Revealing Hi-C subcompartments by imputing inter-chromosomal chromatin interactions

Kyle Xiong,Jian Ma

doi:10.1038/s41467-019-12954-4

Kyle Xiong, Jian Ma

Open Access

https://doi.org/10.1038/s41467-019-12954-4

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Abstract

Higher-order genome organization and its variation in different cellular conditions remain poorly understood. Recent high-coverage genome-wide chromatin interaction mapping using Hi-C has revealed spatial segregation of chromosomes in the human genome into distinct subcompartments. However, subcompartment annotation, which requires Hi-C data with high sequencing coverage, is currently only available in the GM12878 cell line, making it impractical to compare subcompartment patterns across cell types. Here we develop a computational approach, SNIPER (Subcompartment iNference using Imputed Probabilistic ExpRessions), based on denoising autoencoder and multilayer perceptron classifier to infer subcompartments using typical Hi-C datasets with moderate coverage. SNIPER accurately reveals subcompartments using moderate coverage Hi-C datasets and outperforms an existing method that uses epigenomic features in GM12878. We apply SNIPER to eight additional cell lines and find that chromosomal regions with conserved and cell-type specific subcompartment annotations have different patterns of functional genomic features. SNIPER enables the identification of subcompartments without high-coverage Hi-C data and provides insights into the function and mechanisms of spatial genome organization variation across cell types.

Highlights

Higher-order genome organization and its variation in different cellular conditions remain poorly understood
These results demonstrate that SNIPER provides us with the capability to reliably compare Hi-C subcompartment annotations in multiple cell types and reveal cross cell type patterns of conservation and variation of Hi-C subcompartments
We introduced SNIPER, a computational method that imputes inter-chromosomal contacts missing from sparse Hi-C datasets and predicts subcompartment annotations at 100kb scale across multiple cell types

Summary

Introduction

Higher-order genome organization and its variation in different cellular conditions remain poorly understood. Recent high-coverage genome-wide chromatin interaction mapping using Hi-C has revealed spatial segregation of chromosomes in the human genome into distinct subcompartments. We apply SNIPER to eight additional cell lines and find that chromosomal regions with conserved and cell-type specific subcompartment annotations have different patterns of functional genomic features. SNIPER enables the identification of subcompartments without high-coverage Hi-C data and provides insights into the function and mechanisms of spatial genome organization variation across cell types. Rao et al.[5] identified Hi-C subcompartments that divide A/B compartments into five primary subcompartments: A1, A2, B1, B2, and B3 These Hi-C subcompartments show distinct and more refined associations with various genomic and epigenomic features such as gene expression, active and repressive histone marks, DNA replication timing, and specific subnuclear structures[5]. ChIP-seq datasets in GM12878, MEGABASE was trained to predict the original subcompartment annotations in GM12878 from Rao et al.[5] with over 60% consistency in each subcompartment compared to the original annotations

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