Sep 3, 2019

Cis-Regulatory Accessibility Directs Muller Glial Development and Regenerative Capacity

BioRxiv : the Preprint Server for Biology
Thomas A RehKristen E Cox

Abstract

Diseases of the retina can lead to losses in neurons and vision. Although the mammalian retina has no inherent regenerative capabilities, fish robustly regenerate from Muller glia (MG). Driving expression of Ascl1 in adult mouse MG stimulates neurogenesis; however, Ascl1-expressing MG primarily generate bipolar cells. To better understand the limits of MG-based regeneration in mouse retinas, we used ATAC- and RNA-seq to compare newborn progenitors with MG. Our analysis demonstrated striking similarities between MG and progenitors, with losses in regulatory motifs for neurogenesis genes. Young MG were found to have intermediate expression profiles and accessible DNA, which is mirrored in the ability of Ascl1 to direct bipolar neurogenesis in young MG. When comparing what makes bipolar and photoreceptor cells distinct from glial cells, we find that bipolar-specific accessible regions are more frequently linked to bHLH motifs and Ascl1 binding, indicating that Ascl1 preferentially binds to bipolar regions. Overall, our analysis indicates a loss of neurogenic gene expression and motif accessibility during glial maturation that may prevent efficient reprogramming.

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Mentioned in this Paper

Photoreceptors
Neurons
Vision
Retinal Bipolar Cells
Neuroglia
Nerve Regeneration
Cellular Reprogramming
ASCL1
Zebrafish
Binding (Molecular Function)

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