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Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury

Lipponen, Anssi, El-Osta, Assam, Kaspi, Antony, Ziemann, Mark, Khurana, Ishant, Kn, Harikrishnan, Navarro-Ferrandis, Vicente, Puhakka, Noora, Paananen, Jussi and Pitkänen, Asla 2018, Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury, Acta neuropathologica communications, vol. 6, no. 1, pp. 1-16, doi: 10.1186/s40478-018-0519-z.

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Title Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury
Formatted title Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury
Author(s) Lipponen, Anssi
El-Osta, Assam
Kaspi, Antony
Ziemann, MarkORCID iD for Ziemann, Mark orcid.org/0000-0002-7688-6974
Khurana, Ishant
Kn, Harikrishnan
Navarro-Ferrandis, Vicente
Puhakka, Noora
Paananen, Jussi
Pitkänen, Asla
Journal name Acta neuropathologica communications
Volume number 6
Issue number 1
Article ID 17
Start page 1
End page 16
Total pages 16
Publisher BMC
Place of publication London, Eng.
Publication date 2018
ISSN 2051-5960
Keyword(s) DNA methylation
LINCS analysis
MBD-seq
RNA-seq
Recovery
Treatment
Science & Technology
Life Sciences & Biomedicine
Neurosciences
Neurosciences & Neurology
HISTONE DEACETYLASE INHIBITOR
CLOSED-HEAD INJURY
ACTIVATED PROTEIN-KINASE
GENE-EXPRESSION
CANNABINOID RECEPTOR
MICROGLIAL ACTIVATION
CEREBRAL-CORTEX
MESSENGER-RNA
IN-VITRO
MICROARRAY ANALYSIS
Summary Traumatic brain injury (TBI) induces a wide variety of cellular and molecular changes that can continue for days to weeks to months, leading to functional impairments. Currently, there are no pharmacotherapies in clinical use that favorably modify the post-TBI outcome, due in part to limited understanding of the mechanisms of TBI-induced pathologies. Our system biology analysis tested the hypothesis that chronic transcriptomics changes induced by TBI are controlled by altered DNA-methylation in gene promoter areas or by transcription factors. We performed genome-wide methyl binding domain (MBD)-sequencing (seq) and RNA-seq in perilesional, thalamic, and hippocampal tissue sampled at 3 months after TBI induced by lateral fluid percussion in adult male Sprague-Dawley rats. We investigated the regulated molecular networks and mechanisms underlying the chronic regulation, particularly DNA methylation and transcription factors. Finally, we identified compounds that modulate the transcriptomics changes and could be repurposed to improve recovery. Unexpectedly, DNA methylation was not a major regulator of chronic post-TBI transcriptomics changes. On the other hand, the transcription factors Cebpd, Pax6, Spi1, and Tp73 were upregulated at 3 months after TBI (False discovery rate < 0.05), which was validated using digital droplet polymerase chain reaction. Transcription regulatory network analysis revealed that these transcription factors regulate apoptosis, inflammation, and microglia, which are well-known contributors to secondary damage after TBI. Library of Integrated Network-based Cellular Signatures (LINCS) analysis identified 118 pharmacotherapies that regulate the expression of Cebpd, Pax6, Spi1, and Tp73. Of these, the antidepressant and/or antipsychotic compounds trimipramine, rolipramine, fluspirilene, and chlorpromazine, as well as the anti-cancer therapies pimasertib, tamoxifen, and vorinostat were strong regulators of the identified transcription factors, suggesting their potential to modulate the regulated transcriptomics networks to improve post-TBI recovery.
Language eng
DOI 10.1186/s40478-018-0519-z
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2018, The Authors
Free to Read? Yes
Use Rights Creative Commons Attribution licence
Persistent URL http://hdl.handle.net/10536/DRO/DU:30113072

Document type: Journal Article
Collections: School of Life and Environmental Sciences
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Every reasonable effort has been made to ensure that permission has been obtained for items included in DRO. If you believe that your rights have been infringed by this repository, please contact drosupport@deakin.edu.au.