DeepLoop enables robust mapping of DNA loops from low-depth single cell or allele-resolved Hi-C data at high resolution. DeepLoop enables robust mapping of DNA loops from low-depth single cell or allele-resolved Hi-C data at high resolution

High-resolution mapping of the gene regulatory chromatin interactions from noisy Hi-C contact heatmaps remains a major challenge in 3D genome research due to the complex bias structure and severe data sparsity. Here we present DeepLoop, which addresses this problem by combining a rigorous bias correction strategy (HiCorr) and deep learning-based signal enhancement techniques. We demonstrated that DeepLoop can robustly identify high-resolution chromatin interactions from low-depth and single cell Hi-C data. With DeepLoop, we for the first-time mapped the genetic and epigenetic determinants of human homolog-specific chromatin loops in GM12878 cells at 5kb-resolution. We nominated two new imprinting loci with unbalanced DNA folding in additional to the well-known H19/IGF2 locus. Interestingly, we also found that the sub-TAD loops at the DXZ4 “megadomain” boundary escapes X-inactivation, but the loops at the FIRRE “superloop” locus do not escape. Unexpectedly, DeepLoop detected four previously unknown Mb-sized heterozygous structure variants in the GM12878 genome, including two large inversions causing allele-specific gene expression via enhancer rewiring. Finally, DeepLoop also pinpointed dozens of loop regulatory SNPs that often have transcriptional consequences. Taken together, DeepLoop expands the use of Hi-C to provide genome-wide insights into the genetics of 3D genome at loop resolution. Overall design: DeepLoop robustly identify high-resolution chromatin loops regardless of noise and depth. Each text file (300K) contains a chromatin loop calling list from Hi-C data for one cell type.从带有噪声的Hi-C（高通量染色体构象捕获）接触热图中实现基因调控染色质相互作用的高分辨率图谱绘制，因存在复杂的偏差结构与严重的数据稀疏性，仍是三维基因组研究领域的一大核心挑战。本研究提出DeepLoop方法，通过结合严谨的偏差校正策略（HiCorr）与基于深度学习的信号增强技术解决该问题。本研究证实，DeepLoop可从低深度及单细胞Hi-C数据中稳健识别高分辨率染色质相互作用。借助DeepLoop，本研究首次在5千碱基分辨率下，绘制了GM12878细胞中人类同源物特异性染色质环的遗传与表观遗传决定因子图谱。除经典的H19/IGF2位点外，本研究还鉴定出两个具备非平衡DNA折叠特性的全新印记基因座。有趣的是，本研究还发现，DXZ4‘巨型结构域’边界处的亚拓扑关联结构域（sub-TAD）环可逃逸X染色体失活，而FIRRE‘超级环’位点处的环则无法逃逸。出乎意料的是，DeepLoop在GM12878基因组中检测到4个此前未被报道的兆碱基级杂合结构变异，其中包括2个通过增强子重编程导致等位基因特异性基因表达的大片段倒位。最后，DeepLoop还精准定位了数十个通常会产生转录调控效应的染色质环调控单核苷酸多态性（SNPs）。综上，DeepLoop拓展了Hi-C技术的应用范围，可在染色质环分辨率下为三维基因组遗传学研究提供全基因组层面的见解。【总体设计】：无论数据噪声与测序深度如何，DeepLoop均可稳健识别高分辨率染色质环。每个文本文件（300K）包含来自单种细胞类型的Hi-C数据染色质环调用列表。