Cell

Biology

Gene

Enhancer

Epigenomics

Gene expression

Cell type

DNA methylation

Computational biology

Cell biology

Epigenetics

Genetics

Chromatin

Chromosome conformation capture

Nature Methods

Dynamic three-dimensional chromatin conformation is a critical mechanism for gene regulation during development and disease. Despite this, profiling of three-dimensional genome structure from complex tissues with cell-type specific resolution remains challenging. Recent efforts have demonstrated that cell-type specific epigenomic features can be resolved in complex tissues using single-cell assays. However, it remains unclear whether single-cell chromatin conformation capture (3C) or Hi-C profiles can effectively identify cell types and reconstruct cell-type specific chromatin conformation maps. To address these challenges, we have developed single-nucleus methyl-3C sequencing to capture chromatin organization and DNA methylation information and robustly separate heterogeneous cell types. Applying this method to &gt;4,200 single human brain prefrontal cortex cells, we reconstruct cell-type specific chromatin conformation maps from 14 cortical cell types. These datasets reveal the genome-wide association between cell-type specific chromatin conformation and differential DNA methylation, suggesting pervasive interactions between epigenetic processes regulating gene expression. Single-nucleus methyl-3C sequencing jointly interrogates 3D chromatin organization and DNA methylation in human cells, and these joint measurements more accurately distinguish different cell types than either unimodal method.

Simultaneous profiling of 3D genome structure and DNA methylation in single human cells