Transcription factors Tp73, Cebpd Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury
Open accessAbstract
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.
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Genome-wide MBD-seq and RNA-seq of brain tissues in TBI induced by lateral fluid percussion in adult male Sprague-Dawley rats showed molecular networks and mechanisms underlying chronic dysregulation.
“Genome-wide methyl binding domain (MBD)-seq and RNA-seq of brain tissues in TBI induced by lateral fluid percussion in adult male Spraque-Dawley rats showed molecular networks and mechanism underlying the chronic dysregulation [51].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [51]
PU.1 also plays a role in traumatic brain injury.
“PU.1 also plays a role in traumatic brain injury (TBI).”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [51]
Transcription factors including Spi1, Cebpd, Pax6, and Tp73 were upregulated at 3 months after TBI.
“Transcription factors including Spi1, Cebpd, Pax6, Tp73 were upregulated at 3 months after TBI [51].”
From Transcriptional and Epigenetic Regulation of Microglia in Health and Disease (2019) · cites this paper as [51]
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Microarray-based gene expression analysis of an animal model for closed head injury
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Research works printed but not linked: 1
- [124]von Gertten C Morales A Holmin S Mathiesen T Nordqvist A-C Ray S Genomic responses in rat cerebral cortex after traumatic brain injury BMC Neurosci 2005 6 69 10.1186/1471-2202-6-69 16318630 PMC1310614 · DOI
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Sorted by citations
Transcriptional and Epigenetic Regulation of Microglia in Health and Disease
Yeh, H., & Ikezu, T. (2019) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2018.11.004 · Cited by 135 · see citing works
- Authors
- Lipponen, A., El-Osta, A., Kaspi, A., Ziemann, M., Khurana, I., KN, H., Navarro-Ferrandis, V., Puhakka, N., Paananen, J., & Pitkänen, A.
- Affiliations
- University of Eastern Finland (FI)
- Monash University (AU)
- Corresponding author
- Pitkänen, Asla
- ORCID
- Venue
- Acta Neuropathologica Communications
- Published
- 2018-02-27
- Volume
- 6
- Issue
- 1
- Pages
- 17-17
- ISSN
- 2051-5960 (ISSN-L)
- PMC
- PMC5828078
- OpenAlex
- W2797431873
- Cited by
- 47
- References
- 135
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 15 · 2023: 4 · 2022: 4 · 2021: 6 · 2020: 6 · 2019: 2 · 2018: 2
- FWCI
- 2.72
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- Acta Neuropathologica Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Monash University Research Portal (Monash University) (submittedVersion, cc-by)
- UEF eRepo (University of Eastern Finland) (submittedVersion, cc-by)
- Minerva Access (University of Melbourne) (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- Academy of Finland
- European Science Foundation
- FP7 Health (602102)
- Topics
- Health Sciences › Medicine › Neurology › Traumatic Brain Injury and Neurovascular Disturbances
- Health Sciences › Medicine › Epidemiology › Traumatic Brain Injury Research
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Automotive and Human Injury Biomechanics
- Keywords
- traumatic brain injury, DNA methylation, transcription factors, p73, CEBPD, Pax6, PU.1, transcriptional regulatory networks, drug repurposing, antidepressants, anticancer agents, secondary brain injury, microglia, apoptosis, inflammation, hippocampus, thalamus, perilesional tissue, lateral fluid percussion injury
- MeSH terms
- Brain Injuries, Traumatic, PAX6 Transcription Factor, Tumor Protein p73, Proto-Oncogene Protein Spi-1, Animals, Brain, Chronic Disease, Disease Models, Animal, Male, Proto-Oncogene Proteins, Trans-Activators, Up-Regulation, Rats, Sprague-Dawley, DNA Methylation, CCAAT-Enhancer-Binding Protein-delta, Transcriptome
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