HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE239656 | GEO | 2024/01/16
REPOSITORIES: GEO
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Project description:Lysine lactylation (Kla) links metabolism and gene regulation and plays a key role in multiple biological processes. We report that HBO1 functions as a lysine lactyltransferase to regulate transcription. Quantitative proteomic analysis further revealsed 95 endogenous Kla sites targeted by HBO1, with the majority located on histones.
2024-04-13 | PXD051415 | Pride
Project description:HBO1 catalyzes lysine lactylation and mediates histone H3K9la to regulate gene transcription
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Project description:Lysine benzoylation (Kbz) is a newly discovered protein post-translational modification (PTM). This PTM can be stimulated by benzoate and contributes to gene expression. However, its regulatory enzymes and substrate proteins remain largely unknown, hindering further functional studies. Here we identified and validated the lysine acetyltransferase (KAT) HBO1 as a “writer” of Kbz in mammalian cells. In addition, we report the first benzoylome in mammalian cells, identifying 1747 Kbz sites, among them at least 77 are the HBO1-targeted Kbz substrates. Bioinformatics analysis showed that HBO1-targeted Kbz sites were involved in multiple processes, including chromatin remodeling, transcription regulation, immune regulation, and tumor growth. Our results thus identify key regulatory elements of the Kbz pathway, and reveal new enzymatic activity and functions of HBO1 in cellular physiology.
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Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and hypoxia-associated L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here, we report the identification of GTPSCS as a lactyl-CoA ligase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone H3 lysine 18 lactylation (H3K18la). This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit but also acetylation at the G2 subunit residue K73 (for the interaction between GTPSCS and p300). GTPSCS-p300-mediated histone H3K18la promotes glioma cell proliferation and tumor formation in mice. In addition, histone H3K18la is positively associated with glioma grade and poor prognosis in glioma patients. The LDHA-GTPSCS-lactyltransferase-histone Kla axis thus represents a signal-stimulated epigenetic pathway that mediates the downstream impact of the Warburg effect and hypoxia
2024-12-04 | PXD037672 | Pride
Project description:Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. However, how this histone mark acts in cancers remains unexplored due in part to a lack of knowledge about its reader proteins. Here, we observe that cervical cancer (CC) cells undergo metabolic reprogram by which lactate accumulation and thereby boost histone lactylation, particularly H3K14la. Utilizing a multivalent photoaffinity probe in combination with quantitative proteomics approach, we identify DPF2 as a candidate target of H3K14la. Biochemical studies as well as CUT&Tag analysis reveal that DPF2 is capable of binding to H3K14la, and co-localizes with it on promoters of oncogenic genes. Notably, disrupting the association between DPF2 and histone lactylation through structure-guided mutation blunts those cancer-related gene expression along with cell survival. Together, our findings reveal DPF2 as a bona fide H3K14la effector that couples histone lactylation to gene transcription and cell survival, offering insight into how histone Kla engages in transcription and tumorigenesis.
2024-06-17 | GSE267109 | GEO
Project description:Lysine lactylation (Kla) is a new type of histone mark implicated in the regulation of various functional processes such as transcription. However, how this histone mark acts in cancers remains unexplored due in part to a lack of knowledge about its reader proteins. Here, we observe that cervical cancer (CC) cells undergo metabolic reprogram by which lactate accumulation and thereby boost histone lactylation, particularly H3K14la. Utilizing a multivalent photoaffinity probe in combination with quantitative proteomics approach, we identify DPF2 as a candidate target of H3K14la. Biochemical studies as well as CUT&Tag analysis reveal that DPF2 is capable of binding to H3K14la, and co-localizes with it on promoters of oncogenic genes. Notably, disrupting the association between DPF2 and histone lactylation through structure-guided mutation blunts those cancer-related gene expression along with cell survival. Together, our findings reveal DPF2 as a bona fide H3K14la effector that couples histone lactylation to gene transcription and cell survival, offering insight into how histone Kla engages in transcription and tumorigenesis.
2024-06-17 | GSE267107 | GEO
Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a robust lactyl-CoA synthetase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation of glioma cells and facilitates tumor formation in mice. In addition, GTPSCS is upregulated in glioma and correlates with glioma malignancy, while histone H3K18la, and GDF15 levels are positively associated with glioma malignancy and poor prognosis in GBM patients. The GTPSCS-lactyltransferase-histone Kla axis thus represents an epigenetic pathway linking lactate metabolism with an oncogenic gene expression pattern in glioma.
2024-11-26 | GSE247800 | GEO
Project description:Histone lysine lactylation is a physiologically relevant epigenetic pathway that can be stimulated by the Warburg effect and L-lactate. Nevertheless, the mechanism by which cells use L-lactate to generate lactyl-CoA, the cofactor for the modification, and how this process is regulated remain unknown. Here we report identification of GTPSCS as a robust lactyl-CoA synthetase using biochemistry and cell biology approaches. The mechanism of this catalytic activity was elucidated using the crystallographic structure of GTPSCS in complex with L-lactate, followed by mutagenesis experiments. GTPSCS translocates into the nucleus and interacts with p300 to form a functional lactyltransferase to elevate histone lactylation, but not histone succinylation. This process is dependent on not only a nuclear localization signal in the GTPSCS G1 subunit, but also acetylation at G2 subunit residue K73 which mediates the interaction with p300. GTPSCS-p300 collaboration synergistically regulates histone H3K18la, subsequently enhancing the expression of GDF15. This process promotes the proliferation of glioma cells and facilitates tumor formation in mice. In addition, GTPSCS is upregulated in glioma and correlates with glioma malignancy, while histone H3K18la, and GDF15 levels are positively associated with glioma malignancy and poor prognosis in GBM patients. The GTPSCS-lactyltransferase-histone Kla axis thus represents an epigenetic pathway linking lactate metabolism with an oncogenic gene expression pattern in glioma.
2024-11-26 | GSE248703 | GEO
Project description:Hypoxia promotes tumorigenesis and lactate accumulation in esophageal squamous cell carcinoma (ESCC). Lactate can induce histone lysine lactylation (Kla, a recently-identified histone marks) to regulate transcription. However, the functional consequence of histone Kla under hypoxia in ESCC remains to be explored. Here, we reveal that hypoxia facilitates histone H3K9la to enhance LAMC2 transcription for proliferation of ESCC. We found that global level of Kla was elevated under hypoxia, and thus identified the landscape of histone Kla in ESCC by quantitative proteomics. Furthermore, we show a significant increase of H3K9la level induced by hypoxia. Next, MNseq ChIP-seq and RNA-seq analysis suggest that H3K9la is enriched at the promoter of cell junction genes. Finally, we demonstrate that the histone H3K9la facilitates the expression of LAMC2 for ESCC invasion by in vivo and in vitro experiments. Briefly, our study reveal a vital role of histone Kla triggered by hypoxia in cancer.
2024-05-22 | GSE255352 | GEO
Project description:Lactate produced in glycolysis has recently been discovered to modify lysine residues on eukaryotic proteins, a post-translational modification (PTM) called lysine lactylation (Kla). This modification not only participates in regulating gene expression through lactylation of histones, but also impacts the function of non-histone proteins. However, lactylation in prokaryotes has not been reported. Here, we report the identification of 1869 lysine lactylation sites in 465 proteins in the cariogenic organism Streptococcus mutans using a newly developed 4-dimensional label-free quantitative proteomic approach, representing the first Kla dataset in prokaryotes. Combining quantitative analysis, we report that the modification levels of 282 sites from 124 proteins increased by over 1.5-fold, and 80 sites from 52 proteins decreased by over 0.67-fold in the biofilm growth state. These results provide a systematic perspective of the distribution and function of Kla and improve our understanding of the role of lactate in the metabolic regulation of prokaryotes.
2023-08-24 | PXD037027 | Pride