Metabolic regulation of gene expression by histone lactylation

By Di Zhang, Zhanyun Tang, He Huang, Guolin Zhou, Chang Cui, Yejing Weng, Wenchao Liu, Sunjoo Kim, Sangkyu Lee, Mathew Perez-Neut and 12 more. Nature, 2019

3,550 citations recorded by the source corpus.

The Warburg effect, which originally described increased production of lactate in cancer, is associated with diverse cellular processes such as angiogenesis, hypoxia, polarization of macrophages and activation of T cells. This phenomenon is intimately linked to several diseases including neoplasia, sepsis and autoimmune diseases1,2. Lactate, which is converted from pyruvate in tumour cells, is widely known as an energy source and metabolic by-product. However, its non-metabolic functions in physiology and disease remain unknown. Here we show that lactate-derived lactylation of histone lysine residues serves as an epigenetic modification that directly stimulates gene transcription from chromatin. We identify 28 lactylation sites on core histones in human and mouse cells. Hypoxia and bacterial challenges induce the production of lactate by glycolysis, and this acts as a precursor that stimulates histone lactylation. Using M1 macrophages that have been exposed to bacteria as a model system, we show that histone lactylation has different temporal dynamics from acetylation. In the late phase of M1 macrophage polarization, increased histone lactylation induces homeostatic genes that are involved in wound healing, including Arg1. Collectively, our results suggest that an endogenous ‘lactate clock’ in bacterially challenged M1 macrophages turns on gene expression to promote homeostasis. Histone lactylation thus represents an opportunity to improve our understanding of the functions of lactate and its role in diverse pathophysiological conditions, including infection and cancer. The lactylation of lysine residues on histones in mammalian cells is stimulated by hypoxia and bacterial challenges, and increased histone lactylation induces genes involved in wound healing.

Subfields: Cancer Research, Immunology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/1d65f467616c214cab1926433d317d56a2e6114a

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Cancer Research

1. Ping Gao
2. S. Kierans
3. Cormac T. Taylor
4. Huafeng Zhang
5. Linchong Sun

In Molecular Biology

1. Ping Gao
2. Xianqun Fan
3. Cormac T. Taylor
4. Huafeng Zhang
5. Yingming Zhao
6. Linchong Sun
7. J. Wong

Citations in the corpus

• Macrophages in immunoregulation and therapeutics (2023, background): “Lactylation of histones provides novel insight into the roles of lactate in a wide range of pathological states, from infection to cancer.(245) The miRNAs consist of small molecular non-coding RNA (ncRNA) (with a span of ~22 nucleotides) capable of controlling gene expression after the post-transcri”
• Metabolic reprogramming and epigenetic modifications on the path to cancer (2021, background): “…2017), and human SIRT3 acts as an eraser to selectively remove histone βhydroxybutyrylation with a preference for H3K4, K9, K18, K23, K27, and H4K16 but has no activity with H4K5, K8, and K12, which distinguishes it from Zn-dependent class I HDACs (Abmayr and Workman, 2019; Zhang et al., 2019b).”
• Class I histone deacetylases (HDAC1–3) are histone lysine delactylases (2021, background): “In particular, the growing landscape of histone acyl modifications has revealed a dynamic and diverse network of metabolic modifications that regulate transcription in health and disease (12, 47, 48).”
• Histone lactylation drives oncogenesis by facilitating m6A reader protein YTHDF2 expression in ocular melanoma (2021, methodology): “stimulating histone lactylation and subsequently activating downstream gene expression [11].”
• Regulation of glycolysis by the hypoxia‐inducible factor (HIF): implications for cellular physiology (2020, background): “The effect of this increased lactylation is the increased expression of genes typical of M2-macrophage polarisation in M1-macrophages (Zhang et al. 2019).”
• Unraveling the Role of Tumor-Infiltrating Immune Cells in Head and Neck Squamous Cell Carcinoma: Implications for Antitumor Immune Responses and Immunotherapy (2025, unknown): “Additionally, tumor cells under Warburg effect secrete a large amount of lactic acid, which among other effects, induce M2 polarization of TAMs through histones lactyla-tion [85].”