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Jared Austin Tangeman, Raúl Pérez-Estrada, Emily Van Zeeland, Lin Liu, Chun Liang, Katia Del Rio-Tsonis; RPE neural competency is restricted by alterations to a homeobox transcription factor regulatory network. Invest. Ophthalmol. Vis. Sci. 2022;63(7):1867.
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© ARVO (1962-2015); The Authors (2016-present)
Embryonic amniotes and some adult salamanders can regenerate neural retina from cells of the retinal pigment epithelium (RPE). Injured embryonic chicken RPE can regenerate neural retina if stimulated with FGF2 at embryonic day 4 (E4), but for reasons that are not understood, this ability is lost by embryonic day 5 (E5). We hypothesize that alterations to transcription factor (TF) networks restrict the neural competency of the developing RPE.
RPE cells from developing E4 and E5 chickens were collected and subjected to gene expression profiling via bulk and single-nuclei RNA-seq, as well as chromatin accessibility profiling via ATAC-seq. In parallel, RPE was collected at both E4 and E5 at several timepoints following retinectomy in the presence or absence of FGF2 treatment. Changes in gene expression and chromatin accessibility were integrated to assess TF DNA-binding activity and differential behavior of downstream targets.
E4 RPE responds to retinectomy and FGF2 by elevating the expression of genes encoding neural retina TFs, such as PAX6, VSX2, and ASCL1, while simultaneously down-regulating RPE markers OTX2 and MITF. In contrast, the E5 RPE can be induced to express neural retina TFs, but also displays enhanced hallmarks of maturity independent of injury or FGF2 treatment, pertaining to pigmentation, retinoic acid synthesis, extracellular matrix deposition, and reduced proliferative status. Accessibility changes across the E4 to E5 window suggest altered activity of the RPE-determining TF OTX2, which has the potential to regulate downstream targets that enhance RPE fate and block neural retina identity.
RPE lineage commitment is accompanied by widespread shifts in the regulation of RPE maturation genes and neural retina-associated TFs. An altered homeobox TF network at E5 promotes RPE fate and blocks neural retina identity, in part through enhanced OTX2 activity. These findings implicate OTX2 activity as a determinant of RPE lineage commitment and assess several indicators of RPE maturity in relation to neural competence.
This abstract was presented at the 2022 ARVO Annual Meeting, held in Denver, CO, May 1-4, 2022, and virtually.
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