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HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration

New patterns of gene expression are enacted and regulated during tissue regeneration. Histone deacetylases (HDACs) regulate gene expression by removing acetylated lysine residues from histones and proteins that function directly or indirectly in transcriptional regulation. Previously we showed that...

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Autores principales: Voss, S. Randal, Smith, Jeramiah J., Cecil, Raissa F., Kabangu, Mirindi, Duerr, Timothy J., Monaghan, James R., Timoshevskaya, Nataliya, Ponomareva, Larissa V., Thorson, Jon S., Veliz-Cuba, Alan, Murrugarra, David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759488/
https://www.ncbi.nlm.nih.gov/pubmed/35036404
http://dx.doi.org/10.3389/fcell.2021.767377
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author Voss, S. Randal
Smith, Jeramiah J.
Cecil, Raissa F.
Kabangu, Mirindi
Duerr, Timothy J.
Monaghan, James R.
Timoshevskaya, Nataliya
Ponomareva, Larissa V.
Thorson, Jon S.
Veliz-Cuba, Alan
Murrugarra, David
author_facet Voss, S. Randal
Smith, Jeramiah J.
Cecil, Raissa F.
Kabangu, Mirindi
Duerr, Timothy J.
Monaghan, James R.
Timoshevskaya, Nataliya
Ponomareva, Larissa V.
Thorson, Jon S.
Veliz-Cuba, Alan
Murrugarra, David
author_sort Voss, S. Randal
collection PubMed
description New patterns of gene expression are enacted and regulated during tissue regeneration. Histone deacetylases (HDACs) regulate gene expression by removing acetylated lysine residues from histones and proteins that function directly or indirectly in transcriptional regulation. Previously we showed that romidepsin, an FDA-approved HDAC inhibitor, potently blocks axolotl embryo tail regeneration by altering initial transcriptional responses to injury. Here, we report on the concentration-dependent effect of romidepsin on transcription and regeneration outcome, introducing an experimental and conceptual framework for investigating small molecule mechanisms of action. A range of romidepsin concentrations (0–10 μM) were administered from 0 to 6 or 0 to 12 h post amputation (HPA) and distal tail tip tissue was collected for gene expression analysis. Above a threshold concentration, romidepsin potently inhibited regeneration. Sigmoidal and biphasic transcription response curve modeling identified genes with inflection points aligning to the threshold concentration defining regenerative failure verses success. Regeneration inhibitory concentrations of romidepsin increased and decreased the expression of key genes. Genes that associate with oxidative stress, negative regulation of cell signaling, negative regulation of cell cycle progression, and cellular differentiation were increased, while genes that are typically up-regulated during appendage regeneration were decreased, including genes expressed by fibroblast-like progenitor cells. Using single-nuclei RNA-Seq at 6 HPA, we found that key genes were altered by romidepin in the same direction across multiple cell types. Our results implicate HDAC activity as a transcriptional mechanism that operates across cell types to regulate the alternative expression of genes that associate with regenerative success versus failure outcomes.
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spelling pubmed-87594882022-01-15 HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration Voss, S. Randal Smith, Jeramiah J. Cecil, Raissa F. Kabangu, Mirindi Duerr, Timothy J. Monaghan, James R. Timoshevskaya, Nataliya Ponomareva, Larissa V. Thorson, Jon S. Veliz-Cuba, Alan Murrugarra, David Front Cell Dev Biol Cell and Developmental Biology New patterns of gene expression are enacted and regulated during tissue regeneration. Histone deacetylases (HDACs) regulate gene expression by removing acetylated lysine residues from histones and proteins that function directly or indirectly in transcriptional regulation. Previously we showed that romidepsin, an FDA-approved HDAC inhibitor, potently blocks axolotl embryo tail regeneration by altering initial transcriptional responses to injury. Here, we report on the concentration-dependent effect of romidepsin on transcription and regeneration outcome, introducing an experimental and conceptual framework for investigating small molecule mechanisms of action. A range of romidepsin concentrations (0–10 μM) were administered from 0 to 6 or 0 to 12 h post amputation (HPA) and distal tail tip tissue was collected for gene expression analysis. Above a threshold concentration, romidepsin potently inhibited regeneration. Sigmoidal and biphasic transcription response curve modeling identified genes with inflection points aligning to the threshold concentration defining regenerative failure verses success. Regeneration inhibitory concentrations of romidepsin increased and decreased the expression of key genes. Genes that associate with oxidative stress, negative regulation of cell signaling, negative regulation of cell cycle progression, and cellular differentiation were increased, while genes that are typically up-regulated during appendage regeneration were decreased, including genes expressed by fibroblast-like progenitor cells. Using single-nuclei RNA-Seq at 6 HPA, we found that key genes were altered by romidepin in the same direction across multiple cell types. Our results implicate HDAC activity as a transcriptional mechanism that operates across cell types to regulate the alternative expression of genes that associate with regenerative success versus failure outcomes. Frontiers Media S.A. 2021-12-31 /pmc/articles/PMC8759488/ /pubmed/35036404 http://dx.doi.org/10.3389/fcell.2021.767377 Text en Copyright © 2021 Voss, Smith, Cecil, Kabangu, Duerr, Monaghan, Timoshevskaya, Ponomareva, Thorson, Veliz-Cuba and Murrugarra. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Cell and Developmental Biology
Voss, S. Randal
Smith, Jeramiah J.
Cecil, Raissa F.
Kabangu, Mirindi
Duerr, Timothy J.
Monaghan, James R.
Timoshevskaya, Nataliya
Ponomareva, Larissa V.
Thorson, Jon S.
Veliz-Cuba, Alan
Murrugarra, David
HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
title HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
title_full HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
title_fullStr HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
title_full_unstemmed HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
title_short HDAC Inhibitor Titration of Transcription and Axolotl Tail Regeneration
title_sort hdac inhibitor titration of transcription and axolotl tail regeneration
topic Cell and Developmental Biology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8759488/
https://www.ncbi.nlm.nih.gov/pubmed/35036404
http://dx.doi.org/10.3389/fcell.2021.767377
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