NOMe-HiC: joint profiling of genetic variants, DNA methylation, chromatin accessibility, and 3D genome in the same DNA molecule

Cis-regulatory elements coordinate the regulation of their targeted genes’ expression. However, the joint measurement of cis-regulatory elements’ activities and their interactions in spatial proximity is limited by the current sequencing approaches. We describe a method, NOMe-HiC, which simultaneously captures single nucleotide polymorphisms, DNA methylation, chromatin accessibility (GpC methyltransferase footprints), and chromosome conformation changes from the same DNA molecule, together with the transcriptome, in a single assay. NOMe-HiC shows high concordance with state-of-the-art mono-omic assays across different molecular measurements and reveals coordinated chromatin accessibility at distal genomic segments in spatial proximity and novel types of long-range allele-specific chromatin accessibility.