Gene regulatory networks controlling temporal patterning, neurogenesis, and cell-fate specification in mammalian retina

• Published in: Cell reports (Cambridge) Vol. 37; no. 7; p. 109994
• Main Authors: Lyu, Pin, Hoang, Thanh, Santiago, Clayton P., Thomas, Eric D., Timms, Andrew E., Appel, Haley, Gimmen, Megan, Le, Nguyet, Jiang, Lizhi, Kim, Dong Won, Chen, Siqi, Espinoza, David F., Telger, Ariel E., Weir, Kurt, Clark, Brian S., Cherry, Timothy J., Qian, Jiang, Blackshaw, Seth
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 16-11-2021; Elsevier
• Subjects: Animals; Body Patterning - genetics; Cell Differentiation - genetics; Cell Lineage - genetics; development; Eye Proteins - metabolism; Female; Gene Expression - genetics; Gene Expression Regulation, Developmental - genetics; gene regulatory network; Gene Regulatory Networks - genetics; Homeodomain Proteins - metabolism; Humans; Male; Mice - embryology; neurogenesis; Neurogenesis - genetics; NFI; NFI Transcription Factors - metabolism; progenitor; retina; Retina - embryology; Retinal Neurons - metabolism; Retinal Rod Photoreceptor Cells - metabolism; single-cell ATAC-seq; single-cell RNA-seq; temporal patterning; Trans-Activators - metabolism; transcription factor; NFI; transcription factor; development; single-cell ATAC-seq; retina; neurogenesis; single-cell RNA-seq; progenitor; temporal patterning; gene regulatory network
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109994

Gene regulatory networks (GRNs), consisting of transcription factors and their target sites, control neurogenesis and cell-fate specification in the developing central nervous system. In this study, we use integrated single-cell RNA and single-cell ATAC sequencing (scATAC-seq) analysis in developing mouse and human retina to identify multiple interconnected, evolutionarily conserved GRNs composed of cell-type-specific transcription factors that both activate genes within their own network and inhibit genes in other networks. These GRNs control temporal patterning in primary progenitors, regulate transition from primary to neurogenic progenitors, and drive specification of each major retinal cell type. We confirm that NFI transcription factors selectively activate expression of genes promoting late-stage temporal identity in primary retinal progenitors and identify other transcription factors that regulate rod photoreceptor specification in postnatal retina. This study inventories cis- and trans-acting factors that control retinal development and can guide cell-based therapies aimed at replacing retinal neurons lost to disease.
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•Single-cell profile of chromatin accessibility changes during mouse retinal development•Identification of conserved gene regulatory networks controlling retinal development•NFI factors directly active genes promoting late-stage retinal progenitor identity•Identification of regulators of rod photoreceptor specification
Using integrated analysis of gene expression and chromatin accessibility at the single-cell level, Lyu et al. identify evolutionarily conserved gene regulatory networks that regulate temporal patterning, neurogenesis, and cell-fate specification for all major cell types in the developing mouse and human retina and functionally validate these predictions.