bims-meprid 2021-05-09 papers

Mech Ageing Dev. 2021 Apr 28. pii: S0047-6374(21)00067-1. [Epub ahead of print]196 111495

Propionate hampers differentiation and modifies histone propionylation and acetylation in skeletal muscle cells.

Bart Lagerwaard, Marjanne D van der Hoek, Joris Hoeks, Lotte Grevendonk, Arie G Nieuwenhuizen, Jaap Keijer, Vincent C J de Boer.

Protein acylation via metabolic acyl-CoA intermediates provides a link between cellular metabolism and protein functionality. A process in which acetyl-CoA and acetylation are fine-tuned is during myogenic differentiation. However, the roles of other protein acylations remain unknown. Protein propionylation could be functionally relevant because propionyl-CoA can be derived from the catabolism of amino acids and fatty acids and was shown to decrease during muscle differentiation. We aimed to explore the potential role of protein propionylation in muscle differentiation, by mimicking a pathophysiological situation with high extracellular propionate which increases propionyl-CoA and protein propionylation, rendering it a model to study increased protein propionylation. Exposure to extracellular propionate, but not acetate, impaired myogenic differentiation in C2C12 cells and propionate exposure impaired myogenic differentiation in primary human muscle cells. Impaired differentiation was accompanied by an increase in histone propionylation as well as histone acetylation. Furthermore, chromatin immunoprecipitation showed increased histone propionylation at specific regulatory myogenic differentiation sites of the Myod gene. Intramuscular propionylcarnitine levels are higher in old compared to young males and females, possibly indicating increased propionyl-CoA levels with age. The findings suggest a role for propionylation and propionyl-CoA in regulation of muscle cell differentiation and ageing, possibly via alterations in histone acylation.

Keywords: Aging; Histone acylation; Propionylation; Skeletal muscle differentiation

DOI: https://doi.org/10.1016/j.mad.2021.111495

Free Radic Biol Med. 2021 Apr 28. pii: S0891-5849(21)00227-6. [Epub ahead of print]

Aberrant Redox Biology and Epigenetic Reprogramming: Co-conspirators across Multiple Human Diseases.

Frederick E Domann, Michael J Hitchler.

An epigenetic landscape encompasses a series of dynamic interconnected mechanisms working together to fashion a diverse set of phenotypes from a singular genotype. The epigenetic plasticity observed in disease and development is facilitated by enzymes that create and remove covalent modifications to DNA and histones. Several important discoveries within the past decade have revealed that epigenetic control mechanisms are subject to redox regulation and mitochondrial-to-nuclear retrograde signaling. This has led to our current understanding that the writers and erasers of the epigenome are influenced by several levels of redox and metabolic control including the bioavailability of oxygen, nutrients, and metabolite co-factors necessary for optimal enzyme activity. Thus, these enzymes perceive a cell's redox state, metabolic status, and environmental signals to influence chromatin structure and accessibility to the transcriptional apparatus. Not only are the activities of epigenetic enzymes affected by cellular redox conditions, but also, in feedback loop fashion, genes encoding antioxidant enzymes as well as prooxidant enzymes can be altered in their expression patterns by epigenetic silencing mechanisms. The altered expression of the anti- and prooxidant genes can then contribute to the onset or progression of disease. Epigenetic regulation of gene expression by the confluence of redox biology and gene-environment interactions is an active area of research and our understanding of these links continues to evolve. Given the emergent importance of crosstalk between redox biology and epigenetic regulatory mechanisms, it is timely that this issue should explore the current state of knowledge on this topic and how changes in metabolism and redox flux can result in tectonic shifts of the epigenetic landscape.

Keywords: DNA methylation; Epigenetics; Iron; Mitochondria; Reactive oxygen species; Redox signalling; development; histone; metabolism; redox biology

DOI: https://doi.org/10.1016/j.freeradbiomed.2021.04.020

FASEB J. 2021 Jun;35(6): e21612

Activating transcription factor 4 regulates angiogenesis under lipid overload via methionine adenosyltransferase 2A-mediated endothelial epigenetic alteration.

Li Chen, Xiaojing Liu, Hao Zhou, Guoyong Li, Fangyang Huang, Jialiang Zhang, Tianli Xia, Wenhua Lei, Jiahao Zhao, Changming Li, Mao Chen.

Lipid overload is intimately connected with the change of endothelial epigenetic status which impacts cellular signaling activities and endothelial function. Activating transcription factor 4 (ATF4) is involved in the regulation of lipid metabolism and meanwhile an epigenetic modifier. However, the role of ATF4 in the angiogenesis under lipid overload is not well understood. Here, to induce lipid overload status, we employed high-fat diet (HFD)-induced obese mouse model in vivo and palmitic acid (PA) to stimulate endothelial cells in vitro. Compared with mice fed with normal chow diet (NCD), HFD-induced obese mice showed angiogenic defects evidenced by decline in (1) blood flow recovery after hind limb ischemia, (2) wound healing speed after skin injury, (3) capillary density in injured tissues and matrigel plugs, and (4) endothelial sprouts of aortic ring. ATF4 deficiency aggravated above angiogenic defects in mice while ATF4 overexpression improved the blunted angiogenic response. Mechanistically, lipid overload lowered the H3K4 methylation levels at the regulatory regions of NOS3 and ERK1 genes, leading to reduced angiogenic signaling activity. Methionine adenosyltransferase 2A (MAT2A) is identified as a target of ATF4 and formed complex with ATF4 to direct lysine methyltransferase 2A (MLL1) to the regulatory regions of both genes for the maintenance of the H3K4 methylation level and angiogenic signaling activity. Here, we uncovered a novel metabolic-epigenetic coupling orchestrated by the ATF4-MAT2A axis for angiogenesis. The ATF4-MAT2A axis links lipid overload milieu to altered epigenetic status of relevant angiogenic signaling in endothelial cells, suggesting a potential therapeutic target for angiogenesis impaired by lipid overload.

Keywords: activating transcription factor 4; angiogenesis; epigenetics; lipid overload; methionine adenosyltransferase 2a

DOI: https://doi.org/10.1096/fj.202100233R

Cell Metab. 2021 May 04. pii: S1550-4131(21)00178-9. [Epub ahead of print]33(5): 849-850

The serine's call: Suppressing interferon responses.

Benedikt Agerer, Alexander Lercher, Andreas Bergthaler.

Cellular metabolism and immune function are closely linked. In this issue of Cell Metabolism, Shen et al. (2021) identify serine metabolism as a central integration hub of cellular metabolism, antiviral immunity, and epigenetic regulation.

DOI: https://doi.org/10.1016/j.cmet.2021.04.012

Curr Protoc. 2021 May;1(5): e117

O-GlcNAc Engineering on a Target Protein in Cells with Nanobody-OGT and Nanobody-splitOGA.

Daniel H Ramirez, Yun Ge, Christina M Woo.

The monosaccharide O-linked N-acetyl glucosamine (O-GlcNAc) is an essential and dynamic post-translational modification (PTM) that decorates thousands of nucleocytoplasmic proteins. Interrogating the role of O-GlcNAc on a target protein is crucial yet challenging to perform in cells. We recently reported a pair of methods to selectively install or remove O-GlcNAc on a target protein in cells using an engineered O-GlcNAc transferase (OGT) or split O-GlcNAcase (OGA) fused to a nanobody. Target protein O-GlcNAcylation and de-O-GlcNAcylation complements methods to interrogate the role of O-GlcNAc on a global scale or at individual glycosites. Herein, we describe a protocol for utilizing the nanobody-OGT and nanobody-splitOGA systems to screen for O-GlcNAc functionality on a target protein. We additionally include associated protocols for the detection of O-GlcNAc and cloning procedures to adapt the method for the user's target protein of interest. © 2021 Wiley Periodicals LLC. Basic Protocol 1: Target protein O-GlcNAcylation of JunB using nanobody-OGT Basic Protocol 2: Target protein deglycosylation of Nup62 using nanobody-splitOGA Alternate Protocol: Verification of the O-GlcNAc state of a tagged target protein through chemoenzymatic labeling Support Protocol: Cloning of new nanobody-OGT/nanobody-splitOGA and target protein pairs.

Keywords: O-GlcNAc; deglycosylation; glycosylation; nanobodies; post-translational modification; proximity-direction

DOI: https://doi.org/10.1002/cpz1.117