Class I histone deacetylases (HDAC1–3) are histone lysine delactylases

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Abstract

Lysine L-lactylation [K(L-la)] is a newly discovered histone mark stimulated under conditions of high glycolysis, such as the Warburg effect. K(L-la) is associated with functions that are different from the widely studied histone acetylation. While K(L-la) can be introduced by the acetyltransferase p300, histone delactylases enzymes remained unknown. Here, we report the systematic evaluation of zinc- and nicotinamide adenine dinucleotide–dependent histone deacetylases (HDACs) for their ability to cleave ε- N-L-lactyllysine marks. Our screens identified HDAC1–3 and SIRT1–3 as delactylases in vitro. HDAC1–3 show robust activity toward not only K(L-la) but also K(D-la) and diverse short-chain acyl modifications. We further confirmed the de-L-lactylase activity of HDACs 1 and 3 in cells. Together, these data suggest that histone lactylation is installed and removed by regulatory enzymes as opposed to spontaneous chemical reactivity. Our results therefore represent an important step toward full characterization of this pathway’s regulatory elements.

Abstract

Deacetylase enzymes cleave lactyl modifications from lysine side chains, showing that histone lactylation is actively regulated.

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Metabolic regulation of gene expression by histone lactylation

Di Zhang, Zhanyun Tang, He Huang … (2019)

The Warburg effect, originally describing augmented lactogenesis in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, macrophage polarization, and T-cell activation. This phenomenon is intimately linked with multiple diseases including neoplasia, sepsis, and autoimmune diseases 1,2 . Lactate, a compound generated during Warburg effect, is widely known as an energy source and metabolic byproduct. However, its non-metabolic functions in physiology and disease remain unknown. Here we report lactate-derived histone lysine lactylation as a new epigenetic modification and demonstrate that histone lactylation directly stimulates gene transcription from chromatin. In total, we identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce production of lactate through glycolysis that in turn serves as precursor for stimulating histone lactylation. Using bacterially exposed M1 macrophages as a model system, we demonstrate that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, elevated histone lactylation induces homeostatic genes involved in wound healing including arginase 1. Collectively, our results suggest the presence of an endogenous “lactate clock” in bacterially challenged M1 macrophages that turns on gene expression to promote homeostasis. Histone lactylation thus represents a new avenue for understanding the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer.

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Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics.

Shao-En Ong, Blagoy Blagoev, Irina Kratchmarova … (2002)

Quantitative proteomics has traditionally been performed by two-dimensional gel electrophoresis, but recently, mass spectrometric methods based on stable isotope quantitation have shown great promise for the simultaneous and automated identification and quantitation of complex protein mixtures. Here we describe a method, termed SILAC, for stable isotope labeling by amino acids in cell culture, for the in vivo incorporation of specific amino acids into all mammalian proteins. Mammalian cell lines are grown in media lacking a standard essential amino acid but supplemented with a non-radioactive, isotopically labeled form of that amino acid, in this case deuterated leucine (Leu-d3). We find that growth of cells maintained in these media is no different from growth in normal media as evidenced by cell morphology, doubling time, and ability to differentiate. Complete incorporation of Leu-d3 occurred after five doublings in the cell lines and proteins studied. Protein populations from experimental and control samples are mixed directly after harvesting, and mass spectrometric identification is straightforward as every leucine-containing peptide incorporates either all normal leucine or all Leu-d3. We have applied this technique to the relative quantitation of changes in protein expression during the process of muscle cell differentiation. Proteins that were found to be up-regulated during this process include glyceraldehyde-3-phosphate dehydrogenase, fibronectin, and pyruvate kinase M2. SILAC is a simple, inexpensive, and accurate procedure that can be used as a quantitative proteomic approach in any cell culture system.

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THE METABOLISM OF TUMORS IN THE BODY

Otto Warburg, Franz Wind, Erwin Negelein (1927)

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Author and article information

Contributors

Carlos Moreno-Yruela:

ORCID: https://orcid.org/0000-0003-2450-6519

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Di Zhang:

ORCID: https://orcid.org/0000-0002-9341-9884

Role: ConceptualizationRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Wei Wei: Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: VisualizationRole: Writing - review & editing

Michael Bæk:

ORCID: https://orcid.org/0000-0001-7416-9421

Role: ConceptualizationRole: Formal analysisRole: InvestigationRole: MethodologyRole: ValidationRole: Writing - review & editing

Wenchao Liu: Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: ValidationRole: Writing - review & editing

Jinjun Gao:

ORCID: https://orcid.org/0000-0002-7390-5578

Role: Formal analysisRole: Investigation

Daniela Danková:

ORCID: https://orcid.org/0000-0003-1957-3514

Role: InvestigationRole: MethodologyRole: ResourcesRole: Validation

Alexander L. Nielsen:

ORCID: https://orcid.org/0000-0003-1195-0143

Role: Formal analysisRole: InvestigationRole: MethodologyRole: ResourcesRole: Validation

Julie E. Bolding:

ORCID: https://orcid.org/0000-0003-2735-2519

Role: Formal analysisRole: InvestigationRole: MethodologyRole: Validation

Lu Yang: Role: InvestigationRole: Resources

Samuel T. Jameson: Role: InvestigationRole: ResourcesRole: Validation

Jiemin Wong:

ORCID: https://orcid.org/0000-0002-5311-842X

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: Validation

Christian A. Olsen:

ORCID: https://orcid.org/0000-0002-2953-8942

Role: ConceptualizationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: ResourcesRole: SupervisionRole: Writing - original draftRole: Writing - review & editing

Yingming Zhao:

ORCID: https://orcid.org/0000-0003-1928-2151

Role: ConceptualizationRole: Data curationRole: Funding acquisitionRole: MethodologyRole: Project administrationRole: SupervisionRole: ValidationRole: VisualizationRole: Writing - original draftRole: Writing - review & editing

Journal

Journal ID (nlm-ta): Sci Adv

Journal ID (iso-abbrev): Sci Adv

Journal ID (publisher-id): sciadv

Journal ID (hwp): advances

Title: Science Advances

Publisher: American Association for the Advancement of Science

ISSN (Electronic): 2375-2548

Publication date Collection: January 2022

Publication date (Electronic, pub): 19 January 2022

Volume: 8

Issue: 3

Electronic Location Identifier: eabi6696

Affiliations

[1 ]Center for Biopharmaceuticals and Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark.

[2 ]Ben May Department for Cancer Research, The University of Chicago, Chicago, IL 60637, USA.

[3 ]Shanghai Key Laboratory of Regulatory Biology, Institute of Biomedical Sciences and School of Life Sciences, East China Normal University, Shanghai 200241, China.

Author notes

[* ]Corresponding author. Email: yingming.zhao@ 123456uchicago.edu (Y.Z.); cao@ 123456sund.ku.dk (C.A.O.)

[†]

These authors contributed equally to this work.

[‡]

Present address: State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences and Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.

[§]

Present address: Institute of Chemical Sciences and Engineering, Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne CH-1015, Switzerland.

Author information

Carlos Moreno-Yruela https://orcid.org/0000-0003-2450-6519

Di Zhang https://orcid.org/0000-0002-9341-9884

Michael Bæk https://orcid.org/0000-0001-7416-9421

Jinjun Gao https://orcid.org/0000-0002-7390-5578

Daniela Danková https://orcid.org/0000-0003-1957-3514

Alexander L. Nielsen https://orcid.org/0000-0003-1195-0143

Julie E. Bolding https://orcid.org/0000-0003-2735-2519

Jiemin Wong https://orcid.org/0000-0002-5311-842X

Christian A. Olsen https://orcid.org/0000-0002-2953-8942

Yingming Zhao https://orcid.org/0000-0003-1928-2151

Article

Publisher ID: abi6696

DOI: 10.1126/sciadv.abi6696

PMC ID: 8769552

PubMed ID: 35044827

SO-VID: 2e42c2fc-9fa4-4449-acee-d7e9d52c1f26

Copyright © Copyright © 2022 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution NonCommercial License 4.0 (CC BY-NC).

License:

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

History

Date received : 24 March 2021

Date accepted : 25 November 2021

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: GM135504

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: DK118266

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: CA251677

Funded by: FundRef http://dx.doi.org/10.13039/100000002, National Institutes of Health;

Award ID: AR078555

Funded by: FundRef http://dx.doi.org/10.13039/501100000781, European Research Council;

Award ID: ERC-CoG-725172–SIRFUNCT

Funded by: FundRef http://dx.doi.org/10.13039/501100002808, Carlsbergfondet;

Award ID: 2013-01-0333

Funded by: FundRef http://dx.doi.org/10.13039/501100002808, Carlsbergfondet;

Award ID: CF15-011

Funded by: danish independent research council;

Award ID: 6108-00166B

Funded by: Danish Independent Research Fund-Technical and Production Sciences;

Award ID: 0136-00412B

Funded by: Ministry of Science and Technology of China;

Award ID: 2017YFA054201

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Class I histone deacetylases (HDAC1–3) are histone lysine delactylases

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Most cited references 76

Metabolic regulation of gene expression by histone lactylation

Stable isotope labeling by amino acids in cell culture, SILAC, as a simple and accurate approach to expression proteomics.

THE METABOLISM OF TUMORS IN THE BODY

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