摘要
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.
基金
supported by the Major Scientific Research Program for Young and Middle-aged Health Professionals of Fujian Province(Grant No.2022ZQNZD011 to Yu Liu)
the Shanghai Key Laboratory of Clinical Molecular Diagnostics for Pediatrics(Grant No.20dz2260900 to Yu Liu)
the National Natural Science Foundation of China(Grant No.31970627 to Yu Liu)
the Foundation of National Research Center for Translational Medicine at Shanghai[Grant No.NRCTM(SH)-2019-04 to Shuhong Shen]
the Shanghai Municipal Health Commission(Grant No.20234Z0003 to Meng Yin)
the Shanghai Science and Technology Development Foundation(Grant No.23Y11907200 to Meng Yin),China.
