Chd4 remodels chromatin to control retinal cell type specification and lineage termination.

During development, neural progenitor cells modify their output over time to produce different types of neurons and glia in chronological sequences. Epigenetic processes have been shown to regulate neural progenitor potential, but the underlying mechanisms are not well understood. Here, we generated retina-specific conditional mouse knockouts (cKOs) in the key nucleosome remodeller Chd4. Chd4 cKOs overproduced early-born retinal ganglion and amacrine cells. Postnatally, later-born rod photoreceptors were drastically underproduced. Progenitors failed to differentiate into Müller glia on schedule and continued to proliferate beyond their normal developmental window. Next, to determine how Chd4 regulates the genome, we performed CUT&RUN-seq and ATAC-seq, revealing that genome accessibility was significantly increased at ∼10,000 regulatory elements. Accordingly, multiplexed single-cell transcriptomics demonstrated that deletion of Chd4 led to corresponding increases in transcription. These results suggest that Chd4 restricts the genome to repress progenitor identity and promote differentiation. Taken together, our data suggest that Chd4-dependent nucleosome remodelling plays a crucial role in the temporal transition that governs lineage termination, but does not regulate earlier temporal transitions.