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

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...

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Autores principales: VandenBosch, Leah S., Wohl, Stefanie G., Wilken, Matthew S., Hooper, Marcus, Finkbeiner, Connor, Cox, Kristen, Chipman, Laura, Reh, Thomas A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423883/
https://www.ncbi.nlm.nih.gov/pubmed/32788677
http://dx.doi.org/10.1038/s41598-020-70334-1
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author VandenBosch, Leah S.
Wohl, Stefanie G.
Wilken, Matthew S.
Hooper, Marcus
Finkbeiner, Connor
Cox, Kristen
Chipman, Laura
Reh, Thomas A.
author_facet VandenBosch, Leah S.
Wohl, Stefanie G.
Wilken, Matthew S.
Hooper, Marcus
Finkbeiner, Connor
Cox, Kristen
Chipman, Laura
Reh, Thomas A.
author_sort VandenBosch, Leah S.
collection PubMed
description 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.
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spelling pubmed-74238832020-08-13 Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential VandenBosch, Leah S. Wohl, Stefanie G. Wilken, Matthew S. Hooper, Marcus Finkbeiner, Connor Cox, Kristen Chipman, Laura Reh, Thomas A. Sci Rep Article 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. Nature Publishing Group UK 2020-08-12 /pmc/articles/PMC7423883/ /pubmed/32788677 http://dx.doi.org/10.1038/s41598-020-70334-1 Text en © The Author(s) 2020 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Article
VandenBosch, Leah S.
Wohl, Stefanie G.
Wilken, Matthew S.
Hooper, Marcus
Finkbeiner, Connor
Cox, Kristen
Chipman, Laura
Reh, Thomas A.
Developmental changes in the accessible chromatin, transcriptome and Ascl1-binding correlate with the loss in Müller Glial regenerative potential
title 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_short 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
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7423883/
https://www.ncbi.nlm.nih.gov/pubmed/32788677
http://dx.doi.org/10.1038/s41598-020-70334-1
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