A three-dimensional map of the human genome at kilobase resolution reveals principles of chromatin looping

By Suhas S. P. Rao, Miriam H. Huntley, Neva C. Durand, Elena K. Stamenova, Ivan D. Bochkov, James T. Robinson, Adrian L. Sanborn, Ido Machol, Arina D. Omer, Eric S. Lander and 1 more. Cell, 2014

8,229 citations recorded by the source corpus.

Summary We use in situ Hi-C to probe the three-dimensional architecture of genomes, constructing haploid and diploid maps of nine cell types. The densest, in human lymphoblastoid cells, contains 4.9 billion contacts, achieving 1-kilobase resolution. We find that genomes are partitioned into local domains, which are associated with distinct patterns of histone marks and segregate into six subcompartments. We identify ~10,000 loops. These loops frequently link promoters and enhancers, correlate with gene activation, and show conservation across cell types and species. Loop anchors typically occur at domain boundaries and bind CTCF. CTCF sites at loop anchors occur predominantly (>90%) in a convergent orientation, with the asymmetric motifs ‘facing’ one another. The inactive X-chromosome splits into two massive domains and contains large loops anchored at CTCF-binding repeats.

Subfields: Molecular Biology

View Paper: https://www.semanticscholar.org/paper/eb9a0cf8f006fa24eea5af405c7f088073e486a1

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Molecular Biology

Citations in the corpus

Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci (2016, methodology): “We thus interrogated high resolution, genome-wide topological maps (Rao et al., 2014) to establish the relative positioning of pcRNAs and their coding genes relative to genomic loops.”
Chromatin organization by an interplay of loop extrusion and compartmental segregation (2017, background): “Cohesin topologically entraps DNA (24), can slide along DNA and over small DNA-bound proteins and nucleosomes (25, 26), and is enriched at TAD boundaries (9) and corner peaks (27).”
Chromatin extrusion explains key features of loop and domain formation in wild-type and engineered genomes (2015, methodology): “A third feature of chromatin folding is the formation of loops, which bring pairs of genomic sites that lie far apart along the linear genome into close spatial proximity (8, 11).”
Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions (2015, background): “Chromatin Interaction Landscape of the Extended WNT6/IHH/EPHA4/PAX3 Region To elucidate the genetic basis of these birth defects, we sought to examine the regulatory landscape at this locus in more detail.”
A Compendium of Chromatin Contact Maps Reveal Spatially Active Regions in the Human Genome (2016, neutral): “Our data indicate that FIREs are hotspots of local chromatin interactions that are distinct from compartments, TADs, and chromatin loops (Rao et al., 2014), which are generally anchored by convergent CTCF binding.”
The Juicebox Assembly Tools module facilitates de novo assembly of mammalian genomes with chromosome-length scaffolds for under $1000 (2018, methodology): “Second, we generate an in situ Hi-C library (Rao, Huntley et al. 2014), and sequence 100 million paired-end reads (2x150).”
Cell-free DNA comprises an in vivo nucleosome footprint that informs its tissues-of-origin (2016, neutral): “We further examined the median peak-to-peak spacing within 100 kilobase (kb) windows that had been assigned to compartment A (enriched for open chromatin) or compartment B (enriched for closed chromatin) on the basis of chromatin contact maps in a lymphoblastoid cell line (Rao et al., 2014).”
Machine Learning for Integrating Data in Biology and Medicine: Principles, Practice, and Opportunities (2018, background): “Rao et al. [120] have shown that chromatin compartmental-izes itself into either gene dense, highly expressed regions, or lowly expressed regions.”
Ever-changing landscapes: transcriptional enhancers in development and evolution (2016, background): “In fact, high-resolution Hi-C maps in mammalian cell lines revealed that 86% of roughly 10,000 long-range contact peaks, interpreted as anchors for chromatin loops, are associated with CTCF (Rao et al., 2014).”
Topologically associating domains and chromatin loops depend on cohesin and are regulated by CTCF, WAPL, and PDS5 proteins (2017, methodology): “…our experiments, combined with the previous observations that cohesin and CTCF are enriched at TAD boundaries and loop anchors (Dixon et al, 2012; Rao et al, 2014), strongly support the hypothesis that cohesin is a key determinant of chromatin structure at multiple levels, that in the case of…”
Insights about clonal hematopoiesis from 8,342 mosaic chromosomal alterations (2018, background): “Most individuals displayed strong consistent allele-specific expression across the three SNPs, as expected for XCI in clonal lymphoblastoid cell lines39; however, we observed no evidence of systematically biased XCI in favour of one allele or the other (Supplementary Table 10).”