bims-meprid 2022-04-17 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2022–04–17
ten papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells.
Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification.
A Nutrient-Based Cellular Model to Characterize Acetylation-Dependent Protein-Protein Interactions.
Does chromatin function as a metabolite reservoir?
ACOT12-mediated acetyl-CoA hydrolysis suppresses intrahepatic cholangiocarcinoma metastasis by inhibiting epithelial-mesenchymal transition.
Metabolic Remodeling Impacts the Epigenetic Landscape of Dental Mesenchymal Stem Cells.
Nutritional Epigenetics in Cancer.
Nutrition, metabolism, and epigenetics: pathways of circadian reprogramming.
Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.
Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.

Mol Nutr Food Res. 2022 Apr 15. e2200028

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells.

Lujing Wang, Ahmad Abdel Fat Shannar, Renyi Wu, Pochung Chou, Md Shahid Sarwar, Hsiao-Chen Kuo, Rebecca Mary Peter, Yujue Wang, Xiaoyang Su, Ah-Ng Kong.

   SCOPE: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear.
METHODS AND RESULTS: Sodium butyrate (NaB) dose-dependently inhibited the growth of CRC HCT116 cells. NaB inhibited NRF2/NRF2-target genes and blocked NRF2-ARE signaling. NaB increased NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 were correlated with their promoters' CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulated the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics.
CONCLUSION: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model. This article is protected by copyright. All rights reserved.

Keywords:  colorectal cancer; epigenetic; metabolomics; nuclear factor erythroid-2 like 2 (NRF2); sodium butyrate

DOI:  https://doi.org/10.1002/mnfr.202200028
J Exp Clin Cancer Res. 2022 Apr 15. 41(1): 144

Oncometabolites drive tumorigenesis by enhancing protein acylation: from chromosomal remodelling to nonhistone modification.

Yidian Fu, Jie Yu, Fang Li, Shengfang Ge.

  Metabolites are intermediate products of cellular metabolism catalysed by various enzymes. Metabolic remodelling, as a biochemical fingerprint of cancer cells, causes abnormal metabolite accumulation. These metabolites mainly generate energy or serve as signal transduction mediators via noncovalent interactions. After the development of highly sensitive mass spectrometry technology, various metabolites were shown to covalently modify proteins via forms of lysine acylation, including lysine acetylation, crotonylation, lactylation, succinylation, propionylation, butyrylation, malonylation, glutarylation, 2-hydroxyisobutyrylation and β-hydroxybutyrylation. These modifications can regulate gene expression and intracellular signalling pathways, highlighting the extensive roles of metabolites. Lysine acetylation is not discussed in detail in this review since it has been broadly investigated. We focus on the nine aforementioned novel lysine acylations beyond acetylation, which can be classified into two categories: histone acylations and nonhistone acylations. We summarize the characteristics and common functions of these acylation types and, most importantly, provide a glimpse into their fine-tuned control of tumorigenesis and potential value in tumour diagnosis, monitoring and therapy.

Keywords:  Epigenetic modification; Lysine acylation; Metabolites; Tumour

DOI:  https://doi.org/10.1186/s13046-022-02338-w
Front Mol Biosci. 2022 ;9 831758

A Nutrient-Based Cellular Model to Characterize Acetylation-Dependent Protein-Protein Interactions.

Jérémy Loehr, Pata-Eting Kougnassoukou Tchara, Kevin Gonthier, Chahinez Noufi, Naomie Linteau, Étienne Audet-Walsh, Jean-Philippe Lambert.

  Cellular homeostasis requires the orderly expression of thousands of transcripts. Gene expression is regulated by numerous proteins that recognize post-translational modifications-in particular, the acetylation of lysine residues (Kac) on histones. In addition to affecting the general condensation state of the chromatin, acetylated histones act as anchor points for bromodomain (BRD)-containing adapter proteins. BRDs are the primary Kac reader domains in humans, and proteins containing them act as chromatin scaffolds that organize large networks of interactions to regulate transcription. To characterize BRD-dependent interaction networks, we established cell lines in which histone acetylation is dependent on acetate supplementation. To do this, we used genome editing to knock out ATP citrate lyase (ACLY), the enzyme responsible for converting citrate to oxaloacetate and acetyl-CoA in the cytoplasm and nucleus. In our cellular model, removing acetate from the culture medium resulted in the rapid catabolism of acetylated histones to restore the nucleocytoplasmic acetyl-CoA pool. Here we report the use of our new model in functional proteomics studies to characterize BRD-dependent interaction networks on the chromatin.

Keywords:  ATP citrate lyase; acetate; acetyl-CoA; bromodomain; chromatin; functional proteomics; interactome mapping; lysine acetylation

DOI:  https://doi.org/10.3389/fmolb.2022.831758
Trends Biochem Sci. 2022 Apr 11. pii: S0968-0004(22)00075-5. [Epub ahead of print]

Does chromatin function as a metabolite reservoir?

Vinícius D Nirello, Dieggo Rodrigues de Paula, Nathália V P Araújo, Patrick D Varga-Weisz.

  Alternative histone acylations integrate gene expression with cellular metabolic states. Recent measurements of cellular acyl-coenzyme A (acyl-CoA) pools highlight the potential that histone post-translational modifications (PTMs) contribute directly to the regulation of metabolite pools. A metabolite-centric view throws new light onto roles and evolution of histone PTMs.

Keywords:  acyl-CoA; acylations; chromatin; histone modifications; metabolism; quiescence

DOI:  https://doi.org/10.1016/j.tibs.2022.03.016
J Cancer. 2022 ;13(6): 1734-1744

ACOT12-mediated acetyl-CoA hydrolysis suppresses intrahepatic cholangiocarcinoma metastasis by inhibiting epithelial-mesenchymal transition.

Xu Zhou, Yu Zhou, Weiqing Shao, Liang Hong, Ming Lu, Wenwei Zhu.

  Intrahepatic cholangiocarcinoma (ICC) is the most common malignant bile duct tumor in the liver and the second most common primary liver cancer with increasing morbidity and poor prognosis. Metabolic aberration plays key roles in cancer progression. As a key metabolic intermediate, acetyl-CoA accumulation shows close association with cancer metastasis. However, the role of acetyl-CoA metabolic aberration in ICC is still undetermined. Here, by investigating tissue samples from ICC patients and ICC cell lines, we found that acyl-CoA thioesterase 12 (ACOT12) expression is significantly down-regulated in ICC tissues, and is associated with poor prognosis of ICC. In vitro and in vivo studies demonstrated that ACOT12 suppressed ICC cells metastasis. Further mechanistic studies revealed that down-regulation of ACOT12 promoted ICC metastasis by inducing Slug expression and epithelial-mesenchymal transition (EMT). Our findings link ACOT12-regulated-acetyl-coA metabolic aberration with ICC metastasis and imply that ACOT12 could be a prognostic marker and a potential therapeutic target for ICC metastasis.

Keywords:  ACOT12; Acetyl-CoA; EMT; ICC; cancer metastasis; histone acetylation

DOI:  https://doi.org/10.7150/jca.62169
Stem Cells Int. 2022 ;2022 3490433

Metabolic Remodeling Impacts the Epigenetic Landscape of Dental Mesenchymal Stem Cells.

Haiyun Luo, Yachuan Zhou, Wenjing Liu.

Epigenetic regulation can dynamically adjust the gene expression program of cell fate decision according to the cellular microenvironment. Emerging studies have shown that metabolic activities provide fundamental components for epigenetic modifications and these metabolic-sensitive epigenetic events dramatically impact the cellular function of stem cells. Dental mesenchymal stem cells are promising adult stem cell resource for in situ injury repair and tissue engineering. In this review, we discuss the impact of metabolic fluctuations on epigenetic modifications in the oral and maxillofacial regions. The principles of the metabolic link to epigenetic modifications and the interaction between metabolite substrates and canonical epigenetic events in dental mesenchymal stem cells are summarized. The coordination between metabolic pathways and epigenetic events plays an important role in cellular progresses including differentiation, inflammatory responses, and aging. The metabolic-epigenetic network is critical for expanding our current understanding of tissue homeostasis and cell fate decision and for guiding potential therapeutic approaches in dental regeneration and infectious diseases.

DOI: https://doi.org/10.1155/2022/3490433
Adv Nutr. 2022 Apr 14. pii: nmac039. [Epub ahead of print]

Nutritional Epigenetics in Cancer.

Maria J Barrero, Paloma Cejas, Henry W Long, Ana Ramírez de Molina.

  Alterations in the epigenome are well known to affect cancer development and progression. Epigenetics is highly influenced by the environment including diet, which is a source of metabolic substrates that influence the synthesis of co-factors or substrates for chromatin and RNA modifying enzymes. In addition, plants are a common source of bioactives that can directly modify the activity of these enzymes. Here, we review and discuss the impact of diet on epigenetic mechanisms, including chromatin and RNA regulation, and its potential implications for cancer prevention and treatment.

Keywords:  DNA methylation; RNA modifications; bioactives; enhancer; histone modifications; metabolism; obesity

DOI:  https://doi.org/10.1093/advances/nmac039
EMBO Rep. 2022 Apr 12. e52412

Nutrition, metabolism, and epigenetics: pathways of circadian reprogramming.

Tomoki Sato, Paolo Sassone-Corsi.

  Food intake profoundly affects systemic physiology. A large body of evidence has indicated a link between food intake and circadian rhythms, and ~24-h cycles are deemed essential for adapting internal homeostasis to the external environment. Circadian rhythms are controlled by the biological clock, a molecular system remarkably conserved throughout evolution. The circadian clock controls the cyclic expression of numerous genes, a regulatory program common to all mammalian cells, which may lead to various metabolic and physiological disturbances if hindered. Although the circadian clock regulates multiple metabolic pathways, metabolic states also provide feedback on the molecular clock. Therefore, a remarkable feature is reprogramming by nutritional challenges, such as a high-fat diet, fasting, ketogenic diet, and caloric restriction. In addition, various factors such as energy balance, histone modifications, and nuclear receptor activity are involved in the remodeling of the clock. Herein, we review the interaction of dietary components with the circadian system and illustrate the relationships linking the molecular clock to metabolism and critical roles in the remodeling process.

Keywords:  circadian clock; energy metabolism; epigenetics; nutrition

DOI:  https://doi.org/10.15252/embr.202152412
Nat Cancer. 2022 Apr 14.

Loss of MAT2A compromises methionine metabolism and represents a vulnerability in H3K27M mutant glioma by modulating the epigenome.

Brian J Golbourn, Matthew E Halbert, Katharine Halligan, Srinidhi Varadharajan, Brian Krug, Nneka E Mbah, Nisha Kabir, Ann-Catherine J Stanton, Abigail L Locke, Stephanie M Casillo, Yanhua Zhao, Lauren M Sanders, Allison Cheney, Steven J Mullett, Apeng Chen, Michelle Wassell, Anthony Andren, Jennifer Perez, Esther P Jane, Daniel R David Premkumar, Robert F Koncar, Shideh Mirhadi, Lauren H McCarl, Yue-Fang Chang, Yijen L Wu, Taylor A Gatesman, Andrea F Cruz, Michal Zapotocky, Baoli Hu, Gary Kohanbash, Xiuxing Wang, Alenoush Vartanian, Michael F Moran, Frank Lieberman, Nduka M Amankulor, Stacy G Wendell, Olena M Vaske, Ashok Panigrahy, James Felker, Kelsey C Bertrand, Claudia L Kleinman, Jeremy N Rich, Robert M Friedlander, Alberto Broniscer, Costas Lyssiotis, Nada Jabado, Ian F Pollack, Stephen C Mack, Sameer Agnihotri.

Diffuse midline gliomas (DMGs) bearing driver mutations of histone 3 lysine 27 (H3K27M) are incurable brain tumors with unique epigenomes. Here, we generated a syngeneic H3K27M mouse model to study the amino acid metabolic dependencies of these tumors. H3K27M mutant cells were highly dependent on methionine. Interrogating the methionine cycle dependency through a short-interfering RNA screen identified the enzyme methionine adenosyltransferase 2A (MAT2A) as a critical vulnerability in these tumors. This vulnerability was not mediated through the canonical mechanism of MTAP deletion; instead, DMG cells have lower levels of MAT2A protein, which is mediated by negative feedback induced by the metabolite decarboxylated S-adenosyl methionine. Depletion of residual MAT2A induces global depletion of H3K36me3, a chromatin mark of transcriptional elongation perturbing oncogenic and developmental transcriptional programs. Moreover, methionine-restricted diets extended survival in multiple models of DMG in vivo. Collectively, our results suggest that MAT2A presents an exploitable therapeutic vulnerability in H3K27M gliomas.

DOI: https://doi.org/10.1038/s43018-022-00348-3
Trends Biochem Sci. 2022 Apr 06. pii: S0968-0004(22)00067-6. [Epub ahead of print]

Mitochondrial-to-nuclear communication in aging: an epigenetic perspective.

Di Zhu, Xinyu Li, Ye Tian.

  Age-associated changes in mitochondria are closely involved in aging. Apart from the established roles in bioenergetics and biosynthesis, mitochondria are signaling organelles that communicate their fitness to the nucleus, triggering transcriptional programs to adapt homeostasis stress that is essential for organismal health and aging. Emerging studies revealed that mitochondrial-to-nuclear (mito-nuclear) communication via altered levels of mitochondrial metabolites or stress signals causes various epigenetic changes, facilitating efforts to maintain homeostasis and affect aging. Here, we summarize recent studies on the mechanisms by which mito-nuclear communication modulates epigenomes and their effects on regulating the aging process. Insights into understanding how mitochondrial metabolites serve as prolongevity signals and how aging affects this communication will help us develop interventions to promote longevity and health.

Keywords:  UPR(mt); aging; epigenetic regulation; longevity; mitochondrial metabolites; mitochondrial–nuclear communication

DOI:  https://doi.org/10.1016/j.tibs.2022.03.008