Glycolysis Induces Abnormal Transcription Through Histone Lactylation in T-cell Acute Lymphoblastic Leukemia
The Warburg effect, characterized by excessive lactate production, and transcriptional dysregulation are two hallmarks of tumors. However, the precise influence of lactate on epigenetic modifications at a genome-wide level and its impact on gene transcription in tumor cells remain unclear. In this study, we conducted genome-wide profiling of histone H3 lysine 18 lactylation (H3K18la) in T-cell acute lymphoblastic leukemia (T-ALL). We observed elevated lactate and H3K18la levels in T-ALL cells compared to normal T cells, with H3K18la levels positively associated with cell proliferation. Accordingly, we observed a significant shift in genome-wide H3K18la modifications from T cell immunity in normal T cells to leukemogenesis in T-ALL, correlated with altered gene transcription profiles. We showed that H3K18la primarily functions in active transcriptional regulation and observed clusters of H3K18la modifications resembling super-enhancers. Disrupting H3K18la modification revealed both synergistic and divergent changes between H3K18la and histone H3 lysine 27 acetylation (H3K27ac) modifications. Finally, we found that the high transcription of H3K18la target genes, IGFBP2 and IARS, is associated with inferior prognosis of T-ALL. These findings enhance our understanding of how metabolic disruptions contribute to transcription dysregulation through epigenetic changes in T-ALL, underscoring the interplay of histone modifications in maintaining oncogenic epigenetic stability.
Authors
- Rongrong Fan (ORCID: https://orcid.org/0000-0002-5707-1497)
- Wenyan Wu (ORCID: https://orcid.org/0000-0002-6954-3164)
- Shuhong Shen (ORCID: https://orcid.org/0000-0002-0001-642X)
- Liang Zheng (ORCID: https://orcid.org/0000-0002-5346-4111)
- Bowen Cui (ORCID: https://orcid.org/0000-0003-4467-1669)
- Yu Liu (ORCID: https://orcid.org/0000-0002-7968-0162)
- Kefei Wu (ORCID: https://orcid.org/0000-0003-0599-1272)
- Jianan Rao
- Xiaoyu Wu (ORCID: https://orcid.org/0000-0003-1816-1550)
- Jingyi Zhang (ORCID: https://orcid.org/0000-0002-5292-8279)
- Ying Wang (ORCID: https://orcid.org/0000-0002-1819-294X)
- Ying Zhong (ORCID: https://orcid.org/0000-0002-8498-1373)
- Xiang Wang (ORCID: https://orcid.org/0000-0003-0992-8553)
- Han Wang (ORCID: https://orcid.org/0000-0002-9406-5387)
- Xiaoxiao Chen (ORCID: https://orcid.org/0009-0006-8369-0570)
- Yanjun Pan (ORCID: https://orcid.org/0009-0005-2862-7977)
- Ronghua Wang (ORCID: https://orcid.org/0000-0003-1864-4827)
- Xinrong Liu (ORCID: https://orcid.org/0000-0003-1376-2699)
- Meng Yin (ORCID: https://orcid.org/0000-0002-8966-4051)
- Yangyang Xie (ORCID: https://orcid.org/0000-0002-5522-5966)
- Shuang Zhao (ORCID: https://orcid.org/0000-0003-4252-3347)
- Huiying Sun (ORCID: https://orcid.org/0009-0004-2484-7617)
- Kai Luo (ORCID: https://orcid.org/0000-0002-4567-4039)
Institutions
- Fujian Medical University (CN)
- Shanghai Jiao Tong University (CN)
- Shanghai Children's Medical Center (CN)
- Shanghai Children's Hospital (CN)
Publication Details
- Journal
- Genomics Proteomics & Bioinformatics
- Published
- 2025-04-01
- DOI
- https://doi.org/10.1093/gpbjnl/qzaf029
- Citations
- 8
- Primary Topic
- Epigenetics and DNA Methylation
- Type
- article
- Field-Weighted Citation Impact
- 6.45
Funders
- Shanghai Science and Technology Development Foundation
- Shanghai Municipal Health Commission
- National Natural Science Foundation of China