GSE171026
SINEultaneous profiling of epigenetic heterogeneity and transcriptome in single cells [AML01 scTEM-seq]
Global changes in DNA methylation are observed in several developmental and disease contexts, and single-cell analyses are beginning to reveal the heterogeneous regulation of these processes. However, these studies are limited by the poor alignment rates and high sequencing demands associated with single-cell analysis of DNA methylation. We present single-cell transposable element methylation sequencing (scTEM-seq) for cost-effective estimation of global DNA methylation levels. By targeting high-copy LINE-1 and SINE Alu elements, we achieve amplicon bisulphite sequencing with thousands of annotated loci covered in each scTEM-seq library. Parallel transcriptome analysis of the same single cell is also performed to link global DNA methylation heterogeneity with transcriptional consequences. We apply scTEM-seq to KG1a acute myeloid leukaemia (AML) cells, and primary cells from an AML patient. Treatment of KG1a cells with the hypomethylating agent, decitabine, induces global DNA methylation heterogeneity associated with altered expression of viral response pathways. We also compare global levels of DNA methylation to expression of transposable elements and find a predominance of negative correlations in both the KG1a and patient cells. Finally, we observe co-ordinated upregulation of many transposable elements in a sub-set of decitabine treated KG1a cells. These observations suggest that viral mimicry processes important for epigenetic therapy and tumour immunogenicity are variably active in AML cells. By linking global DNA methylation heterogeneity with transcriptional consequences, scTEM-seq will refine our understanding of epigenetic regulation in cancer and beyond. Overall design: scTEM-seq (single-cell transposable element methylation sequencing)