Long-range epigenetic concordance revealed by simultaneous profiling of DNA methylation and chromosomal conformation changes in bulk and single cell Methyl-HiC

Genomic sequences, as well as its covalent epigenetic modifications, are spatially organized into three-dimensional structures. Here, we developed Methyl-HiC by combining in situ Hi-C and whole genome bisulfite sequencing (WGBS) to simultaneously capture genome-wide chromosome conformation changes and DNA methylation within the same DNA molecule. Methyl-HiC generated consistent information compared with in situ Hi-C and WGBS from the same cell line. We detected long-range DNA methylation concordance in general but varied in different chromatin states. We extended Methyl-HiC to single cell level and applied it on 103 primed and 47 naïve mouse embryonic stem cells (mESCs). We revealed the heterogeneity of chromosomal conformation changes by grouping cells in their DNA methylation level alone. We also observed increases of DNA methylation stochasticity and decreases of contact frequency together in late replication timing regions. Our method here paves the road to evaluate the direct long-range effect of epigenetic alterations in different pathological and healthy conditions at genome-wide and single cell level.