TABLE 3.

Summary of intra-TAD alterations (Single nucleotide polymorphisms and gain-of-function alterations), the disease/abnormality they caused and their description.

Single nucleotide polymorphisms (SNPs)
HSBL1-MYB locus	Hemoglobinopathies	SNPs affect the recruitment of the LDB1 complex to the MYB enhancer, impairing its interaction with the MYB promoter. Consequently, decrease of MYB expression results in an increase of HbF expression (Stadhouders et al., 2014)
CLEC16A locus	Autoimmune disease	SNPs in intron 19 of the CLEC16A gene have been shown to promote the interaction of the intron with the adjacent DEXI gene, resulting to its expression (Davison et al., 2012)
FTO locus	Obesity	An intron of the FTO gene containing obesity-associated SNPs interacts with the distal IRX3 gene, and thus controlling its expression (Smemo et al., 2014; Schoenfelder and Fraser, 2019)
SNCA locus	Parkinson disease	A common Parkinson disease SNP in a non-coding distal enhancer factor prevents two repressive transcription factors, EMX2 and NKX6-1, from binding to a regulatory element, and thus, resulting in SNCA transcriptional upregulation (Soldner et al., 2016)
Various loci	Chronic Kidney Disease (CKD)	SNPs in both coding and non-coding regions have been discovered in studies of CKD, and dysregulation of gene expression of the 23 genes identified to be associated with such SNPs is possibly a contributing factor in CKD pathophysiology (Brandt et al., 2018)
Intra-TAD gain-of-function alterations
SHH locus	Polydactyly	Point mutations in the Sonic hedgehog (SHH) regulatory region ZRS result in the ectopic expression of SHH at the anterior margin in mouse. Although not formerly demonstrated in this study, these mutations allow the formation of chromatin looping between the ZRS region and the SHH promoter (Lettice et al., 2003).
MYC locus	Lung adenocarcinoma	Amplification of MYC-regulating enhancers results in a slightly higher MYC expression than in samples without amplification of MYC enhancers. The enhancer-amplified samples had a comparable MYC expression levels when compared to samples with MYC coding area amplification (Zhang et al., 2016; Agrawal et al., 2019)
IHH locus	Craniosynostosis and synpolydactyly	Duplications of regulatory elements within the IHH locus led to misexpression or overexpression of IHH and by this affect the complex regulatory signaling network during digit and skull development respectively (Klopocki et al., 2011)
CTSB locus	Keratolytic winter erythema	Overexpression of CTSB as a result of enhancer duplications (Ngcungcu et al., 2017)
Various loci	Prostate cancer	SNPs, associated with prostate cancer, co-localize/affect regions of active histone modification and transcription factor binding sites. 15 of the 17 identified genes in these loci exhibit a substantial change in expression, suggesting that the genes physically interacting with risk loci are associated to prostate cancer (Du et al., 2016)
Various loci	Atherosclerotic disease	294 additional candidate expressed genes for coronary artery disease (CAD) and large artery stroke (LAS) have been identified as potential factors in the pathophysiology of human atherosclerotic disease (Haitjema et al., 2017)
Various loci	Inflammatory bowel disease (IBD)	Mutations in DNA regulatory elements (DREs) can contribute to IBD etiology by altering gene expression (Meddens et al., 2016)
Pitx1 locus	Liebenberg syndrome	Deletion mutations upstream of the hindlimb expressed Pitx1 gene result in intra-TAD conformation changes, merging a forelimb and hindlimb Pitx1 gene enhancer (Kragesteen et al., 2018)
PITX1 locus	As previous	Translocation of two enhancers from chromosome 18 upstream of the PITX1 on chromosome 5 (TAD shuffling), resulted in an increased PITX1 expression (Spielmann et al., 2012)