Abstract
Chromatin in the interphase nucleus is organised as a hierarchical series of structural domains, including self-interacting domains called topologically associating domains (TADs). This arrangement is thought to bring enhancers into closer physical proximity with their target genes, which often are located hundreds of kilobases away in linear genomic distance. TADs are demarcated by boundary regions bound by architectural proteins, such as CTCF and cohesin, although much remains to be discovered about the structure and function of these domains. Recent studies of TAD boundaries disrupted in engineered mouse models show that boundary mutations can recapitulate human developmental disorders as a result of aberrant promoter-enhancer interactions in the affected TADs. Similar boundary disruptions in certain cancers can result in oncogene overexpression, and CTCF binding sites at boundaries appear to be hyper-mutated across cancers. Further insights into chromatin organisation, in parallel with accumulating whole genome sequence data for disease cohorts, are likely to yield additional valuable insights into the roles of noncoding sequence variation in human disease.
Highlights
The past decade has seen a series of revolutions in the fields of human chromatin structure and regulatory genomics, driven largely by novel, high-throughput sequencing-based assays and large consortium projects
The development of chromatin conformation capture (3C) methods, most prominently high-throughput chromosome conformation capture (Hi-C), has provided a view of the higher-order folding and nuclear organisation of human chromosomes[2]. These data reveal a landscape of physically interacting regions along chromosomes and, at a larger scale, the existence of preferentially self-interacting chromatin domains, extending across hundreds of kilobases up to multimegabase regions
The results suggest that up to about 12% of deletions in the DECIPHER database resulted in enhancer adoption, based on the tissue-specific activity of a given enhancer and the tissue that was affected in the disease phenotype of the patient who carried the deletion
Summary
F1000 Faculty Reviews are written by members of the prestigious F1000 Faculty. They are commissioned and are peer reviewed before publication to ensure that the final, published version is comprehensive and accessible. The reviewers who approved the final version are listed with their names and affiliations. Any comments on the article can be found at the end of the article
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