Robust Hi-C Maps of Enhancer-Promoter Interactions Reveal the Function of Non-coding Genome in Neural Development and Diseases

Abstract

Genome-wide mapping of chromatin interactions at high resolution remains experimentally and computationally challenging. Here we used a low-input ''easy Hi-C'' protocol to map the 3D genome architecture in human neurogenesis and brain tissues and also demonstrated that a rigorous Hi-C bias-correction pipeline (HiCorr) can significantly improve the sensitivity and robustness of Hi-C loop identification at sub-TAD level, especially the enhancer-promoter (E-P) interactions. We used HiCorr to compare the high-resolution maps of chromatin interactions from 10 tissue or cell types with a focus on neurogenesis and brain tissues. We found that dynamic chromatin loops are better hallmarks for cellular differentiation than compartment switching. HiCorr allowed direct observation of cell-type-and differentiation-specific E-P aggregates spanning large neighborhoods, suggesting a mechanism that stabilizes enhancer contacts during development. Interestingly, we concluded that Hi-C loop outperforms eQTL in explaining neurological GWAS results, revealing a unique value of high-resolution 3D genome maps in elucidating the disease etiology.

Experience-independent transformation of single-cell 3D genome structure and transcriptome during postnatal development of the mammalian brain

“…populationaveraged chromatin contact maps), but not actual 3D structures. These methods also lump together the diverse sub-types of neurons (and in many cases, glia, too) and mask critical celltype-specific features (Lu et al, 2020;Won et al, 2016). So far, bulk Hi-C only revealed 3D genome refolding in neurons that are differentiated in vitro (Bonev et al, 2017;Lu et al, 2020;Rajarajan et al, 2018), or isolated at a single time point from the embryonic (day 14.5) mouse brain (Bonev et al, 2017).…”

“…These methods also lump together the diverse sub-types of neurons (and in many cases, glia, too) and mask critical celltype-specific features (Lu et al, 2020;Won et al, 2016). So far, bulk Hi-C only revealed 3D genome refolding in neurons that are differentiated in vitro (Bonev et al, 2017;Lu et al, 2020;Rajarajan et al, 2018), or isolated at a single time point from the embryonic (day 14.5) mouse brain (Bonev et al, 2017). Single-cell 3C/Hi-C has been achieved in adult human brains (Lee et al, 2019), but had low resolution, yielded no 3D structures, and could not distinguish different neuronal sub-types-such as excitatory and inhibitory neurons, whose imbalance leads to many psychiatric disorders-based on structural information alone.…”

Somatic mutations in Parkinson disease are enriched in synaptic and neuronal processes

“…This limited our power to observe different cell lineages and their presence at each tissue or perform mutational signature deconvolution. Furthermore, the decreasing cost of sequencing and recent advances in contact maps (Lu et al 2020) make finding and interpreting non-coding variants more accessible.…”

HiCRes: a computational method to estimate and predict the resolution of HiC libraries

“…Within each chromosome, the chromatin can be organized into megabase-size domains, called topologically associated domains (TADs) [3,4]. At the kilobase level, two genomic loci can join together to form chromatin loops [4][5][6]. This organization is dynamic and changes during distinct stages of a cell's life including cell cycle [7][8][9], differentiation [5,10,11] and senescence [12,13].…”

“…At the kilobase level, two genomic loci can join together to form chromatin loops [4][5][6]. This organization is dynamic and changes during distinct stages of a cell's life including cell cycle [7][8][9], differentiation [5,10,11] and senescence [12,13]. 3D chromatin organization is associated with gene expression regulation [14][15][16][17][18][19] and DNA replication timing [7,[20][21][22][23][24], but the relationship between these features is still poorly known.…”