bims-meprid 2021-03-28 papers

J Exp Med. 2021 May 03. pii: e20200924. [Epub ahead of print]218(5):

Mitochondrial metabolism supports resistance to IDH mutant inhibitors in acute myeloid leukemia.

Lucille Stuani, Marie Sabatier, Estelle Saland, Guillaume Cognet, Nathalie Poupin, Claudie Bosc, Florence A Castelli, Lara Gales, Evgenia Turtoi, Camille Montersino, Thomas Farge, Emeline Boet, Nicolas Broin, Clément Larrue, Natalia Baran, Madi Y Cissé, Marc Conti, Sylvain Loric, Tony Kaoma, Alexis Hucteau, Aliki Zavoriti, Ambrine Sahal, Pierre-Luc Mouchel, Mathilde Gotanègre, Cédric Cassan, Laurent Fernando, Feng Wang, Mohsen Hosseini, Emeline Chu-Van, Laurent Le Cam, Martin Carroll, Mary A Selak, Norbert Vey, Rémy Castellano, François Fenaille, Andrei Turtoi, Guillaume Cazals, Pierre Bories, Yves Gibon, Brandon Nicolay, Sébastien Ronseaux, Joseph R Marszalek, Koichi Takahashi, Courtney D DiNardo, Marina Konopleva, Véra Pancaldi, Yves Collette, Floriant Bellvert, Fabien Jourdan, Laetitia K Linares, Christian Récher, Jean-Charles Portais, Jean-Emmanuel Sarry.

Mutations in IDH induce epigenetic and transcriptional reprogramming, differentiation bias, and susceptibility to mitochondrial inhibitors in cancer cells. Here, we first show that cell lines, PDXs, and patients with acute myeloid leukemia (AML) harboring an IDH mutation displayed an enhanced mitochondrial oxidative metabolism. Along with an increase in TCA cycle intermediates, this AML-specific metabolic behavior mechanistically occurred through the increase in electron transport chain complex I activity, mitochondrial respiration, and methylation-driven CEBPα-induced fatty acid β-oxidation of IDH1 mutant cells. While IDH1 mutant inhibitor reduced 2-HG oncometabolite and CEBPα methylation, it failed to reverse FAO and OxPHOS. These mitochondrial activities were maintained through the inhibition of Akt and enhanced activation of peroxisome proliferator-activated receptor-γ coactivator-1 PGC1α upon IDH1 mutant inhibitor. Accordingly, OxPHOS inhibitors improved anti-AML efficacy of IDH mutant inhibitors in vivo. This work provides a scientific rationale for combinatory mitochondrial-targeted therapies to treat IDH mutant AML patients, especially those unresponsive to or relapsing from IDH mutant inhibitors.

DOI: https://doi.org/10.1084/jem.20200924

Biomed Res Int. 2021 ;2021 6635225

Function and Mechanism of Novel Histone Posttranslational Modifications in Health and Disease.

Huiwen Xu, Maoyan Wu, Xiumei Ma, Wei Huang, Yong Xu.

Histone posttranslational modifications (HPTMs) are crucial epigenetic mechanisms regulating various biological events. Different types of HPTMs characterize and shape functional chromatin states alone or in combination, and dedicated effector proteins selectively recognize these modifications for gene expression. The dysregulation of HPTM recognition events takes part in human diseases. With the application of mass spectrometry- (MS-) based proteomics, novel histone lysine acylation has been successively discovered, e.g., propionylation, butyrylation, 2-hydroxyisobutyrylation, β-hydroxybutyrylation, malonylation, succinylation, crotonylation, glutarylation, and lactylation. These nine types of modifications expand the repertoire of HPTMs and regulate chromatin remodeling, gene expression, cell cycle, and cellular metabolism. Recent researches show that HPTMs have a close connection with the pathogenesis of cancer, metabolic diseases, neuropsychiatric disorders, infertility, kidney diseases, and acquired immunodeficiency syndrome (AIDS). This review focuses on the chemical structure, sites, functions of these novel HPTMs, and underlying mechanism in gene expression, providing a glimpse into their complex regulation in health and disease.

DOI: https://doi.org/10.1155/2021/6635225

Mol Cell. 2021 Mar 17. pii: S1097-2765(21)00177-5. [Epub ahead of print]

mTORC1 stimulates cell growth through SAM synthesis and m6A mRNA-dependent control of protein synthesis.

Elodie Villa, Umakant Sahu, Brendan P O'Hara, Eunus S Ali, Kathryn A Helmin, John M Asara, Peng Gao, Benjamin D Singer, Issam Ben-Sahra.

The mechanistic target of rapamycin complex 1 (mTORC1) regulates metabolism and cell growth in response to nutrient, growth, and oncogenic signals. We found that mTORC1 stimulates the synthesis of the major methyl donor, S-adenosylmethionine (SAM), through the control of methionine adenosyltransferase 2 alpha (MAT2A) expression. The transcription factor c-MYC, downstream of mTORC1, directly binds to intron 1 of MAT2A and promotes its expression. Furthermore, mTORC1 increases the protein abundance of Wilms' tumor 1-associating protein (WTAP), the positive regulatory subunit of the human N6-methyladenosine (m6A) RNA methyltransferase complex. Through the control of MAT2A and WTAP levels, mTORC1 signaling stimulates m6A RNA modification to promote protein synthesis and cell growth. A decline in intracellular SAM levels upon MAT2A inhibition decreases m6A RNA modification, protein synthesis rate, and tumor growth. Thus, mTORC1 adjusts m6A RNA modification through the control of SAM and WTAP levels to prime the translation machinery for anabolic cell growth.

Keywords: Cell growth; MAT2A; Methionine cycle; N(6)-methyladenosine; Protein Synthesis; RNA metabolism; S-adenosylmethionine; WTAP; mTOR; mTORC1

DOI: https://doi.org/10.1016/j.molcel.2021.03.009

Genomics Proteomics Bioinformatics. 2021 Mar 18. pii: S1672-0229(21)00073-5. [Epub ahead of print]

Global Profiling of the Lysine Crotonylome in Different Pluripotent States.

Yuan Lv, Chen Bu, Jin Meng, Carl Ward, Giacomo Volpe, Jieyi Hu, Mengling Jiang, Lin Guo, Jiekai Chen, Miguel A Esteban, Xichen Bao, Zhongyi Cheng.

Pluripotent stem cells (PSCs) can be expanded in vitro in different culture conditions, resulting in a spectrum of cell states with distinct properties. Understanding how PSCs transition from one state to another, ultimately leading to lineage-specific differentiation, is important for developmental biology and regenerative medicine. Although there is significant information regarding gene expression changes controlling these transitions, less is known about post-translational modifications of proteins. Protein crotonylation is a newly discovered post-translational modification where lysine residues are modified with a crotonyl group. Here, we employed affinity purification of crotonylated peptides and liquid chromatography-tandem mass spectrometry (LC-MS/MS) to systematically profile protein crotonylation in mouse PSCs in different states including ground, metastable, and primed states, as well as metastable PSCs undergoing early pluripotency exit. We successfully identified 3628 high-confidence crotonylated sites in 1426 proteins. These crotonylated proteins are enriched for factors involved in functions/processes related to pluripotency such as RNA biogenesis, central carbon metabolism, and proteasome function. Moreover, we found that increasing the cellular levels of crotonyl-coenzyme A (crotonyl-CoA) through crotonic acid treatment promotes proteasome activity in metastable PSCs and delays their differentiation, consistent with previous observations showing that enhanced proteasome activity helps to sustain pluripotency. Our atlas of protein crotonylation will be valuable for further studies of pluripotency regulation and may also provide insights into the role of metabolism in other cell fate transitions.

Keywords: Crotonylation; Metabolism; Pluripotency; Proteasome; RNA-binding proteins

DOI: https://doi.org/10.1016/j.gpb.2021.01.004

Circulation. 2021 Mar 25.

ALDH1A3 Coordinates Metabolism with Gene Regulation in Pulmonary Arterial Hypertension.

Dan Li, Ning-Yi Shao, Jan-Renier Moonen, Zhixin Zhao, Minyi Shi, Shoichiro Otsuki, Lingli Wang, Tiffany Nguyen, Elaine Yan, David P Marciano, Kévin Contrepois, Caiyun G Li, Joseph C Wu, Michael P Snyder, Marlene Rabinovitch.

Background: Metabolic alterations provide substrates that influence chromatin structure to regulate gene expression that determines cell function in health and disease. Heightened proliferation of smooth muscle cells (SMC) leading to the formation of a neointima is a feature of pulmonary arterial hypertension (PAH) and systemic vascular disease. Increased glycolysis is linked to the proliferative phenotype of these SMC. Methods: RNA Sequencing was applied to pulmonary arterial (PA) SMC from PAH patients with and without a BMPR2 mutation vs. control PASMC to uncover genes required for their heightened proliferation and glycolytic metabolism. Assessment of differentially expressed genes established metabolism as a major pathway, and the most highly upregulated metabolic gene in PAH PASMC was aldehyde dehydrogenase family 1 member 3 (ALDH1A3), an enzyme previously linked to glycolysis and proliferation in cancer cells and systemic vascular SMC. We determined if these functions are ALDH1A3-dependent in PAH PASMC, and if ALDH1A3 is required for the development of pulmonary hypertension in a transgenic mouse. Nuclear localization of ALDH1A3 in PAH PASMC led us to determine whether and how this enzyme coordinately regulates gene expression and metabolism in PAH PASMC. Results: ALDH1A3 mRNA and protein were increased in PAH vs control PASMC, and ALDH1A3 was required for their highly proliferative and glycolytic properties. Mice with Aldh1a3 deleted in SMC did not develop hypoxia-induced PA muscularization or pulmonary hypertension. Nuclear ALDH1A3 converted acetaldehyde to acetate to produce acetyl-CoA to acetylate H3K27, marking active enhancers. This allowed for chromatin modification at nuclear factor Y (NFY)A binding sites via the acetyltransferase KAT2B and permitted NFY mediated transcription of cell cycle and metabolic genes that is required for ALDH1A3-dependent proliferation and glycolysis. Loss of BMPR2 in PAH SMC with or without a mutation upregulated ALDH1A3, and transcription of NFYA and ALDH1A3 in PAH PASMC was β-catenin dependent. Conclusions: Our studies have uncovered a metabolic-transcriptional axis explaining how dividing cells use ALDH1A3 to coordinate their energy needs with the epigenetic and transcriptional regulation of genes required for SMC proliferation. They suggest that selectively disrupting the pivotal role of ALDH1A3 in PAH SMC, but not EC, is an important therapeutic consideration.

Keywords: ALDH1A3

DOI: https://doi.org/10.1161/CIRCULATIONAHA.120.048845