Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
Department of Genetics, The Edison Family Center for Genome Sciences and Systems Biology, Washington University School of Medicine, St. Louis, MO, USA.
Nat Immunol. 2022 Apr;23(4):619-631. doi: 10.1038/s41590-022-01164-8. Epub 2022 Mar 24.
Innate lymphocytes encompass a diverse array of phenotypic identities with specialized functions. DNA methylation and hydroxymethylation are essential for epigenetic fidelity and fate commitment. The landscapes of these modifications are unknown in innate lymphocytes. Here, we characterized the whole-genome distribution of methyl-CpG and 5-hydroxymethylcytosine (5hmC) in mouse innate lymphoid cell 3 (ILC3), ILC2 and natural killer (NK) cells. We identified differentially methylated regions (DMRs) and differentially hydroxymethylated regions (DHMRs) between ILC and NK cell subsets and correlated them with transcriptional signatures. We associated lineage-determining transcription factors (LDTFs) with demethylation and demonstrated unique patterns of DNA methylation/hydroxymethylation in relationship to open chromatin regions (OCRs), histone modifications and TF-binding sites. We further identified an association between hydroxymethylation and NK cell superenhancers (SEs). Using mice lacking the DNA hydroxymethylase TET2, we showed the requirement for TET2 in optimal production of hallmark cytokines by ILC3s and interleukin-17A (IL-17A) by inflammatory ILC2s. These findings provide a powerful resource for studying innate lymphocyte epigenetic regulation and decode the regulatory logic governing their identity.
先天淋巴细胞具有多种表型特征和特定功能。DNA 甲基化和羟甲基化对于表观遗传保真度和命运决定至关重要。这些修饰的图谱在先天淋巴细胞中尚不清楚。在这里,我们描述了小鼠先天淋巴样细胞 3(ILC3)、ILC2 和自然杀伤(NK)细胞中全基因组甲基化-CpG 和 5-羟甲基胞嘧啶(5hmC)的分布。我们鉴定了 ILC 和 NK 细胞亚群之间的差异甲基化区域(DMRs)和差异羟甲基化区域(DHMRs),并将其与转录特征相关联。我们将谱系决定转录因子(LDTFs)与去甲基化相关联,并证明了与开放染色质区域(OCRs)、组蛋白修饰和 TF 结合位点相关的独特 DNA 甲基化/羟甲基化模式。我们还发现了羟甲基化与 NK 细胞超级增强子(SEs)之间的关联。使用缺乏 DNA 羟甲基酶 TET2 的小鼠,我们表明 TET2 对于 ILC3 产生标志性细胞因子和炎症性 ILC2 产生白细胞介素-17A(IL-17A)至关重要。这些发现为研究先天淋巴细胞表观遗传调控提供了有力资源,并解码了控制其身份的调控逻辑。