ABSTRACT
How the diverse neural cell types emerge from multipotent neural progenitor cells during central nervous system development remains poorly understood. Recent scRNA-seq studies have delineated the developmental trajectories of individual neural cell types in many neural systems including the neural retina. Further understanding of the formation of neural cell diversity requires knowledge about how the epigenetic landscape shifts along individual cell lineages and how key transcription factors regulate these changes. In this study, we dissect the changes in the epigenetic landscape during early retinal cell differentiation by scATAC-seq and identify globally the enhancers, enriched motifs, and potential interacting transcription factors underlying the cell state/type specific gene expression in individual lineages. Using CUT&Tag, we further identify the enhancers bound directly by four key transcription factors, Otx2, Atoh7, Pou4f2, and Isl1, and uncover their roles in shaping the epigenetic landscape and controlling gene expression in a sequential and combinatorial fashion along individual retinal cell lineages such as retinal ganglion cells (RGCs). Our results reveal a general paradigm in which transcription factors collaborate and compete to regulate the emergence of distinct retinal cell types such as RGCs from multipotent retinal progenitor cells (RPCs).
Competing Interest Statement
The authors have declared no competing interest.
Footnotes
1. Comparison between E14.5 and E17.5 data were performed and added. 2. Comparison of other cell states/types pairs between wild-type and Atoh7-null data at E14.5 was performed. 3. Correlation between epigenetic and gene expression changes in early RGCs between wild-type and Atoh7-null retina was analyzed. 4. Additional in situ hybridization data for two more developmental stages, E12.5 and E17.5 in the enhancer deletion mutants were performed.
