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@article{1836438,
author = {Kwik, M. and Hainzl, S. and Oppelt, Jan and Tichý, Boris and Koller, U. and Bernardinelli, E. and Steiner, M. and Zara, G. and Nofziger, C. and Weis, S. and Paulmichl, M. and Dossena, S. and Patsch, W. and Soyal, S.M.},
article_location = {Basel},
article_number = {7},
doi = {http://dx.doi.org/10.3390/ijms22073296},
keywords = {PPARGC1A; PGC-1α CNS-specific transcripts and isoforms; CRISPR; RNA sequencing; RNA expression; exon usage; neurodegenerative diseases},
language = {eng},
issn = {1422-0067},
journal = {International Journal of Molecular Sciences},
title = {Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases},
url = {https://www.mdpi.com/1422-0067/22/7/3296},
volume = {22},
year = {2021}
}
TY - JOUR
ID - 1836438
AU - Kwik, M. - Hainzl, S. - Oppelt, Jan - Tichý, Boris - Koller, U. - Bernardinelli, E. - Steiner, M. - Zara, G. - Nofziger, C. - Weis, S. - Paulmichl, M. - Dossena, S. - Patsch, W. - Soyal, S.M.
PY - 2021
TI - Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases
JF - International Journal of Molecular Sciences
VL - 22
IS - 7
SP - 3296
EP - 3296
PB - Multidisciplinary Digital Publishing Institute
SN - 14220067
KW - PPARGC1A
KW - PGC-1α CNS-specific transcripts and isoforms
KW - CRISPR
KW - RNA sequencing
KW - RNA expression
KW - exon usage
KW - neurodegenerative diseases
UR - https://www.mdpi.com/1422-0067/22/7/3296
N2 - The transcriptional regulator peroxisome proliferator activated receptor gamma coactivator 1A (PGC-1 alpha), 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-1 alpha 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.
ER -
KWIK, M., S. HAINZL, Jan OPPELT, Boris TICHÝ, U. KOLLER, E. BERNARDINELLI, M. STEINER, G. ZARA, C. NOFZIGER, S. WEIS, M. PAULMICHL, S. DOSSENA, W. PATSCH and S.M. SOYAL. Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases. \textit{International Journal of Molecular Sciences}. Basel: Multidisciplinary Digital Publishing Institute, 2021, vol.~22, No~7, p.~3296-3319. ISSN~1422-0067. Available from: https://dx.doi.org/10.3390/ijms22073296.
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