Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, Room 404, 2121. W. Holcombe Blvd, Houston, TX, 77030, USA.
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
Clin Epigenetics. 2022 Jun 28;14(1):81. doi: 10.1186/s13148-022-01297-5.
Epigenetic abnormalities in DNA hydroxymethylation (5hmC) have been detected in patients with myeloid neoplasms, suggesting that 5hmC might act as a valuable epigenetic mark to reflect the disease status of myeloid neoplasms. Here, we report systematic genome-wide mapping of the DNA hydroxymethylomes in over 70 patients with myeloid neoplasms. Our integrative analysis leads to the identification of distinct 5hmC signatures that can sensitively discriminate patients from healthy individuals. At the molecular level, we unveiled dynamic 5hmC changes within key transcription factor (e.g., the CEBP family) binding motifs that are essential for hematopoiesis and myeloid lineage specification. 5hmC redistribution was found to alter the genome-wide binding of CEBP-α, thereby reprogramming transcriptional outputs to affect leukemia cell survival and stemness. Taken together, we provide a comprehensive 5hmC atlas representative of myeloid neoplasms, which sets the stage for future exploration on the epigenetic etiology of hematological malignancies. Mechanistically, our study further furnishes important insights into how abnormal 5hmC distribution in patients directly interrupts the binding of transcription factors to reshape transcriptional landscapes and aggravate leukemogenesis.
在骨髓增生性肿瘤患者中已经检测到 DNA 羟甲基化（5hmC）的表观遗传异常，这表明 5hmC 可能作为一种有价值的表观遗传标记来反映骨髓增生性肿瘤的疾病状态。在这里，我们报告了对 70 多名骨髓增生性肿瘤患者的全基因组 DNA 羟甲基组进行了系统的图谱绘制。我们的综合分析导致了可以敏感地区分患者与健康个体的独特 5hmC 特征的识别。在分子水平上，我们揭示了关键转录因子（如 CEBP 家族）结合基序内的动态 5hmC 变化，这些变化对于造血和髓系细胞分化至关重要。发现 5hmC 的重新分布改变了 CEBP-α 的全基因组结合，从而重新编程转录输出以影响白血病细胞的存活和干性。总之，我们提供了一个代表骨髓增生性肿瘤的全面 5hmC 图谱，为进一步探索血液恶性肿瘤的表观遗传病因奠定了基础。从机制上讲，我们的研究进一步提供了重要的见解，即患者中异常的 5hmC 分布如何直接干扰转录因子的结合，从而重塑转录景观并加重白血病发生。
