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

Anssi Lipponen, Assam El-Osta, Antony Kaspi, Mark Ziemann, Ishant Khurana, Harikrishnan Kn, Vicente Navarro-Ferrandis, Noora Puhakka, Jussi Paananen, Asla Pitkänen

Research output: Contribution to journalArticleResearchpeer-review

Abstract

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.

Original languageEnglish
Article number17
Number of pages16
JournalActa neuropathologica communications
Volume6
Issue number1
DOIs
Publication statusPublished - 27 Feb 2018

Keywords

  • DNA methylation
  • LINCS analysis
  • MBD-seq
  • Recovery
  • RNA-seq
  • Treatment

Cite this

Lipponen, Anssi ; El-Osta, Assam ; Kaspi, Antony ; Ziemann, Mark ; Khurana, Ishant ; Kn, Harikrishnan ; Navarro-Ferrandis, Vicente ; Puhakka, Noora ; Paananen, Jussi ; Pitkänen, Asla. / Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury. In: Acta neuropathologica communications. 2018 ; Vol. 6, No. 1.
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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; Pitkänen, Asla.

In: Acta neuropathologica communications, Vol. 6, No. 1, 17, 27.02.2018.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Lipponen, Anssi

AU - El-Osta, Assam

AU - Kaspi, Antony

AU - Ziemann, Mark

AU - Khurana, Ishant

AU - Kn, Harikrishnan

AU - Navarro-Ferrandis, Vicente

AU - Puhakka, Noora

AU - Paananen, Jussi

AU - Pitkänen, Asla

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