Hypoxia and Chromatin Remodeling: Essential Regulators of Ocular Lens Cell Differentiation

The ocular lens is comprised of an epithelial cell population that undergoes a continuous process of cellular remodeling and differentiation to form elongated transparent fiber cells. This lens differentiation process is hallmarked by the complete elimination of organelles at the center of the lens, elongation of lens fiber cells, and production of lens fiber-cell specific crystallin proteins to form the mature functional structure of the transparent ocular lens. To date, our understanding of the mechanisms that drive the lens differentiation process is incomplete. This dissertation sought to elucidate the potential roles of both hypoxia and epigenetic chromatin remodeling processes as novel regulators of lens differentiation.
The lens lacks a direct blood supply and thus resides in a hypoxic microenvironment. Previous studies revealed the presence of a decreasing oxygen gradient in the region of the lens where cellular remodeling and organelle elimination occur to form mature transparent lens fiber cells. Thus we hypothesized that the hypoxic environment of the lens itself, was required to induce gene expression changes to drive the lens differentiation process. We utilized a multimoics analysis combining CUT&RUN and RNAseq high-throughput sequencing technologies to identify a role for the hypoxia-inducible transcription factor HIF1a as a novel regulator of lens gene expression during lens differentiation.