Perspectives for the reconstruction of 3D chromatin conformation using single cell Hi-C data

Abstract

Construction of chromosomes 3D models based on single cell Hi-C data constitute an important challenge. We present a reconstruction approach, DPDchrom, that incorporates basic knowledge whether the reconstructed conformation should be coil-like or globular and spring relaxation at contact sites. In contrast to previously published protocols, DPDchrom can naturally form globular conformation due to the presence of explicit solvent. Benchmarking of this and several other methods on artificial polymer models reveals similar reconstruction accuracy at high contact density and DPDchrom advantage at low contact density. To compare 3D structures insensitively to spatial orientation and scale, we propose the Modified Jaccard Index. We analyzed two sources of the contact dropout: contact radius change and random contact sampling. We found that the reconstruction accuracy exponentially depends on the number of contacts per genomic bin allowing to estimate the reconstruction accuracy in advance. We applied DPDchrom to model chromosome configurations based on single-cell Hi-C data of mouse oocytes and found that these configurations differ significantly from a random one, that is consistent with other studies.

Super-resolution visualization of chromatin loop folding in human lymphoblastoid cells using interferometric photoactivated localization microscopy

“…S28 ) and observed significant heterogeneity regarding both loop shape and size in the single cells. We confirmed our observation by calculating the IMJ score 62 between distance maps from all reconstructed loop conformations. The average similarity was 35% which is close to 30% reported as cell-to-cell variability 62 (Fig.…”

“…S22 ). We further validated our modeling method by verifying how the abscence of a relatively continuous DNA region would influence the reliability of reconstructed structures using random walk polymer simulations and the Modified Jaccard Index 61 . The average IMJ between the reconstructed and the original structure depending on the gap size is presented in Fig.…”

“…Having the coordinates of all the 30-kb segments we then tried to infer the original chromatin structure using our TSP approach. We then compared the inferred order of the chromatin segments with the models from Bintu et al using Modified Jaccard Index (IMJ) 62 of the distances between the corresponding segments (Fig. S30 ).…”

“…Each of the original sets of beads was then reconstructed from each of our “leaky” structures by our modeling procedure (TSP solver) and interpolated to 340 beads. Then we used the Modified Jaccard Index (IMJ) 61 to compare the distance maps of these structures with the distance map of the original model (Fig. S23 ).…”

Biology and Model Predictions of the Dynamics and Heterogeneity of Chromatin-Nuclear Lamina Interactions

“…The structures allow inference on the regionalization of chromatin states ( Di Stefano et al, 2016 ; Paulsen et al, 2018 ; Paulsen et al, 2019 ), and on radial positioning of loci ( Briand et al, 2018 ), disease-associated LADs ( Paulsen et al, 2017 ) and cancer mutations ( Garcia-Nieto et al, 2017 ) ( Figure 2C ). It will be interesting to compare outputs of restraint-based model ensembles and of models generated from single-cell data ( Cardozo Gizzi, 2021 ; Kos et al, 2021 ) to determine the most powerful strategy for predicting chromatin structure dynamics. This would be relevant in the study of 3D cancer genomes, as cell-to-cell heterogeneity within tumors hampers many investigations.…”