Wu Wenyan, Zhang Jingyi, Sun Huiying, Wu Xiaoyu, Wang Han, Cui Bowen, Zhao Shuang, Wu Kefei, Pan Yanjun, Fan Rongrong, Zhong Ying, Wang Xiang, Wang Ying, Chen Xiaoxiao, Rao Jianan, Wang Ronghua, Luo Kai, Liu Xinrong, Zheng Liang, Shen Shuhong, Yin Meng, Xie Yangyang, Liu Yu
Key Laboratory of Pediatric Hematology & Oncology Ministry of Health, Department of Hematology & Oncology, Pediatric Translational Medicine Institute, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Department of Cardiothoracic Surgery, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
Genomics Proteomics Bioinformatics. 2025 Apr 7. doi: 10.1093/gpbjnl/qzaf029.
The Warburg effect, which excessively produce lactate, 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. We conducted an analysis of genome-wide histone H3 lysine 18 lactylation (H3K18la) modifications in T-cell acute lymphoblastic leukemia (T-ALL). We found an increased level of lactate and H3K18la in T-ALL tumor cells compared to normal T cells and the H3K18la modification is associated with cell proliferation. Accordingly, we observed a significant shift in genome-wide H3K18la modification from T cell immunity in normal T cells to leukemogenesis in T-ALL, which correlated with altered gene transcription profiles. We showed that H3K18la is primarily involved in actively regulating gene transcription and observed clusters of H3K18la modifications exhibiting patterns reminiscent of 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.
过量产生乳酸的瓦博格效应和转录失调是肿瘤的两个标志。然而，乳酸在全基因组水平上对表观遗传修饰的精确影响及其对肿瘤细胞基因转录的影响仍不清楚。我们对T细胞急性淋巴细胞白血病（T-ALL）进行了全基因组组蛋白H3赖氨酸18乳酸化（H3K18la）修饰分析。我们发现，与正常T细胞相比，T-ALL肿瘤细胞中乳酸和H3K18la水平升高，且H3K18la修饰与细胞增殖相关。因此，我们观察到全基因组H3K18la修饰从正常T细胞的T细胞免疫显著转变为T-ALL中的白血病发生，这与基因转录谱的改变相关。我们表明，H3K18la主要参与积极调节基因转录，并观察到H3K18la修饰簇呈现出类似于超级增强子的模式。破坏H3K18la修饰揭示了H3K18la与组蛋白H3赖氨酸27乙酰化（H3K27ac）修饰之间的协同和差异变化。最后，我们发现H3K18la靶基因IGFBP2和IARS的高转录与T-ALL的不良预后相关。这些发现加深了我们对代谢紊乱如何通过T-ALL中的表观遗传变化导致转录失调的理解，强调了组蛋白修饰在维持致癌表观遗传稳定性中的相互作用。
