bims-meprid 2024-03-03 papers

bims-meprid

Biomed News

on Metabolic-dependent epigenetic reprogramming in differentiation and disease

Issue of 2024–03–03
seven papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine

The mitochondrial thiolase ACAT1 regulates monocyte/macrophage type I interferon via epigenetic control.
Short-chain fatty acids propionate and butyrate control growth and differentiation linked to cellular metabolism.
Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.
Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest.
Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.
Histone deficiency and hypoacetylation in the aging retinal pigment epithelium.
An iron rheostat controls hematopoietic stem cell fate.

bioRxiv. 2024 Jan 31. pii: 2024.01.29.577773. [Epub ahead of print]

The mitochondrial thiolase ACAT1 regulates monocyte/macrophage type I interferon via epigenetic control.

Jing Wu, Komudi Singh, Vivian Shing, Anand K Gupta, Rebecca D Huffstutler, Duck-Yeon Lee, Michael N Sack.

Lipid-derived acetyl-CoA is shown to be the major carbon source for histone acetylation. However, there is no direct evidence demonstrating lipid metabolic pathway contribututions to this process. Mitochondrial acetyl-CoA acetyltransferase 1 (ACAT1) catalyzes the final step of ß-oxidation, the aerobic process catabolizing fatty acids (FA) into acetyl-CoA. To investigate this in the context of immunometabolism, we generated macrophage cell line lacking ACAT1. 13 C-carbon tracing combined with mass spectrometry confirmed incorporation of FA-derived carbons into histone H3 and this incorporation was reduced in ACAT1 KO macrophage cells. RNA-seq identified a subset of genes downregulated in ACAT1 KO cells including STAT1/2 and interferon stimulated genes (ISGs). CHIP analysis demonstrated reduced acetyl-H3 binding to STAT1 promoter/enhancer regions. Increasing histone acetylation rescued STAT1/2 expression in ACAT1 KO cells. Concomitantly, ligand triggered IFNβ release was blunted in ACAT1 KO cells and rescued by reconstitution of ACAT1. Furthermore, ACAT1 promotes FA-mediated histone acetylation in an acetylcarnitine shuttle-dependent manner. In patients with obesity, levels of ACAT1 and histone acetylation are abnormally elevated. Thus, our study identified a novel link between ACAT1 mediated FA metabolism and epigenetic modification on STAT1/2 that uncovers a regulatory role of lipid metabolism in innate immune signaling and opens novel avenues for interventions in human diseases such as obesity.

DOI: https://doi.org/10.1101/2024.01.29.577773
Res Sq. 2024 Feb 16. pii: rs.3.rs-3935562. [Epub ahead of print]

Short-chain fatty acids propionate and butyrate control growth and differentiation linked to cellular metabolism.

Michael Nshanian, Benjamin Geller, Joshua Gruber, Faye Chleilat, Jeannie Camarillo, Neil Kelleher, Yingming Zhao, Michael Snyder.

The short-chain fatty acids (SCFA) propionate and butyrate are produced in large amounts by microbial metabolism and have been identified as unique acyl lysine histone marks. In order to better understand the function of these modifications we used ChIP-seq to map the genome-wide location of four short-chain acyl histone marks H3K18pr/bu and H4K12pr/bu in treated and untreated colorectal cancer (CRC) and normal cells, as well as in mouse intestines in vivo . We correlate these marks with open chromatin regions along with gene expression to access the function of the target regions. Our data demonstrate that propionate and butyrate act as promoters of growth, differentiation as well as ion transport. We propose a mechanism involving direct modification of specific genomic regions, resulting in increased chromatin accessibility, and in case of butyrate, opposing effects on the proliferation of normal versus CRC cells.

DOI: https://doi.org/10.21203/rs.3.rs-3935562/v1
Nat Cell Biol. 2024 Mar 01.

Cancer-associated fibroblast-derived acetate promotes pancreatic cancer development by altering polyamine metabolism via the ACSS2-SP1-SAT1 axis.

Divya Murthy, Kuldeep S Attri, Surendra K Shukla, Ravi Thakur, Nina V Chaika, Chunbo He, Dezhen Wang, Kanupriya Jha, Aneesha Dasgupta, Ryan J King, Scott E Mulder, Joshua Souchek, Teklab Gebregiworgis, Vikant Rai, Rohit Patel, Tuo Hu, Sandeep Rana, Sai Sundeep Kollala, Camila Pacheco, Paul M Grandgenett, Fang Yu, Vikas Kumar, Audrey J Lazenby, Adrian R Black, Susanna Ulhannan, Ajay Jain, Barish H Edil, David L Klinkebiel, Robert Powers, Amarnath Natarajan, Michael A Hollingsworth, Kamiya Mehla, Quan Ly, Sarika Chaudhary, Rosa F Hwang, Kathryn E Wellen, Pankaj K Singh.

The ability of tumour cells to thrive in harsh microenvironments depends on the utilization of nutrients available in the milieu. Here we show that pancreatic cancer-associated fibroblasts (CAFs) regulate tumour cell metabolism through the secretion of acetate, which can be blocked by silencing ATP citrate lyase (ACLY) in CAFs. We further show that acetyl-CoA synthetase short-chain family member 2 (ACSS2) channels the exogenous acetate to regulate the dynamic cancer epigenome and transcriptome, thereby facilitating cancer cell survival in an acidic microenvironment. Comparative H3K27ac ChIP-seq and RNA-seq analyses revealed alterations in polyamine homeostasis through regulation of SAT1 gene expression and enrichment of the SP1-responsive signature. We identified acetate/ACSS2-mediated acetylation of SP1 at the lysine 19 residue that increased SP1 protein stability and transcriptional activity. Genetic or pharmacologic inhibition of the ACSS2-SP1-SAT1 axis diminished the tumour burden in mouse models. These results reveal that the metabolic flexibility imparted by the stroma-derived acetate enabled cancer cell survival under acidosis via the ACSS2-SP1-SAT1 axis.

DOI: https://doi.org/10.1038/s41556-024-01372-4
Mol Oncol. 2024 Feb 29.

Vitamin-C-dependent downregulation of the citrate metabolism pathway potentiates pancreatic ductal adenocarcinoma growth arrest.

Aiora Cenigaonandia-Campillo, Ana Garcia-Bautista, Anxo Rio-Vilariño, Arancha Cebrian, Laura Del Puerto, José Antonio Pellicer, José Antonio Gabaldón, Horacio Pérez-Sánchez, Miguel Carmena-Bargueño, Carolina Meroño, Javier Traba, María Jesús Fernandez-Aceñero, Natalia Baños-Herraiz, Lorena Mozas-Vivar, Estrella Núñez-Delicado, Jesús Garcia-Foncillas, Óscar Aguilera.

  In pancreatic ductal adenocarcinoma (PDAC), metabolic rewiring and resistance to standard therapy are closely associated. PDAC cells show enormous requirements for glucose-derived citrate, the first rate-limiting metabolite in the synthesis of new lipids. Both the expression and activity of citrate synthase (CS) are extraordinarily upregulated in PDAC. However, no previous relationship between gemcitabine response and citrate metabolism has been documented in pancreatic cancer. Here, we report for the first time that pharmacological doses of vitamin C are capable of exerting an inhibitory action on the activity of CS, reducing glucose-derived citrate levels. Moreover, ascorbate targets citrate metabolism towards the de novo lipogenesis pathway, impairing fatty acid synthase (FASN) and ATP citrate lyase (ACLY) expression. Lowered citrate availability was found to be directly associated with diminished proliferation and, remarkably, enhanced gemcitabine response. Moreover, the deregulated citrate-derived lipogenic pathway correlated with a remarkable decrease in extracellular pH through inhibition of lactate dehydrogenase (LDH) and overall reduced glycolytic metabolism. Modulation of citric acid metabolism in highly chemoresistant pancreatic adenocarcinoma, through molecules such as vitamin C, could be considered as a future clinical option to improve patient response to standard chemotherapy regimens.

Keywords:  PDAC; citrate synthase; gemcitabine; metabolism; vitamin C

DOI:  https://doi.org/10.1002/1878-0261.13616
Nat Metab. 2024 Feb 27.

Histone butyrylation in the mouse intestine is mediated by the microbiota and associated with regulation of gene expression.

Leah A Gates, Bernardo Sgarbi Reis, Peder J Lund, Matthew R Paul, Marylene Leboeuf, Annaelle M Djomo, Zara Nadeem, Mariana Lopes, Francisca N Vitorino, Gokhan Unlu, Thomas S Carroll, Kivanç Birsoy, Benjamin A Garcia, Daniel Mucida, C David Allis.

Post-translational modifications (PTMs) on histones are a key source of regulation on chromatin through impacting cellular processes, including gene expression1. These PTMs often arise from metabolites and are thus impacted by metabolism and environmental cues2-7. One class of metabolically regulated PTMs are histone acylations, which include histone acetylation, butyrylation, crotonylation and propionylation3,8. As these PTMs can be derived from short-chain fatty acids, which are generated by the commensal microbiota in the intestinal lumen9-11, we aimed to define how microbes impact the host intestinal chromatin landscape, mainly in female mice. Here we show that in addition to acetylation, intestinal epithelial cells from the caecum and distal mouse intestine also harbour high levels of butyrylation and propionylation on lysines 9 and 27 of histone H3. We demonstrate that these acylations are regulated by the microbiota and that histone butyrylation is additionally regulated by the metabolite tributyrin. Tributyrin-regulated gene programmes are correlated with histone butyrylation, which is associated with active gene-regulatory elements and levels of gene expression. Together, our study uncovers a regulatory layer of how the microbiota and metabolites influence the intestinal epithelium through chromatin, demonstrating a physiological setting in which histone acylations are dynamically regulated and associated with gene regulation.

DOI: https://doi.org/10.1038/s42255-024-00992-2
Aging Cell. 2024 Feb 26. e14108

Histone deficiency and hypoacetylation in the aging retinal pigment epithelium.

Sushil K Dubey, Rashmi Dubey, Subhash C Prajapati, Kyungsik Jung, Kabhilan Mohan, Xinan Liu, Jacob Roney, Wenjian Tian, Jennifer Abney, Michelle M Giarmarco, Alvaro G Hernandez, Jinze Liu, Mark E Kleinman.

  Histones serve as a major carrier of epigenetic information in the form of post-translational modifications which are vital for controlling gene expression, maintaining cell identity, and ensuring proper cellular function. Loss of histones in the aging genome can drastically impact the epigenetic landscape of the cell leading to altered chromatin structure and changes in gene expression profiles. In this study, we investigated the impact of age-related changes on histone levels and histone acetylation in the retinal pigment epithelium (RPE) and retina of mice. We observed a global reduction of histones H1, H2A, H2B, H3, and H4 in aged RPE/choroid but not in the neural retina. Transcriptomic analyses revealed significant downregulation of histones in aged RPE/choroid including crucial elements of the histone locus body (HLB) complex involved in histone pre-mRNA processing. Knockdown of HINFP, a key HLB component, in human RPE cells induced histone loss, senescence, and the upregulation of senescence-associated secretory phenotype (SASP) markers. Replicative senescence and chronological aging in human RPE cells similarly resulted in progressive histone loss and acquisition of the SASP. Immunostaining of human retina sections revealed histone loss in RPE with age. Acetyl-histone profiling in aged mouse RPE/choroid revealed a specific molecular signature with loss of global acetyl-histone levels, including H3K14ac, H3K56ac, and H4K16ac marks. These findings strongly demonstrate histone loss as a unique feature of RPE aging and provide critical insights into the potential mechanisms linking histone dynamics, cellular senescence, and aging.

Keywords:  HINFP; aging; epigenetics; histone acetylation; histones; replicative senescence; retinal pigment epithelium

DOI:  https://doi.org/10.1111/acel.14108
Cell Stem Cell. 2024 Feb 19. pii: S1934-5909(24)00041-9. [Epub ahead of print]

An iron rheostat controls hematopoietic stem cell fate.

Yun-Ruei Kao, Jiahao Chen, Rajni Kumari, Anita Ng, Aliona Zintiridou, Madhuri Tatiparthy, Yuhong Ma, Maria M Aivalioti, Deeposree Moulik, Sriram Sundaravel, Daqian Sun, Julie A Reisz, Juliane Grimm, Nuria Martinez-Lopez, Stephanie Stransky, Simone Sidoli, Ulrich Steidl, Rajat Singh, Angelo D'Alessandro, Britta Will.

  Mechanisms governing the maintenance of blood-producing hematopoietic stem and multipotent progenitor cells (HSPCs) are incompletely understood, particularly those regulating fate, ensuring long-term maintenance, and preventing aging-associated stem cell dysfunction. We uncovered a role for transitory free cytoplasmic iron as a rheostat for adult stem cell fate control. We found that HSPCs harbor comparatively small amounts of free iron and show the activation of a conserved molecular response to limited iron-particularly during mitosis. To study the functional and molecular consequences of iron restriction, we developed models allowing for transient iron bioavailability limitation and combined single-molecule RNA quantification, metabolomics, and single-cell transcriptomic analyses with functional studies. Our data reveal that the activation of the limited iron response triggers coordinated metabolic and epigenetic events, establishing stemness-conferring gene regulation. Notably, we find that aging-associated cytoplasmic iron loading reversibly attenuates iron-dependent cell fate control, explicating intervention strategies for dysfunctional aged stem cells.

Keywords:  Tip60/KAT5; aging; gene regulation; hematopoiesis; iron; metabolism; stem cells

DOI:  https://doi.org/10.1016/j.stem.2024.01.011