bims-meprid 2021-09-26 papers

Issue of 2021‒09‒26
five papers selected by
Alessandro Carrer
Veneto Institute of Molecular Medicine

Nat Metab. 2021 Sep;3(9): 1259-1274

Heritable shifts in redox metabolites during mitochondrial quiescence reprogramme progeny metabolism.

Helin Hocaoglu, Lei Wang, Mengye Yang, Sibiao Yue, Matthew Sieber.

Changes in maternal diet and metabolic defects in mothers can profoundly affect health and disease in their progeny. However, the biochemical mechanisms that induce the initial reprogramming events at the cellular level have remained largely unknown owing to limitations in obtaining pure populations of quiescent oocytes. Here, we show that the precocious onset of mitochondrial respiratory quiescence causes a reprogramming of progeny metabolic state. The premature onset of mitochondrial respiratory quiescence drives the lowering of Drosophila oocyte NAD+ levels. NAD+ depletion in the oocyte leads to reduced methionine cycle production of the methyl donor S-adenosylmethionine in embryos and lower levels of histone H3 lysine 27 trimethylation, resulting in enhanced intestinal lipid metabolism in progeny. In addition, we show that triggering cellular quiescence in mammalian cells and chemotherapy-resistant human cancer cell models induces cellular reprogramming events identical to those seen in Drosophila, suggesting a conserved metabolic mechanism in systems reliant on quiescent cells.

DOI: https://doi.org/10.1038/s42255-021-00450-3

Nat Commun. 2021 Sep 20. 12(1): 5548

Isonicotinylation is a histone mark induced by the anti-tuberculosis first-line drug isoniazid.

Yuhan Jiang, Yixiao Li, Cheng Liu, Lei Zhang, Danyu Lv, Yejing Weng, Zhongyi Cheng, Xiangmei Chen, Jun Zhan, Hongquan Zhang.

Isoniazid (INH) is a first-line anti-tuberculosis drug used for nearly 70 years. However, the mechanism underlying the side effects of INH has remained elusive. Here, we report that INH and its metabolites induce a post-translational modification (PTM) of histones, lysine isonicotinylation (Kinic), also called 4-picolinylation, in cells and mice. INH promotes the biosynthesis of isonicotinyl-CoA (Inic-CoA), a co-factor of intracellular isonicotinylation. Mass spectrometry reveals 26 Kinic sites in histones in HepG2 cells. Acetyltransferases CREB-binding protein (CBP) and P300 catalyse histone Kinic, while histone deacetylase HDAC3 functions as a deisonicotinylase. Notably, MNase sensitivity assay and RNA-seq analysis show that histone Kinic relaxes chromatin structure and promotes gene transcription. INH-mediated histone Kinic upregulates PIK3R1 gene expression and activates the PI3K/Akt/mTOR signalling pathway in liver cancer cells, linking INH to tumourigenicity in the liver. We demonstrate that Kinic is a histone acylation mark with a pyridine ring, which may have broad biological effects. Therefore, INH-induced isonicotinylation potentially accounts for the side effects in patients taking INH long-term for anti-tuberculosis therapy, and this modification may increase the risk of cancer in humans.

DOI: https://doi.org/10.1038/s41467-021-25867-y

Cell Rep. 2021 Sep 21. pii: S2211-1247(21)01192-X. [Epub ahead of print]36(12): 109739

DOT1L O-GlcNAcylation promotes its protein stability and MLL-fusion leukemia cell proliferation.

Tanjing Song, Qingli Zou, Yingying Yan, Suli Lv, Neng Li, Xuefeng Zhao, Xianyun Ma, Haigang Liu, Borui Tang, Lidong Sun.

Histone lysine methylation functions at the interface of the extracellular environment and intracellular gene expression. DOT1L is a versatile histone H3K79 methyltransferase with a prominent role in MLL-fusion leukemia, yet little is known about how DOT1L responds to extracellular stimuli. Here, we report that DOT1L protein stability is regulated by the extracellular glucose level through the hexosamine biosynthetic pathway (HBP). Mechanistically, DOT1L is O-GlcNAcylated at evolutionarily conserved S1511 in its C terminus. We identify UBE3C as a DOT1L E3 ubiquitin ligase promoting DOT1L degradation whose interaction with DOT1L is susceptible to O-GlcNAcylation. Consequently, HBP enhances H3K79 methylation and expression of critical DOT1L target genes such as HOXA9/MEIS1, promoting cell proliferation in MLL-fusion leukemia. Inhibiting HBP or O-GlcNAc transferase (OGT) increases cellular sensitivity to DOT1L inhibitor. Overall, our work uncovers O-GlcNAcylation and UBE3C as critical determinants of DOT1L protein abundance, revealing a mechanism by which glucose metabolism affects malignancy progression through histone methylation.

Keywords: DOT1L; MLL; O-GlcNAcylation; UBE3C; glucose; hexosamine biosynthesis pathway; histone; leukemia; methylation; ubiquitination

DOI: https://doi.org/10.1016/j.celrep.2021.109739

Mol Cell. 2021 Sep 16. pii: S1097-2765(21)00698-5. [Epub ahead of print]81(18): 3760-3774

Moonlighting functions of metabolic enzymes and metabolites in cancer.

Chaoyun Pan, Bo Li, M Celeste Simon.

The growing field of tumor metabolism has greatly expanded our knowledge of metabolic reprogramming in cancer. Apart from their established roles, various metabolic enzymes and metabolites harbor non-canonical ("moonlighting") functions to support malignant transformation. In this article, we intend to review the current understanding of moonlighting functions of metabolic enzymes and related metabolites broadly existing in cancer cells by dissecting each major metabolic pathway and its regulation of cellular behaviors. Understanding these non-canonical functions may broaden the horizon of the cancer metabolism field and uncover novel therapeutic vulnerabilities in cancer.

DOI: https://doi.org/10.1016/j.molcel.2021.08.031

J Gastroenterol Hepatol. 2021 Sep 21.

O-GlcNAcylation inhibits hepatic stellate cell activation.

Rui Li, Qunxiang Ong, Chi Chun Wong, Eagle Sh Chu, Joseph Jy Sung, Xiaoyong Yang, Jun Yu.

Protein O-GlcNAcylation is a critical post-translational modification regulating gene expression and fundamental cell functions. O-GlcNAc transferase (OGT) emerged as a key regulator of liver pathophysiology and disease. In this study, we aimed to evaluate the role of OGT in hepatic stellate cells (HSCs) and its consequent role in liver fibrosis. OGT protein expression and protein O-GlcNAcylation were significantly decreased in CCl4 - or MCD diet-induced liver fibrosis as compared to normal liver in mice. OGT expression and protein O-GlcNAcylation were also decreased in primary HSCs isolated from liver with CCl4 -induced fibrosis compared to those from normal liver. RNA-seq showed that OGT knockdown in HSCs modulated key signaling pathways involved in HSC activation. Promoter sequence analysis of the differentially expressed genes predicted serum response factor (SRF) as a key transcription factor regulated by OGT. Luciferase reporter assay confirmed that OGT repressed activity of SRF to induce α-SMA transcription. Mutations of specific O-GlcNAcylation sites on SRF increased its transcriptional activity, validating negative regulation of SRF by OGT-mediated O-GlcNAcylation. Our results suggest that OGT functions as a negative regulator of HSC activation by promoting SRF O-GlcNAcylation to protect against liver fibrosis.

Keywords: O-GlcNAcylation; hepatic stellate cell; liver fibrosis; serum response factor

DOI: https://doi.org/10.1111/jgh.15690