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

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.

SPIN reveals genome-wide landscape of nuclear compartmentalization

“…Nuclear compartmentalization analysis has primarily focused on A/B compartments based on Hi-C data. Although five major Hi-C subcompartments were revealed in (Rao et al, 2014) in GM12878 cells, such analysis has not been possible in other datasets with low to moderate coverage until recently (Xiong and Ma, 2019). Additionally, prior work on LADs and inter-LADs also made the binary distinction of chromatin domains associated with the nuclear lamina, where LADs and inter-LADs largely correspond to A/B compartment separations.…”

“…2c). We further compared histone mark changes at the transition boundaries of SPIN states when the boundaries were defined by Hi-C subcompartments in K562 (Xiong and Ma, 2019). This reveals a sharper transition of histone marks at SPIN state boundaries as compared to Hi-C subcompartments ( Fig.…”

“…However, the spatial localization context of Hi-C subcompartments has not been clearly revealed except that Chen et al (2018) used the Hi-C subcompartments to identify the two transcriptional hot-zones based on TSAseq scores by comparing to A1/A2 subcompartments (defined in GM12878 which has extremely high coverage Hi-C data). The recently developed algorithm SNIPER (Xiong and Ma, 2019) facilitates the identification of subcompartments in Hi-C data with low to moderate coverage and provides the Hi-C subcompartment annotations specifically in K562. Here we directly compare the 10 SPIN states with Hi-C subcompartments in K562.…”

“…Earlier studies have shown the correlation between the genome compartmentalization patterns and transcriptional activities (Lieberman-Aiden et al, 2009;Rao et al, 2014;Xiong and Ma, 2019). We sought to assess whether the SPIN states, which offer more detailed compartmentalization patterns, further stratify the transcriptional activity based on spatial locations of the chromatin.…”

“…As we have already shown, Hi-C subcompartments are highly correlated with SPIN states although the SPIN states provide more detailed and explicit compartmen-talization views relative to subnuclear bodies. We compared the SPIN states in K562 with the SNIPER Hi-C subcompartments across 9 human cell types (Xiong and Ma, 2019), including K562, GM12878, HAP1, HeLa, HMEC, HSPC, HUVEC, IMR90, and TCell. We calculated the SNIPER Entropy score as the metric of conservation for Hi-C subcompartments across cell lines (Fig.…”