Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential

• Published in: Scientific reports Vol. 10; no. 1; p. 13615
• Main Authors: VandenBosch, Leah S., Wohl, Stefanie G., Wilken, Matthew S., Hooper, Marcus, Finkbeiner, Connor, Cox, Kristen, Chipman, Laura, Reh, Thomas A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 12-08-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 631/136/2128; 631/136/2435; 631/136/2442; 631/136/368; Animals; ASCL1 protein; Basic Helix-Loop-Helix Transcription Factors - metabolism; Bipolar cells; Cells, Cultured; Cellular Reprogramming; Chromatin; Chromatin - genetics; Chromatin - metabolism; Ependymoglial Cells - cytology; Ependymoglial Cells - metabolism; Epigenomics; Gene expression; Gene Expression Profiling - methods; Gene Expression Regulation; Gene Expression Regulation, Developmental; Humanities and Social Sciences; Maturation; Mice; multidisciplinary; Nerve Regeneration; Neural stem cells; Neuronal-glial interactions; Regeneration; Retina; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Sequence Analysis, RNA
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-020-70334-1

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 neural 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, immature MG (P8-P12), and mature MG. Our analysis demonstrated developmental differences in gene expression and accessible chromatin between progenitors and MG, primarily in neurogenic genes. Overexpression of
Ascl1
is more effective in reprogramming immature MG, than mature MG, consistent with a more progenitor-like epigenetic landscape in the former. We also used ASCL1 ChIPseq to compare the differences in ASCL1 binding in progenitors and reprogrammed MG. We find that bipolar-specific accessible regions are more frequently linked to bHLH motifs and ASCL1 binding. Overall, our analysis indicates a loss of neurogenic gene expression and motif accessibility during glial maturation that may prevent efficient reprogramming.