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.

• Klíčová slova
• CNS-specific transcripts and isoforms, CRISPR, PGC-1α, PPARGC1A, RNA expression, RNA sequencing, exon usage, neurodegenerative diseases,
• MeSH
• aktivace transkripce * MeSH
• exony MeSH
• genové regulační sítě * MeSH
• HEK293 buňky MeSH
• lidé MeSH
• nádorové buněčné linie MeSH
• neurodegenerativní nemoci genetika   MeSH
• neurony metabolismus   MeSH
• nukleotidové motivy MeSH
• PPARGC1A genetika   metabolismus   MeSH
• promotorové oblasti (genetika) * MeSH
• protein - isoformy genetika   metabolismus   MeSH
• transkriptom MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• PPARGC1A protein, human MeSH Prohlížeč
• PPARGC1A MeSH
• protein - isoformy MeSH