Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites
Human monocyte-to-macrophage differentiation involves highly localized gain and loss of DNA methylation at transcription factor binding sites
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人类单核细胞向巨噬细胞分化过程涉及转录因子结合位点处DNA甲基化的高度局部性的获得和缺失。
DOI：
10.1186/s13072-019-0279-4
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发表时间：
2019-06-06
影响因子：
3.9
通讯作者：
de Winther, Menno P. J.
中科院分区：
文献类型：
--
作者：
Dekkers, Koen F.;Neele, Annette E.;de Winther, Menno P. J.
巨噬细胞及其前体单核细胞在炎症和慢性炎症性疾病中起着关键作用。单核细胞到巨噬细胞的分化和激活程序伴随着显着的表观遗传重塑，其中DNA甲基化与细胞身份有关。结果我们比较了人类单核细胞、幼稚巨噬细胞和巨噬细胞之间440,292个CpG位点的基因组DNA甲基化，进一步激活为促炎状态(使用内毒素/干扰素)、抗炎状态(IL-4)或泡沫细胞(oxLDL和acLDL)。此外，我们将这些数据与公开的单核细胞和巨噬细胞全基因组测序数据相结合，以划分差异甲基化区域。我们的分析表明，差异DNA甲基化在单核细胞到巨噬细胞的分化过程中最为明显，通常局限于单个CPGS或非常短的区域，并与谱系特异性增强子共定位，无论它涉及甲基化的获得或丢失。此外，差异甲基化的CPGS位于已知参与单核细胞向巨噬细胞分化的转录因子结合增加的位置，包括C/EBP和Ets用于获得甲基化，AP-1用于甲基化缺失。结论我们的研究强调了细胞分化调控区域DNA甲基化的微妙、局部重塑的参与。
BackgroundMacrophages and their precursors monocytes play a key role in inflammation and chronic inflammatory disorders. Monocyte-to-macrophage differentiation and activation programs are accompanied by significant epigenetic remodeling where DNA methylation associates with cell identity. Here we show that DNA methylation changes characteristic for monocyte-to-macrophage differentiation occur at transcription factor binding sites, and, in contrast to what was previously described, are generally highly localized and encompass both losses and gains of DNA methylation.ResultsWe compared genome-wide DNA methylation across 440,292 CpG sites between human monocytes, naive macrophages and macrophages further activated toward a pro-inflammatory state (using LPS/IFN), an anti-inflammatory state (IL-4) or foam cells (oxLDL and acLDL). Moreover, we integrated these data with public whole-genome sequencing data on monocytes and macrophages to demarcate differentially methylated regions. Our analysis showed that differential DNA methylation was most pronounced during monocyte-to-macrophage differentiation, was typically restricted to single CpGs or very short regions, and co-localized with lineage-specific enhancers irrespective of whether it concerns gain or loss of methylation. Furthermore, differentially methylated CpGs were located at sites characterized by increased binding of transcription factors known to be involved in monocyte-to-macrophage differentiation including C/EBP and ETS for gain and AP-1 for loss of methylation.ConclusionOur study highlights the involvement of subtle, yethighly localized remodeling of DNA methylation at regulatory regions in cell differentiation.