Robust Hi-C Maps of Enhancer-Promoter Interactions Reveal the Function of Non-coding Genome in Neural Development and Diseases

Mol Cell. 2020 Aug 6;79(3):521-534.e15. doi: 10.1016/j.molcel.2020.06.007. Epub 2020 Jun 26.


Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input "easy Hi-C" protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type- and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.

Keywords: GWAS; Hi-C; HiCorr; bias correction; chromatin loop; eHi-C; enhancer-promoter interaction; neurogenesis; transcription regulation.

Publication types

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

MeSH terms

  • Adult
  • Cell Line
  • Cerebrum / cytology
  • Cerebrum / growth & development
  • Cerebrum / metabolism
  • Chromatin / metabolism*
  • Chromatin / ultrastructure
  • Chromosome Mapping
  • Enhancer Elements, Genetic*
  • Fetus
  • Gene Expression Regulation, Developmental*
  • Gene Regulatory Networks*
  • Genome, Human*
  • Histones / genetics
  • Histones / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Nerve Tissue Proteins / classification
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • Neural Stem Cells / cytology
  • Neural Stem Cells / metabolism
  • Neurodegenerative Diseases / genetics
  • Neurodegenerative Diseases / metabolism
  • Neurodegenerative Diseases / pathology
  • Neurogenesis / genetics*
  • Neurons / cytology
  • Neurons / metabolism
  • Promoter Regions, Genetic*
  • Temporal Lobe / cytology
  • Temporal Lobe / growth & development
  • Temporal Lobe / metabolism
  • Transcription Factors / classification
  • Transcription Factors / genetics
  • Transcription Factors / metabolism


  • Chromatin
  • Histones
  • Nerve Tissue Proteins
  • Transcription Factors