HDAC Regulates Transcription at the Outset of Axolotl Tail Regeneration

Authors

S. Randal Voss, University of KentuckyFollow
Larissa V. Ponomareva, University of KentuckyFollow
Varun B. Dwaraka, University of KentuckyFollow
Kaitlin E. Pardue, University of Kentucky
Nour W. Al Haj Baddar, University of KentuckyFollow
A. Katherine Rodgers, University of Kentucky
M. Ryan Woodcock, University of KentuckyFollow
Qingchao Qiu, University of KentuckyFollow
Anne Crowner, University of KentuckyFollow
Dana Blichmann, University of KentuckyFollow
Shivam Khatri, University of KentuckyFollow
Jon S. Thorson, University of KentuckyFollow

Abstract

Tissue regeneration is associated with complex changes in gene expression and post-translational modifications of proteins, including transcription factors and histones that comprise chromatin. We tested 172 compounds designed to target epigenetic mechanisms in an axolotl (Ambystoma mexicanum) embryo tail regeneration assay. A relatively large number of compounds (N = 55) inhibited tail regeneration, including 18 histone deacetylase inhibitors (HDACi). In particular, romidepsin, an FDA-approved anticancer drug, potently inhibited tail regeneration when embryos were treated continuously for 7 days. Additional experiments revealed that romidepsin acted within a very narrow, post-injury window. Romidepsin treatment for only 1-minute post amputation inhibited regeneration through the first 7 days, however after this time, regeneration commenced with variable outgrowth of tailfin tissue and abnormal patterning. Microarray analysis showed that romidepsin altered early, transcriptional responses at 3 and 6-hour post-amputation, especially targeting genes that are implicated in tumor cell death, as well as genes that function in the regulation of transcription, cell differentiation, cell proliferation, pattern specification, and tissue morphogenesis. Our results show that HDAC activity is required at the time of tail amputation to regulate the initial transcriptional response to injury and regeneration.

Document Type

Article

Publication Date

5-1-2019

Notes/Citation Information

Published in Scientific Reports, v. 9, article no. 6751, p. 1-11.

© The Author(s) 2019

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/.

Digital Object Identifier (DOI)

https://doi.org/10.1038/s41598-019-43230-6

Funding Information

This research was funded by the National Institutes of Health through their support of this project (R24OD21479) and Ambystoma Genetic Stock Center (P40OD019794).

Related Content

The raw microarray data (.CEL files) were deposited in the GEO database (accession number GSE118515).

Supplementary information accompanies this paper at https://doi.org/10.1038/s41598-019-43230-6.

Repository Citation

Voss, S. Randal; Ponomareva, Larissa V.; Dwaraka, Varun B.; Pardue, Kaitlin E.; Al Haj Baddar, Nour W.; Rodgers, A. Katherine; Woodcock, M. Ryan; Qiu, Qingchao; Crowner, Anne; Blichmann, Dana; Khatri, Shivam; and Thorson, Jon S., "HDAC Regulates Transcription at the Outset of Axolotl Tail Regeneration" (2019). Neuroscience Faculty Publications. 62.
https://uknowledge.uky.edu/neurobio_facpub/62