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Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration

Neurodegenerative diseases are accompanied by dynamic changes in gene expression, including the upregulation of hallmark stress-responsive genes. While the transcriptional pathways that impart adaptive and maladaptive gene expression signatures have been the focus of intense study, the role of highe...

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Autores principales: Herrera, Ivana, Fernandes, José Alex Lourenço, Shir-Mohammadi, Khatereh, Levesque, Jasmine, Mattar, Pierre
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10600220/
https://www.ncbi.nlm.nih.gov/pubmed/37880237
http://dx.doi.org/10.1038/s41419-023-06224-x
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author Herrera, Ivana
Fernandes, José Alex Lourenço
Shir-Mohammadi, Khatereh
Levesque, Jasmine
Mattar, Pierre
author_facet Herrera, Ivana
Fernandes, José Alex Lourenço
Shir-Mohammadi, Khatereh
Levesque, Jasmine
Mattar, Pierre
author_sort Herrera, Ivana
collection PubMed
description Neurodegenerative diseases are accompanied by dynamic changes in gene expression, including the upregulation of hallmark stress-responsive genes. While the transcriptional pathways that impart adaptive and maladaptive gene expression signatures have been the focus of intense study, the role of higher order nuclear organization in this process is less clear. Here, we examine the role of the nuclear lamina in genome organization during the degeneration of rod photoreceptors. Two proteins had previously been shown to be necessary and sufficient to tether heterochromatin at the nuclear envelope. The lamin B receptor (Lbr) is expressed during development, but downregulates upon rod differentiation. A second tether is the intermediate filament lamin A (LA), which is not normally expressed in murine rods. Here, we show that in the rd1 model of retinitis pigmentosa, LA ectopically upregulates in rod photoreceptors at the onset of degeneration. LA upregulation correlated with increased heterochromatin tethering at the nuclear periphery in rd1 rods, suggesting that LA reorganizes the nucleus. To determine how heterochromatin tethering affects the genome, we used in vivo electroporation to misexpress LA or Lbr in mature rods in the absence of degeneration, resulting in the restoration of conventional nuclear architecture. Using scRNA-seq, we show that reorganizing the nucleus via LA/Lbr misexpression has relatively minor effects on rod gene expression. Next, using ATAC-seq, we show that LA and Lbr both lead to marked increases in genome accessibility. Novel ATAC-seq peaks tended to be associated with stress-responsive genes. Together, our data reveal that heterochromatin tethers have a global effect on genome accessibility, and suggest that heterochromatin tethering primes the photoreceptor genome to respond to stress.
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spelling pubmed-106002202023-10-27 Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration Herrera, Ivana Fernandes, José Alex Lourenço Shir-Mohammadi, Khatereh Levesque, Jasmine Mattar, Pierre Cell Death Dis Article Neurodegenerative diseases are accompanied by dynamic changes in gene expression, including the upregulation of hallmark stress-responsive genes. While the transcriptional pathways that impart adaptive and maladaptive gene expression signatures have been the focus of intense study, the role of higher order nuclear organization in this process is less clear. Here, we examine the role of the nuclear lamina in genome organization during the degeneration of rod photoreceptors. Two proteins had previously been shown to be necessary and sufficient to tether heterochromatin at the nuclear envelope. The lamin B receptor (Lbr) is expressed during development, but downregulates upon rod differentiation. A second tether is the intermediate filament lamin A (LA), which is not normally expressed in murine rods. Here, we show that in the rd1 model of retinitis pigmentosa, LA ectopically upregulates in rod photoreceptors at the onset of degeneration. LA upregulation correlated with increased heterochromatin tethering at the nuclear periphery in rd1 rods, suggesting that LA reorganizes the nucleus. To determine how heterochromatin tethering affects the genome, we used in vivo electroporation to misexpress LA or Lbr in mature rods in the absence of degeneration, resulting in the restoration of conventional nuclear architecture. Using scRNA-seq, we show that reorganizing the nucleus via LA/Lbr misexpression has relatively minor effects on rod gene expression. Next, using ATAC-seq, we show that LA and Lbr both lead to marked increases in genome accessibility. Novel ATAC-seq peaks tended to be associated with stress-responsive genes. Together, our data reveal that heterochromatin tethers have a global effect on genome accessibility, and suggest that heterochromatin tethering primes the photoreceptor genome to respond to stress. Nature Publishing Group UK 2023-10-25 /pmc/articles/PMC10600220/ /pubmed/37880237 http://dx.doi.org/10.1038/s41419-023-06224-x Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/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/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Herrera, Ivana
Fernandes, José Alex Lourenço
Shir-Mohammadi, Khatereh
Levesque, Jasmine
Mattar, Pierre
Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration
title Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration
title_full Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration
title_fullStr Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration
title_full_unstemmed Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration
title_short Lamin A upregulation reorganizes the genome during rod photoreceptor degeneration
title_sort lamin a upregulation reorganizes the genome during rod photoreceptor degeneration
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10600220/
https://www.ncbi.nlm.nih.gov/pubmed/37880237
http://dx.doi.org/10.1038/s41419-023-06224-x
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