Abstract:
DNA methylation plays a critical role in hematopoietic differentiation. Epimutation is a stochastic variation in DNA methylation that induces epigenetic heterogeneity. However, the effects of epimutations on normal hematopoiesis and hematopoietic diseases remain unclear. In this study, we developed a Julia package called EpiMut that enabled rapid and accurate quantification of epimutations. EpiMut was used to evaluate and provide an epimutation landscape in steady-state hematopoietic differentiation involving 13 types of blood cells ranging from hematopoietic stem/progenitor cells to mature cells. We showed that substantial genomic regions exhibited epigenetic variations rather than significant differences in DNA methylation levels between the myeloid and lymphoid lineages. Stepwise dynamics of epimutations were observed during the differentiation of each lineage. Importantly, we found that epimutation significantly enriched signals associated with lineage differentiation. Furthermore, epimutations in hematopoietic stem cells (HSCs) derived from various sources and acute myeloid leukemia were related to the function of HSCs and malignant cell disorders. Taken together, our study comprehensively documented an epimutation map and uncovered its important roles in human hematopoiesis, thereby offering insights into hematopoietic regulation.
摘要:
DNA甲基化在造血分化中起关键作用。Epimutation是DNA甲基化的随机变异,可诱导表观遗传异质性。然而,对正常造血和造血疾病的影响尚不清楚。在这项研究中,我们开发了一个名为EpiMut的Julia软件包,可以快速准确地量化表象。EpiMut用于评估并提供稳态造血分化中的表象景观,涉及从造血干/祖细胞到成熟细胞的13种血细胞。我们表明,大量基因组区域表现出表观遗传变异,而不是骨髓和淋巴谱系之间DNA甲基化水平的显着差异。在每个谱系的分化过程中观察到了进化的逐步动力学。重要的是,我们发现,表象显着丰富与谱系分化相关的信号。此外,各种来源的造血干细胞(HSCs)和急性髓系白血病的表观表达与HSCs的功能和恶性细胞疾病有关。一起来看,我们的研究全面记录了一张表观图谱,揭示了它在人类造血中的重要作用,从而提供对造血调控的见解。