Publication:
Analysis of gene network bifurcation during optic cup morphogenesis in zebrafish.

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2021-06-23

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Buono, Lorena
Corbacho, Jorge
Naranjo, Silvia
Almuedo-Castillo, María
Moreno-Marmol, Tania
de la Cerda, Berta
Sanabria-Reinoso, Estefanía
Polvillo, Rocío
Díaz-Corrales, Francisco-Javier
Bogdanovic, Ozren

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Sight depends on the tight cooperation between photoreceptors and pigmented cells, which derive from common progenitors through the bifurcation of a single gene regulatory network into the neural retina (NR) and retinal-pigmented epithelium (RPE) programs. Although genetic studies have identified upstream nodes controlling these networks, their regulatory logic remains poorly investigated. Here, we characterize transcriptome dynamics and chromatin accessibility in segregating NR/RPE populations in zebrafish. We analyze cis-regulatory modules and enriched transcription factor motives to show extensive network redundancy and context-dependent activity. We identify downstream targets, highlighting an early recruitment of desmosomal genes in the flattening RPE and revealing Tead factors as upstream regulators. We investigate the RPE specification network dynamics to uncover an unexpected sequence of transcription factors recruitment, which is conserved in humans. This systematic interrogation of the NR/RPE bifurcation should improve both genetic counseling for eye disorders and hiPSCs-to-RPE differentiation protocols for cell-replacement therapies in degenerative diseases.

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Animals
Animals, Genetically Modified
Chromatin Immunoprecipitation Sequencing
Cluster Analysis
Gene Expression Profiling
Gene Expression Regulation, Developmental
Gene Regulatory Networks
Humans
Induced Pluripotent Stem Cells
Morphogenesis
RNA-Seq
Retinal Pigment Epithelium
Reverse Transcriptase Polymerase Chain Reaction
Transcription Factors
Zebrafish

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