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Series GSE171992 Query DataSets for GSE171992
Status Public on Apr 14, 2021
Title Selective Activation of CNS and Reference PPARGC1A Promoters Is Associated with Distinct Gene Programs Relevant for Neurodegenerative Diseases
Organism Homo sapiens
Experiment type Expression profiling by high throughput sequencing
Summary 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.
Overall design Selective endogenous activation of the CNS or Reference PPARGC1A promoters in SH-SY5Y cells using CRISPRa.
Contributor(s) 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
Citation(s) 33804860
Submission date Apr 13, 2021
Last update date Jul 18, 2021
Contact name Selma M Soyal
Organization name Paracelsus Private Medical University
Department Institute of Pharmacology and Toxicology
Street address Strubergasse 18
City Salzburg
ZIP/Postal code 5020
Country Austria
Platforms (1)
GPL21697 NextSeq 550 (Homo sapiens)
Samples (9)
GSM5239487 cns1
GSM5239488 cns2
GSM5239489 cns3
BioProject PRJNA721657
SRA SRP314654

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Supplementary file Size Download File type/resource
GSE171992_PPARGC1A_RefSeq_add.gtf.gz 1.1 Kb (ftp)(http) GTF
GSE171992_SH-SY5Y_DEXSeq_deu.xlsx 16.0 Mb (ftp)(http) XLSX
GSE171992_SH-SY5Y_edgeR_de.xlsx 4.0 Mb (ftp)(http) XLSX
GSE171992_SH-SY5Y_edgeR_norm_counts.xlsx 1.7 Mb (ftp)(http) XLSX
GSE171992_SH-SY5Y_raw_counts.xlsx 941.1 Kb (ftp)(http) XLSX
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Raw data are available in SRA
Processed data are available on Series record

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