Nucleome Dynamics during Retinal Development[Hi-C_Mm]

The nuclei of rod photoreceptors in mice and other nocturnal species have an unusual inverted chromatin structure with centrally located heterochromatin that helps to focus light and improve photosensitivity. To gain a deeper understanding of this unique nuclear organization of rod photoreceptors, we have carried out Hi-C on retina at 3 stages of development and on purified rod photoreceptors. Predicted looping interactions from the Hi-C data were validated with fluorescent in situ hybridization (FISH). We discovered that a subset of genes important for retinal development, cancer and stress response in the retina are localized to the facultative heterochromatin domain in a developmental stage– and cell type–specific manner. We used machine learning to develop an algorithm based on our chromatin Hidden Markov Modeling (chromHMM) of retinal development to predict heterochromatin domains and study their dynamics during retinogenesis. FISH data for 264 genomic loci were used to train and validate the algorithm. These integrated data (https://pecan.stjude.cloud/retinalnucleome) were used to identify a developmental stage- and cell type-specific core regulatory circuit super-enhancer (CRC-SE) upstream of the Vsx2 gene that is required for bipolar neuron expression. Deletion of the Vsx2 CRC-SE in mice led to the loss of bipolar neurons in the retina. Overall design: Examination of chromatin interaction profiles in 5 cell types