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

Nat Methods. 2019 Oct;16(10):999-1006. doi: 10.1038/s41592-019-0547-z. Epub 2019 Sep 9.


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 >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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Chromatin / metabolism
  • DNA Methylation*
  • Datasets as Topic
  • Epigenesis, Genetic
  • Gene Expression Regulation
  • Genome, Human*
  • Genome-Wide Association Study
  • Humans
  • Single-Cell Analysis*


  • Chromatin