GTAGMe-seq: joint profiling of genetic variants, DNA methylation, GpC methyltransferase footprints, and 3D genome in the same DNA molecules

Cis-regulatory elements (CREs) coordinate to regulate the expression of their targeted genes, up to megabases away. However, the joint measurement of CREs’ activities and their interactions over large genomic distances is limited by the current sequencing approaches. We report a method, GTAGMe-seq, which simultaneously captures the single nucleotide polymorphisms, DNA methylation, GpC methyltransferase footprints, and chromosome conformation changes from the same DNA molecules, together with transcriptome in the same assay. GTAGMe-seq shows high concordance with the state-of-art mono-omics assays across different molecular measurements. It reveals the coordinated GpC methyltransferase footprints at distal genomic segments in spatial proximity and different types of long-range allele-specific methyltransferase footprints.