Disruptions of Topological Chromatin Domains Cause Pathogenic Rewiring of Gene-Enhancer Interactions

By D. Lupiáñez, K. Kraft, V. Heinrich, P. Krawitz, F. Brancati, E. Klopocki, D. Horn, H. Kayserili, John M. Opitz, R. Laxová and 12 more. Cell, 2015

1,963 citations recorded by the source corpus.

SUMMARY Mammalian genomes are organized into megabase-scale topologically associated domains (TADs). We demonstrate that disruption of TADs can rewire long-range regulatory architecture and result in pathogenic phenotypes. We show that distinct human limb malformations are caused by deletions, inversions, or duplications altering the structure of the TAD-spanning WNT6/IHH/EPHA4/PAX3 locus. Using CRISPR/Cas genome editing, we generated mice with corresponding rearrangements. Both in mouse limb tissue and patient-derived fibroblasts, disease-relevant structural changes cause ectopic interactions between promoters and non-coding DNA, and a cluster of limb enhancers normally associated with Epha4 is misplaced relative to TAD boundaries and drives ectopic limb expression of another gene in the locus. This rewiring occurred only if the variant disrupted a CTCF-associated boundary domain. Our results demonstrate the functional importance of TADs for orchestrating gene expression via genome architecture and indicate criteria for predicting the pathogenicity of human structural variants, particularly in non-coding regions of the human genome.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/183d2e4d4d1dbe2905f336b726a8a6be9dc21090

How researchers see this paper

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

In Genetics

In Molecular Biology

Citations in the corpus

HiGlass: web-based visual exploration and analysis of genome interaction maps (2017, background): “Hi-C maps have helped implicate changes in genome organization in a variety of disorders, including acute lymphoblastic leukemia (Hnisz et al. 2016) , colorectal cancer (Seaman et al. 2017) , and limb development disorders (Lupiáñez et al. 2015) .”
Ever-changing landscapes: transcriptional enhancers in development and evolution (2016, background): “Formation of TAD Boundaries and CTCF-Mediated Loops Since TAD boundaries appear to restrict both enhancer function (Dowen et al., 2014; Flavahan et al., 2016; Guo et al., 2015; Lupiáñez et al., 2015) and spreading of chromatin marks”
Genomic positional conservation identifies topological anchor point (tap)RNAs linked to developmental loci (2016, background): “…important developmental genes are positioned and regulated at such boundaries (Fabre et al., 2015) and these structures can be especially implicated in developmental diseases and cancer (Hnisz et al., 2016; Ibn-Salem et al., 2014; Katainen et al., 2015; Lupianez et al., 2015; Maass et al., 2012).”
Cohesin loss eliminates all loop domains (2017, background): “by preventing enhancers from forming ectopic interactions with targets that lie in a different loop domain (Lupiáñez et al., 2015; Flavahan et al., 2016).”
Single-nucleus Hi-C reveals unique chromatin reorganization at oocyte-to-zygote transition (2017, background): “We also examined whether loops 8 and TADs 15,16 , prominent functional features of chromatin organization 17–19 , are present in individual cells.”
YY1 Is a Structural Regulator of Enhancer-Promoter Loops (2017, positive): “…enhancers and genes within the CTCF-CTCF loops from elements outside those loops (Dixon et al., 2012; Dowen et al., 2014; Hnisz et al., 2016b; Ji et al., 2016; Lupiáñez et al., 2015; Narendra et al., 2015; Nora et al., 2012; Phillips-Cremins et al., 2013; Rao et al., 2014; Tang et al., 2015).”
Targeted degradation of CTCF decouples local insulation of chromosome domains from genomic compartmentalization (2017, positive): “…M anuscript A uthor M anuscript important: inverting a single CTCF site can be enough to rewire the direction of looping and disrupt proper packaging of the underlying chromosomal segment into an insulated TAD (Guo et al., 2015; Lupiáñez et al., 2015; Sanborn et al., 2015; de Wit et al., 2015).”