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. 2019 Apr;14(4):341-351.
doi: 10.1080/15592294.2019.1585176. Epub 2019 Mar 16.

Cell lineage-specific genome-wide DNA methylation analysis of patients with paediatric-onset systemic lupus erythematosus

Kit San Yeung  1 , Tsz Leung Lee  2 , Mo Yin Mok  3 , Christopher Chun Yu Mak  1 , Wanling Yang  1 , Patrick Chun Yin Chong  1 , Pamela Pui Wah Lee  1 , Marco Hok Kung Ho  1 , Sanaa Choufani  4 , Chak Sing Lau  5 , Yu Lung Lau  1 , Rosanna Weksberg  4   6   7 , Brian Hon Yin Chung  1
Affiliations

Cell lineage-specific genome-wide DNA methylation analysis of patients with paediatric-onset systemic lupus erythematosus

Kit San Yeung et al. Epigenetics. 2019 Apr.

Abstract

Patients with paediatric-onset systemic lupus erythematosus (SLE) often present with more severe clinical courses than adult-onset patients. Although genome-wide DNA methylation (DNAm) profiling has been performed in adult-onset SLE patients, parallel data on paediatric-onset SLE are not available. Therefore, we undertook a genome-wide DNAm study in paediatric-onset SLE patients across multiple blood cell lineages. The DNAm profiles of four purified immune cell lineages (CD4 + T cells, CD8 + T cells, B cells and neutrophils) and whole blood were compared in 16 Chinese patients with paediatric-onset SLE and 13 healthy controls using the Illumina HumanMethylationEPIC BeadChip. Comparison of DNAm in whole blood and within each independent cell lineage identified a consistent pattern of loss of DNAm at 21 CpG sites overlapping 15 genes, which represented a robust, disease-specific DNAm signature for paediatric-onset SLE in our cohort. In addition, cell lineage-specific changes, involving both loss and gain of DNAm, were observed in both novel genes and genes with well-described roles in SLE pathogenesis. This study also highlights the importance of studying DNAm changes in different immune cell lineages rather than only whole blood, since cell type-specific DNAm changes facilitated the elucidation of the cell type-specific molecular pathophysiology of SLE.

Keywords: DNA methylation; MethylationEPIC; SLE; blood; cell composition; cell lineage-specific; lupus; paediatric-onset.

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Figures

Figure 1.
Figure 1.
PCA of the DNA methylation dataset in all 145 samples. Each dot represents the DNAm data from one patient sample, either from whole blood or one of the purified lineages. (a) PCA of the raw DNAm data showed that samples clustered according to their cell type but not disease manifestation, indicating a strong cell type-specific DNA methylation signature. (b) PCA using the pSLE-specific DNAm signature showed that samples can be distinguished based on both disease group and cell lineage.
Figure 2.
Figure 2.
Venn diagram showing differentially methylated CpG sites across different cell lineages. The diagram shows the overlap between the differentially methylated CpG sites identified in CD4 + T cells, CD8 + T cells, B cells, neutrophils and whole blood in pSLE. (a) No CpG sites showed differential gain of DNA methylation in any cell type. (b) A total of 21 CpG sites showed differential loss of DNA methylation in all cell types.
Figure 3.
Figure 3.
Heatmap of the pSLE-specific DNAm signature. Unsupervised hierarchical clustering using the pSLE-specific DNAm signature showed that samples were first separated according to disease manifestation, followed by cell lineage. Hierarchical clustering was performed using Euclidian distance metrics.
Figure 4.
Figure 4.
Lineage-specific DNAm changes in pSLE patients. The diagram shows the similarities and differences between the differentially methylated genes identified in CD4 + T cells, CD8 + T cells, B cells and neutrophils in pSLE. Genes showing lineage-specific DNAm changes in pSLE are shown, and genes with multiple probes showing differential methylation changes are underlined.*Both differential hypomethylation and hypermethylation were found in OAS1LOM: loss of DNAm; GOM: gain of DNAm
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Grants and funding

This work was supported by the Research Grant Council’s General Research Fund (Ref: HKU 765513M).