Chromatin is organized hierarchically at multiple scales and this is crucial for the spatiotemporal regulation of transcription. The fundamental units of nuclear organization are the highly self-interacting regions of chromatin termed as ‘Topologically Associated Domains’ or TADs. TADs are formed by a loop-extrusion mechanism mediated by two proteins: cohesin and CTCF. The major function of these units is to limit the action of regulatory elements to genes within the same TAD. Disruption of TAD boundaries can lead to dysregulation of gene expression and accessibility with a dramatic phenotypic consequence on developmental processes and pathogenesis Given the importance of CTCF in the formation of TADs and the role of the latter in gene regulation, it is not surprising that mutation in this protein have been reported in several diseases. While CTCF is a ubiquitously expressed, essential protein, it has a paralogue; CTCFL with a similar DNA binding domain that is normally expressed only in testes. Interestingly, CTCFL is also a cancer/testis antigen expressed in several of the cancers. In my talk, I will describe my work that deciphered how CTCFL competes with CTCF for DNA binding sites leading to rewiring of the chromatin structure, resulting in altered gene expression and tumorigenesis. Broadly, my talk will describe the emerging concepts of how spatial organization of linear genomic DNA play a crucial role in defining its biological function and how their disruption leads to global gene mis-regulation resulting in pathogenic phenotypes.