The adult haematopoietic stem cell CpG island methylome is almost entirely recapitulated in progeny cells: Implications for disease

Background Differences in immune response between individuals is driven in part by epigenetic factors. To understand the contribution of DNA methylation to these differences, we have investigated the role of haematopoietic stem cell methylation in driving variation in daughter cell differentiation and state. Methods Haematopoietic cells (namely CD34+, CD14+ and CD56+) were isolated from peripheral blood of 11 healthy individuals and subject to modified reduced representation bisulfite sequencing. DNA methylation was profiled and compared at CpG islands. Results DNA methylation state is almost entirely recapitulated between progenitor and progeny haematopoietic cells. Fewer differences in DNA methylation were detected between haematopoietic cells than between haematopoietic cells and buccal mucosa. Cell subset differences in methylation were over-represented near genes important in cell lineage specific maturation and function. Methylation differences between individuals at specific CpG islands were generally small. The CpG islands that varied most between individuals consistently across subsets, were associated with several genes, but were not enriched with regard to specific biological processes. Conclusions Overall, this study suggests that the predominant DNA methylation setting in haematopoietic stem cells is transmitted to progeny cells, with differences between cell subsets and between individuals that are likely to be important in immune cell development and variation in response to pathogens and disease. Our findings provide a plausible mechanism by which genetic and environmental factors may contribute to the development of disease via unfavourable DNA methylation settings.

**背景** 个体间免疫应答的差异，部分由表观遗传因素驱动。为阐明DNA甲基化（DNA methylation）对这类差异的贡献，本研究探讨了造血干细胞（haematopoietic stem cell）的甲基化水平在驱动子代细胞分化与状态变异中的作用。

**方法** 从11名健康个体的外周血中分离造血细胞（即CD34+、CD14+与CD56+细胞），并进行改良简化代表性亚硫酸氢盐测序（modified reduced representation bisulfite sequencing）。对CpG岛（CpG islands）处的DNA甲基化水平进行检测与比较。

**结果** 造血祖细胞与子代细胞间的DNA甲基化状态几乎完全一致。造血细胞之间的DNA甲基化差异，少于造血细胞与颊黏膜细胞之间的差异。细胞亚群间的甲基化差异，在细胞谱系特异性成熟与功能相关基因的邻近区域富集度更高。特定CpG岛处的个体间甲基化差异整体较小。在各细胞亚群中均表现出显著个体差异的CpG岛，虽与多个基因相关，但未在特定生物学过程中出现富集。

**结论** 综上，本研究表明造血干细胞中占主导的DNA甲基化模式可传递至子代细胞，细胞亚群间及个体间的甲基化差异，可能在免疫细胞发育以及对病原体与疾病的应答变异中发挥关键作用。本研究结果提出了一种合理的机制：遗传与环境因素可通过异常的DNA甲基化模式促进疾病发生发展。