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Article

Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases

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Institute of Pharmacology and Toxicology, Paracelsus Medical University, Strubergasse 18, 5020 Salzburg, Austria
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EB House Austria, Research Program for Molecular Therapy of Genodermatoses, Department of Dermatology and Allergology, University Hospital of the Paracelsus Medical University, 5020 Salzburg, Austria
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CEITEC-Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
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Department of Pathology and Laboratory Medicine, Perlman School of Medicine, University of Pennsylvania, 614 Stellar-Chance Labs, 422 Curie Blvd, Philadelphia, PA 19104-6100, USA
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Third Medical Department, Cancer Research Institute, Paracelsus Medical University, Cancer Cluster Salzburg, 5020 Salzburg, Austria
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PharmGenetix GmbH, 5081 Niederalm, Austria
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Division of Neuropathology, Neuromed Campus, Kepler University Hospital, 4020 Linz, Austria
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Department of Personalized Medicine, Humanomed, 9020 Klagenfurt, Austria
*
Authors to whom correspondence should be addressed.
Academic Editor: Marika Cordaro
Int. J. Mol. Sci. 2021, 22(7), 3296; https://doi.org/10.3390/ijms22073296
Received: 20 February 2021 / Revised: 17 March 2021 / Accepted: 20 March 2021 / Published: 24 March 2021
(This article belongs to the Special Issue Physiological or Pathological Molecular Alterations in Brain Aging)
The transcriptional regulator peroxisome proliferator activated receptor gamma coactivator 1A (PGC-1α), encoded by PPARGC1A, has been linked to neurodegenerative diseases. Recently discovered CNS-specific PPARGC1A transcripts are initiated far upstream of the reference promoter, spliced to exon 2 of the reference gene, and are more abundant than reference gene transcripts in post-mortem human brain samples. The proteins translated from the CNS and reference transcripts differ only at their N-terminal regions. To dissect functional differences between CNS-specific isoforms and reference proteins, we used clustered regularly interspaced short palindromic repeats transcriptional activation (CRISPRa) for selective endogenous activation of the CNS or the reference promoters in SH-SY5Y cells. Expression and/or exon usage of the targets was ascertained by RNA sequencing. Compared to controls, more differentially expressed genes were observed after activation of the CNS than the reference gene promoter, while the magnitude of alternative exon usage was comparable between activation of the two promoters. Promoter-selective associations were observed with canonical signaling pathways, mitochondrial and nervous system functions and neurological diseases. The distinct N-terminal as well as the shared downstream regions of PGC-1α isoforms affect the exon usage of numerous genes. Furthermore, associations of risk genes of amyotrophic lateral sclerosis and Parkinson’s disease were noted with differentially expressed genes resulting from the activation of the CNS and reference gene promoter, respectively. Thus, CNS-specific isoforms markedly amplify the biological functions of PPARGC1A and CNS-specific isoforms and reference proteins have common, complementary and selective functions relevant for neurodegenerative diseases. View Full-Text
Keywords: PPARGC1A; PGC-1α; CNS-specific transcripts and isoforms; CRISPR; RNA sequencing; RNA expression; exon usage; neurodegenerative diseases PPARGC1A; PGC-1α; CNS-specific transcripts and isoforms; CRISPR; RNA sequencing; RNA expression; exon usage; neurodegenerative diseases
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MDPI and ACS Style

Kwik, M.; Hainzl, S.; Oppelt, J.; Tichy, B.; Koller, U.; Bernardinelli, E.; Steiner, M.; Zara, G.; Nofziger, C.; Weis, S.; Paulmichl, M.; Dossena, S.; Patsch, W.; Soyal, S.M. Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases. Int. J. Mol. Sci. 2021, 22, 3296. https://doi.org/10.3390/ijms22073296

AMA Style

Kwik M, Hainzl S, Oppelt J, Tichy B, Koller U, Bernardinelli E, Steiner M, Zara G, Nofziger C, Weis S, Paulmichl M, Dossena S, Patsch W, Soyal SM. Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases. International Journal of Molecular Sciences. 2021; 22(7):3296. https://doi.org/10.3390/ijms22073296

Chicago/Turabian Style

Kwik, Markus, Stefan Hainzl, Jan Oppelt, Boris Tichy, Ulrich Koller, Emanuele Bernardinelli, Markus Steiner, Greta Zara, Charity Nofziger, Serge Weis, Markus Paulmichl, Silvia Dossena, Wolfgang Patsch, and Selma M. Soyal. 2021. "Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases" International Journal of Molecular Sciences 22, no. 7: 3296. https://doi.org/10.3390/ijms22073296

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