RT Journal Article
SR Electronic
T1 Cis-Regulatory Accessibility Directs Muller Glial Development and Regenerative Capacity
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 752428
DO 10.1101/752428
A1 Leah S. VandenBosch
A1 Stefanie G. Wohl
A1 Matthew S. Wilken
A1 Kristen Cox
A1 Laura Chipman
A1 Thomas A. Reh
YR 2019
UL http://biorxiv.org/content/early/2019/09/03/752428.abstract
AB Diseases and damage to the retina lead to losses in retinal neurons and eventual visual impairment. Although the mammalian retina has no inherent regenerative capabilities, fish have robust regeneration from Müller glia (MG). Recently, we have shown that driving expression of Ascl1 in adult mouse MG stimulates neurogenesis similar to fish regeneration. The regeneration observed in the mouse is limited in the variety of neurons that can be derived from MG; 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.