TABLE 1.
Summary of inter-TAD alterations (Enhancer adoption and TAD fusion), the disease/abnormality they caused and their description.
| Enhancer adoption | ||
| LMNB1 locus | Adult-onset demyelinating leukodystrophy (ADLD) | A deletion eliminates a TAD boundary, leading to new interactions between the LMNB1 promoter and three non-cognate enhancers and its subsequent activation, resulting in the progressive central nervous system demyelination (Giorgio et al., 2014) |
| FOXG1 locus | Rett syndrome | A telomeric deletion, including the TAD border, results in the ectopic activation of FOXG1 by active enhancers in the brain (Allou et al., 2012) |
| GFI1B locus | Medulloblastoma | Somatic structural variants place GFI1 or GFI1B near active enhancer sites, resulting in activation (Northcott et al., 2014) |
| SNCAIP locus | Group 4 medulloblastomas | A duplication of SNCAIP gene results in the ectopic activation of the putative oncogene PRDM6 (Arabzade et al., 2020) |
|
TAD fusion | ||
| EPHA4 locus | Brachydactyly | Deletions in the EPHA4 locus that include a TAD border result in a fusion of the neighboring TADs, which attaches a cluster of limb-associated EPHA4 enhancers to the PAX3 gene and its concomitant mis-expression (Lupiáñez et al., 2015) |
| Six TAD boundaries encompassing T-ALL related genes | T-cell acute-lymphoblastic leukemia (T-ALL) or medulloblastoma | TAD disruption leads to ectopic proto-oncogene activation and abnormal cell proliferation (Northcott et al., 2014; Hnisz et al., 2016b; Weischenfeldt et al., 2017). CRISPR-engineered deletions of the TAD boundaries near the known oncogenes TAL1 and LMO2 result in new interactomes of those oncogenes with distal enhancers, leading to their aberrant activation (Hnisz et al., 2016b) |
| NOTCH1 locus | Ovarian cancer | Downregulation of NOTCH1 gene due to its altered interactome as a result of mutations in the CTCF sites that disrupt the TAD boundary (Ji et al., 2016) |
| Various CTCF binding sites | Colorectal cancer | Frequently mutated CTCF binding sites lead to TAD boundary disruption and altered interactomes between genes and their regulatory elements (Katainen et al., 2015) |
| IRS4 locus | Lung squamous carcinoma, sarcomas and cervical squamous carcinoma | Deletions occurring at TAD boundaries coinciding with CTCF recruitment downstream of the IRS4 locus led to IRS4 overexpression (Weischenfeldt et al., 2017) |
| NEK6 locus | B cell lymphoma cell lines | Deletion of all CTCF-binding sites in the NEK6 super-enhancer borders decreased the expression of NEK6 while increased the expression of the neighboring LHX2 gene (Huang et al., 2017) |