bims-meprid Biomed News
on Metabolic-dependent epigenetic reprogramming in differentiation and disease
Issue of 2024–02–11
six papers selected by
Alessandro Carrer, Veneto Institute of Molecular Medicine
  1. Lysine acetylation of histone acetyltransferase adaptor protein ADA2 is a mechanism of metabolic control of chromatin modification in plants.
  2. Lactate regulates major zygotic genome activation by H3K18 lactylation in mammals.
  3. Gut microbiota regulates hepatic ischemia-reperfusion injury-induced cognitive dysfunction via the HDAC2-ACSS2 axis in mice.
  4. A metabolic-epigenetic mechanism directs cell fate and therapeutic sensitivity in breast cancer.
  5. Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation.
  6. Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy.
  1. Nat Plants. 2024 Feb 07.
    Lysine acetylation of histone acetyltransferase adaptor protein ADA2 is a mechanism of metabolic control of chromatin modification in plants.
    Yue Yu, Feng Zhao, Yaping Yue, Yu Zhao, Dao-Xiu Zhou.
      Histone acetylation is a predominant active chromatin mark deposited by histone acetyltransferases (HATs) that transfer the acetyl group from acetyl coenzyme A (acetyl-CoA) to lysine ε-amino groups in histones. GENERAL CONTROL NON-REPRESSED PROTEIN 5 (GCN5) is one of the best-characterized HATs and functions in association with several adaptor proteins such as ADA2 within multiprotein HAT complexes. ADA2-GCN5 interaction increases GCN5 binding to acetyl-CoA and stimulates its HAT activity. It remains unclear whether the HAT activity of GCN5 (which acetylates not only histones but also cellular proteins) is regulated by acetyl-CoA levels, which vary greatly in cells under different metabolic and nutrition conditions. Here we show that the ADA2 protein itself is acetylated by GCN5 in rice cells. Lysine acetylation exposes ADA2 to a specific E3 ubiquitin ligase and reduces its protein stability. In rice plants, ADA2 protein accumulation reversely parallels its lysine acetylation and acetyl-CoA levels, both of which are dynamically regulated under varying growth conditions. Stress-induced ADA2 accumulation could stimulate GCN5 HAT activity to compensate for the reduced acetyl-CoA levels for histone acetylation. These results indicate that ADA2 lysine acetylation that senses cellular acetyl-CoA variations is a mechanism to regulate HAT activity and histone acetylation homeostasis in plants under changing environments.
    DOI:  https://doi.org/10.1038/s41477-024-01623-0
  2. Natl Sci Rev. 2024 Feb;11(2): nwad295
    Lactate regulates major zygotic genome activation by H3K18 lactylation in mammals.
    Jingyu Li, Weibo Hou, Qi Zhao, Wei Han, Hongdi Cui, Songling Xiao, Ling Zhu, Jiadan Qu, Xiaoyu Liu, Weitao Cong, Jingling Shen, Yuzheng Zhao, Shaorong Gao, Guoning Huang, Qingran Kong.
      Lactate is present at a high level in the microenvironment of mammalian preimplantation embryos in vivo and in vitro. However, its role in preimplantation development is unclear. Here, we report that lactate is highly enriched in the nuclei of early embryos when major zygotic genome activation (ZGA) occurs in humans and mice. The inhibition of its production and uptake results in developmental arrest at the 2-cell stage, major ZGA failure, and loss of lactate-derived H3K18lac, which could be rescued by the addition of Lac-CoA and recapitulated by overexpression of H3K18R mutation. By profiling the landscape of H3K18lac during mouse preimplantation development, we show that H3K18lac is enriched on the promoter regions of most major ZGA genes and correlates with their expressions. In humans, H3K18lac is also enriched in ZGA markers and temporally concomitant with their expressions. Taken together, we profile the landscapes of H3K18lac in mouse and human preimplantation embryos, and demonstrate the important role for H3K18lac in major ZGA, showing that a conserved metabolic mechanism underlies preimplantation development of mammalian embryos.
    Keywords:  epigenetic remodeling; histone lactylation; lactate; mammalian preimplantation development; zygotic genome activation
    DOI:  https://doi.org/10.1093/nsr/nwad295
  3. CNS Neurosci Ther. 2024 Feb;30(2): e14610
    Gut microbiota regulates hepatic ischemia-reperfusion injury-induced cognitive dysfunction via the HDAC2-ACSS2 axis in mice.
    Yanbo Liu, Zhen Li, Tianning Sun, Zhixiao Li, Anne Manyande, Hongbing Xiang, Zhigang He.
       AIMS: Hepatic ischemia-reperfusion injury (HIRI) resulting from hepatic inflow occlusion, which is a common procedure in liver surgery is inevitable. Previous research has confirmed that the cognitive dysfunction induced by HIRI is closely related to dysbiosis of the gut microbiota. This research aims to investigate the mechanisms underlying this complication.
    METHODS: C57BL/6 mice underwent hepatic ischemia experimentally through the occlusion of the left hepatic artery and portal vein. To assess the HDAC2-ACSS2 axis, gut microbiota transplantation. Enzyme-linked immunosorbent assay and LC/MS short-chain fatty acid detection were utilized.
    RESULTS: The findings indicated a notable decline in ACSS2 expression in the hippocampus of mice experiencing hepatic ischemia-reperfusion injury, emphasizing the compromised acetate metabolism in this particular area. Furthermore, the cognitive impairment phenotype and the dysregulation of the HDAC2-ACSS2 axis could also be transmitted to germ-free mice via fecal microbial transplantation. Enzyme-linked immunosorbent assay revealed reduced Acetyl-coenzyme A (acetyl-CoA) and Acetylated lysine levels in the hippocampus.
    CONCLUSION: These findings suggest that acetate metabolism is impaired in the hippocampus of HIRI-induced cognitive impairment mice and related to dysbiosis, leading to compromised histone acetylation.
    Keywords:  HDAC2-ACSS2 axis; cognitive dysfunction; gut microbiota; hepatic ischemia; reperfusion injury
    DOI:  https://doi.org/10.1111/cns.14610
  4. Cancer Res. 2024 Feb 08.
    A metabolic-epigenetic mechanism directs cell fate and therapeutic sensitivity in breast cancer.
    Matthew J Bernard, Andrew S Goldstein.
      Over the past decade, studies have increasingly shed light on a reciprocal relationship between cellular metabolism and cell fate, meaning that a cell's lineage both drives and is governed by its specific metabolic features. A recent study by Zhang and colleagues, published in Cell Metabolism, describes a novel metabolic-epigenetic regulatory axis that governs lineage identity in triple negative breast cancer (TNBC). Among the key findings, the authors demonstrate that the metabolic enzyme pyruvate kinase M2 (PKM2) directly binds to the histone methyltransferase enhancer of zeste homologue 2 (EZH2) in the nucleus to silence expression of a set of genes that includes the mitochondrial carnitine transporter SLC16A9. Perturbation of this metabolic-epigenetic regulatory mechanism induces a metabolic shift away from glycolysis and towards fatty acid oxidation. The ensuing influx of carnitine facilitates the deposition of the activating epigenetic mark H3K27Ac onto the promoter of GATA3, driving a committed luminal lineage state. Importantly, this metabolic-epigenetic axis represents a potentially targetable vulnerability for the treatment of TNBC, a subtype that currently lacks effective therapeutic strategies. These findings lend further support for the paradigm shift underlying our understanding of cancer metabolism: that a cellular fuel source functions not only to provide energy but also to direct the epigenetic regulation of cell fate.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-24-0460
  5. Cell Rep. 2024 Feb 07. pii: S2211-1247(24)00074-3. [Epub ahead of print]43(2): 113746
    Lactic acid induces transcriptional repression of macrophage inflammatory response via histone acetylation.
    Weiwei Shi, Tiffany J Cassmann, Aditya Vijay Bhagwate, Taro Hitosugi, W K Eddie Ip.
      Lactic acid has emerged as an important modulator of immune cell function. It can be produced by both gut microbiota and the host metabolism at homeostasis and during disease states. The production of lactic acid in the gut microenvironment is vital for tissue homeostasis. In the present study, we examined how lactic acid integrates cellular metabolism to shape the epigenome of macrophages during pro-inflammatory response. We found that lactic acid serves as a primary fuel source to promote histone H3K27 acetylation, which allows the expression of immunosuppressive gene program including Nr4a1. Consequently, macrophage pro-inflammatory function was transcriptionally repressed. Furthermore, the histone acetylation induced by lactic acid promotes a form of long-term immunosuppression ("trained immunosuppression"). Pre-exposure to lactic acid induces lipopolysaccharide tolerance. These findings thus indicate that lactic acid sensing and its effect on chromatin remodeling in macrophages represent a key homeostatic mechanism that can provide a tolerogenic tissue microenvironment.
    Keywords:  CP: Immunology; CP: Metabolism; epigenetic reprogramming; histone acetylation; immunosuppression; inflammation; inflammatory bowel disease; lactic acid; macrophage; metabolism; metabolite sensing; tissue microenvironment
    DOI:  https://doi.org/10.1016/j.celrep.2024.113746
  6. Cancer Lett. 2024 Feb 06. pii: S0304-3835(24)00089-2. [Epub ahead of print] 216696
    Palmitoylation alters LDHA activity and pancreatic cancer response to chemotherapy.
    Luojun Chen, Xiaoke Xing, Yue Zhu, Yali Chen, Huadong Pei, Qibin Song, Juanjuan Li, Pingfeng Zhang.
      Lactate dehydrogenase A (LDHA) serves as a key regulator of the Warburg Effect by catalyzing the conversion of pyruvate to lactate in the final step of glycolysis. Both the expression level and enzyme activity of LDHA are upregulated in cancers, however, the underlying mechanism remains incompletely understood. Here, we show that LDHA is post-translationally palmitoylated by ZDHHC9 at cysteine 163, which promotes its enzyme activity, lactate production, and reduces reactive oxygen species (ROS) generation. Replacement of endogenous LDHA with a palmitoylation-deficient mutant leads to reduced pancreatic cancer cell proliferation, increased T-cell infiltration, and limited tumor growth; it also affects pancreatic cancer cell response to chemotherapy. Moreover, LDHA palmitoylation is upregulated in gemcitabine resistant pancreatic cancer cells. Clinically, ZDHHC9 is upregulated in pancreatic cancer and correlated with poor prognoses for patients. Overall, our findings identify ZDHHC9-mediated palmitoylation as a positive regulator of LDHA, with potentially significant implications for cancer etiology and targeted therapy for pancreatic cancer.
    Keywords:  Gemcitabine; LDHA; Palmitoylation; Pancreatic cancer; ZDHHC9
    DOI:  https://doi.org/10.1016/j.canlet.2024.216696
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