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"The organization of the cell's genome in three dimensions is fundamental to different cellular functions. The nucleus is divided into distinct chromosomal territories and each chromsome is segregated into active or repressed regions. While the utility of organizing the chormsome remains under investigation, it is known that multiple mechanisms orchestrate DNA organization. Crucially, Topologically Associating Domains (TADs) serve as key structural units, forming DNA loops that physically segregate active and inactive regions of the chromosome. This segregation ensures that appropriate gene expression to maintain a cell's identity.
We utilize the cochlea as a model to study how cell identities are maintained over an organism's lifetime, a process critically dependent on stable gene expression. We identified a chromatin remodeling protein that specifically localizes to the boundaries of TADs, suggesting a role in maintaining their structural integrity. When we ablate the protein's function, we observe a significant perturbation in the nuclear organization of both facultative and constitutive heterochromatin, which are typically the repressed genomic compartments. This severe structural disruption ultimately triggers cell death in the cochlear hair cells.
We hypothesize that the loss of the TAD boundary causes a global change in chromatin architecture, moving beyond local effects to destabilize the fundamental three-dimensional organization of the genome. This major structural change, can be functionally detrimental. These small shifts in the transcriptional landscape disrupt the genetic program required for maintaiing cochlear hair cell identity and long-term viability, ultimately leading to cell death. To test this, we will investigate whether ablating the protein causes measurable changes in TAD structure and subsequent gene expression."
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