| First Author | Despang A | Year | 2019 |
| Journal | Nat Genet | Volume | 51 |
| Issue | 8 | Pages | 1263-1271 |
| PubMed ID | 31358994 | Mgi Jnum | J:282642 |
| Mgi Id | MGI:6381271 | Doi | 10.1038/s41588-019-0466-z |
| Citation | Despang A, et al. (2019) Functional dissection of the Sox9-Kcnj2 locus identifies nonessential and instructive roles of TAD architecture. Nat Genet 51(8):1263-1271 |
| abstractText | The genome is organized in three-dimensional units called topologically associating domains (TADs), through a process dependent on the cooperative action of cohesin and the DNA-binding factor CTCF. Genomic rearrangements of TADs have been shown to cause gene misexpression and disease, but genome-wide depletion of CTCF has no drastic effects on transcription. Here, we investigate TAD function in vivo in mouse limb buds at the Sox9-Kcnj2 locus. We show that the removal of all major CTCF sites at the boundary and within the TAD resulted in a fusion of neighboring TADs, without major effects on gene expression. Gene misexpression and disease phenotypes, however, were achieved by redirecting regulatory activity through inversions and/or the repositioning of boundaries. Thus, TAD structures provide robustness and precision but are not essential for developmental gene regulation. Aberrant disease-related gene activation is not induced by a mere loss of insulation but requires CTCF-dependent redirection of enhancer-promoter contacts. |
