MOUSE MODELS OF SOX9-KCNJ2 LOCUS (Page 22-23)

; [What happens with inter-TAD duplications?]

Duplications of the boundary and the flanking gene create a new chromatin domain (neo-TAD). In the neo-TAD, the duplicated gene A (gene A') is regulated under the control of the duplicated enhancer of gene B, driving ectopic expression in the developing limbs.

; [What is Cooks syndrome and what causes it?]

Cooks syndrome is characterised by short digits and nail aplasia. It is caused by duplication of a TAD boundary at the SOX9 locus causing neo-TAD formation.

; [What was covered in Lecture 2 regarding the SOX9 locus?]

PRS (Pierre Robin Sequence) enhancer variants near SOX9.

; [What did the Ibrahim lab study at the SOX9-Kcnj2 locus?]

They examined the importance of TAD formation at this locus on gene expression by generating many different mouse models including CTCF site deletions and inversions.

; [What happened when CTCF binding motifs between the Kcnj2-TAD and Sox9-TAD were removed?]

Removal led to the formation of a larger fused TAD, partially mimicking the molecular genetics of Cooks syndrome.

; [What changes in gene expression occurred with neo-TAD formation?]

Neo-TAD formation led to alterations in Sox9 and Kcnj2 gene expression patterns in limb and digit development. Sox9 expression was no longer limited to the digits, while Kcnj2 expression was found de novo in the digits in the absence of the CTCF boundary site.

; [How does this correspond to clinical characteristics?]

This corresponds well to the clinical characteristics of Cooks syndrome.