acids (w-3 FA) affects histone acetylation in various cancers, we investigated whether w-3 FA docosahexaenoic acid (DHA) could modify levels of histone and p53 acetylation in three DLBCL cell lines (at different CREBBP/EP300 mutational status) vs. normal B-cells. Exposure to DHA at clinically attainable doses was shown to significantly alter the genome-wide levels of histone post-translational modifications (PTMs) in a cell-line and dose-dependent manner. Although histone acetylation did not increase uniformly, as initially expected, levels of p53 acetylation increased consistently. qRT-PCR results revealed significant changes in expression of multiple genes, including increased expression of CREBBP and of PRDM1 (required for differentiation into plasma cells or memory B-cells). Taken together, our results provide (to our knowledge) the first characterization of the epigenetic effects of omega-3 fatty acids in DLBCL.
  4. Cell Mol Life Sci. 2023 Jan 06. 80(1): 28
      Little is known about the impact of metabolic stimuli on brain tissue at a molecular level. The ketone body beta-hydroxybutyrate (BHB) can be a signaling molecule regulating gene transcription. Thus, we assessed lysine beta-hydroxybutyrylation (K-bhb) levels in proteins extracted from the cerebral cortex of mice undergoing a ketogenic metabolic challenge (48 h fasting). We found that fasting enhanced K-bhb in a variety of proteins including histone H3. ChIP-seq experiments showed that K9 beta-hydroxybutyrylation of H3 (H3K9-bhb) was significantly enriched by fasting on more than 8000 DNA loci. Transcriptomic analysis showed that H3K9-bhb on enhancers and promoters correlated with active gene expression. One of the most enriched functional annotations both at the epigenetic and transcriptional level was "circadian rhythms''. Indeed, we found that the diurnal oscillation of specific transcripts was modulated by fasting at distinct zeitgeber times both in the cortex and suprachiasmatic nucleus. Moreover, specific changes in locomotor activity daily features were observed during re-feeding after 48-h fasting. Thus, our results suggest that fasting remarkably impinges on the cerebral cortex transcriptional and epigenetic landscape, and BHB acts as a powerful epigenetic molecule in the brain through direct and specific histone marks remodeling in neural tissue cells.
    Keywords:  Beta-hydroxybutyrylation; Cerebral cortex; Epigenome; Fasting; Transcriptome