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

Abstract 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...

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Autores principales:	Leah S. VandenBosch, Stefanie G. Wohl, Matthew S. Wilken, Marcus Hooper, Connor Finkbeiner, Kristen Cox, Laura Chipman, Thomas A. Reh
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2020
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/2236c493995b463399eb89df70e4b027
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spelling	oai:doaj.org-article:2236c493995b463399eb89df70e4b0272021-12-02T18:50:43ZDevelopmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential10.1038/s41598-020-70334-12045-2322https://doaj.org/article/2236c493995b463399eb89df70e4b0272020-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-020-70334-1https://doaj.org/toc/2045-2322Abstract 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.Leah S. VandenBoschStefanie G. WohlMatthew S. WilkenMarcus HooperConnor FinkbeinerKristen CoxLaura ChipmanThomas A. RehNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 10, Iss 1, Pp 1-18 (2020)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Leah S. VandenBosch Stefanie G. Wohl Matthew S. Wilken Marcus Hooper Connor Finkbeiner Kristen Cox Laura Chipman Thomas A. Reh Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential
description	Abstract 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.
format	article
author	Leah S. VandenBosch Stefanie G. Wohl Matthew S. Wilken Marcus Hooper Connor Finkbeiner Kristen Cox Laura Chipman Thomas A. Reh
author_facet	Leah S. VandenBosch Stefanie G. Wohl Matthew S. Wilken Marcus Hooper Connor Finkbeiner Kristen Cox Laura Chipman Thomas A. Reh
author_sort	Leah S. VandenBosch
title	Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential
title_short	Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential
title_full	Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential
title_fullStr	Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential
title_full_unstemmed	Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential
title_sort	developmental changes in the accessible chromatin, transcriptome and ascl1-binding correlate with the loss in müller glial regenerative potential
publisher	Nature Portfolio
publishDate	2020
url	https://doaj.org/article/2236c493995b463399eb89df70e4b027
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_version_	1718377491242942464

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

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