Reconstructing spatial organizations of chromosomes through manifold learning

Nucleic Acids Res. 2018 May 4;46(8):e50. doi: 10.1093/nar/gky065.

Abstract

Decoding the spatial organizations of chromosomes has crucial implications for studying eukaryotic gene regulation. Recently, chromosomal conformation capture based technologies, such as Hi-C, have been widely used to uncover the interaction frequencies of genomic loci in a high-throughput and genome-wide manner and provide new insights into the folding of three-dimensional (3D) genome structure. In this paper, we develop a novel manifold learning based framework, called GEM (Genomic organization reconstructor based on conformational Energy and Manifold learning), to reconstruct the three-dimensional organizations of chromosomes by integrating Hi-C data with biophysical feasibility. Unlike previous methods, which explicitly assume specific relationships between Hi-C interaction frequencies and spatial distances, our model directly embeds the neighboring affinities from Hi-C space into 3D Euclidean space. Extensive validations demonstrated that GEM not only greatly outperformed other state-of-art modeling methods but also provided a physically and physiologically valid 3D representations of the organizations of chromosomes. Furthermore, we for the first time apply the modeled chromatin structures to recover long-range genomic interactions missing from original Hi-C data.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Algorithms
  • Chromatin / chemistry
  • Chromatin / genetics
  • Chromatin / ultrastructure
  • Chromosome Mapping / methods
  • Chromosomes, Human / chemistry*
  • Chromosomes, Human / genetics*
  • Chromosomes, Human / ultrastructure
  • Chromosomes, Human, Pair 14 / chemistry
  • Chromosomes, Human, Pair 14 / genetics
  • Chromosomes, Human, Pair 14 / ultrastructure
  • Computational Biology / methods
  • Computer Simulation
  • Genome, Human
  • Genomics / methods
  • Humans
  • Imaging, Three-Dimensional
  • In Situ Hybridization, Fluorescence
  • Machine Learning
  • Models, Molecular*
  • Molecular Conformation

Substances

  • Chromatin