Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury
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 limite...
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| Format: | Article |
| Language: | English |
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BMC
2018-02-01
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| Series: | Acta Neuropathologica Communications |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40478-018-0519-z |
| _version_ | 1818549490471141376 |
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| author | Anssi Lipponen Assam El-Osta Antony Kaspi Mark Ziemann Ishant Khurana Harikrishnan KN Vicente Navarro-Ferrandis Noora Puhakka Jussi Paananen Asla Pitkänen |
| author_facet | Anssi Lipponen Assam El-Osta Antony Kaspi Mark Ziemann Ishant Khurana Harikrishnan KN Vicente Navarro-Ferrandis Noora Puhakka Jussi Paananen Asla Pitkänen |
| author_sort | Anssi Lipponen |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-12T08:34:01Z |
| format | Article |
| id | doaj.art-70e583e43a604244a0470a3b1f15a4a0 |
| institution | Directory Open Access Journal |
| issn | 2051-5960 |
| language | English |
| last_indexed | 2024-12-12T08:34:01Z |
| publishDate | 2018-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Acta Neuropathologica Communications |
| spelling | doaj.art-70e583e43a604244a0470a3b1f15a4a02022-12-22T00:30:59ZengBMCActa Neuropathologica Communications2051-59602018-02-016111610.1186/s40478-018-0519-zTranscription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injuryAnssi Lipponen0Assam El-Osta1Antony Kaspi2Mark Ziemann3Ishant Khurana4Harikrishnan KN5Vicente Navarro-Ferrandis6Noora Puhakka7Jussi Paananen8Asla Pitkänen9Epilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandEpigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash UniversityEpigenetics in Human Health and Disease Laboratory, Central Clinical School, Faculty of Medicine, Monash UniversityEpilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandEpilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandInstitute of Biomedicine, University of Eastern FinlandEpilepsy Research Laboratory, A. I. Virtanen Institute for Molecular Sciences, University of Eastern FinlandAbstract 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.http://link.springer.com/article/10.1186/s40478-018-0519-zDNA methylationLINCS analysisMBD-seqRecoveryRNA-seqTreatment |
| spellingShingle | Anssi Lipponen Assam El-Osta Antony Kaspi Mark Ziemann Ishant Khurana Harikrishnan KN Vicente Navarro-Ferrandis Noora Puhakka Jussi Paananen Asla Pitkänen Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury Acta Neuropathologica Communications DNA methylation LINCS analysis MBD-seq Recovery RNA-seq Treatment |
| title | Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury |
| title_full | Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury |
| title_fullStr | Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury |
| title_full_unstemmed | Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury |
| title_short | Transcription factors Tp73, Cebpd, Pax6, and Spi1 rather than DNA methylation regulate chronic transcriptomics changes after experimental traumatic brain injury |
| title_sort | transcription factors tp73 cebpd pax6 and spi1 rather than dna methylation regulate chronic transcriptomics changes after experimental traumatic brain injury |
| topic | DNA methylation LINCS analysis MBD-seq Recovery RNA-seq Treatment |
| url | http://link.springer.com/article/10.1186/s40478-018-0519-z |
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