Abstract
PPARGC1A encodes a transcriptional co-activator also termed peroxisome proliferator-activated receptor (PPAR) gamma coactivator 1-alpha (PGC-1α) which orchestrates multiple transcriptional programs. We have recently identified CNS-specific transcripts that are initiated far upstream of the reference gene (RG) promoter. The regulation of these isoforms may be relevant, as experimental and genetic studies implicated the PPARGC1A locus in neurodegenerative diseases. We therefore studied cis- and trans-regulatory elements activating the CNS promoter in comparison to the RG promoter in human neuronal cell lines. A naturally occurring variable guanidine thymidine (GT) repeat polymorphism within a microsatellite region in the proximal CNS promoter increases promoter activity in neuronal cell lines. Both the RG and the CNS promoters are activated by ESRRA, and the PGC-1α isoforms co-activate ESRRA on their own promoters suggesting an autoregulatory feedback loop. The proximal CNS, but not the RG, promoter is induced by FOXA2 and co-activated by PGC-1α resulting in robust activation. Furthermore, the CNS, but not the RG, promoter is targeted by the canonical hypoxia response involving HIF1A. Importantly, the transactivation by HIF1A is modulated by the size of the GT polymorphism. Increased expression of CNS-specific transcripts in response to hypoxia was observed in an established rat model, while RG transcripts encoding the full-length reference protein were not increased. These results suggest a role of the CNS region of the PPARGC1A locus in ischemia and warrant further studies in humans as the activity of the CNS promoter as well as its induction by hypoxia is subject to inter-individual variability due to the GT polymorphism.
Highlights
Peroxisome proliferator–activated receptor gamma coactivator 1A (PGC-1α) encoded by PPARGC1A, is a versatile transcriptional co-activator involved in multiple transcriptional programs [1,2,3]
We recently described several distinct CNS-specific PPARGC1A mRNAs that are transcribed from a novel promoter located ~ 586 kbp upstream of the reference promoter
Since neuronal cells are sensitive to ischemia, we studied potential effects of reduced oxygen tension on the expression levels of CNS and reference gene (RG) transcripts in NT2/D1 cells cultured in 20% and 1% O2, respectively
Summary
Peroxisome proliferator–activated receptor gamma coactivator 1A (PGC-1α) encoded by PPARGC1A, is a versatile transcriptional co-activator involved in multiple transcriptional programs [1,2,3]. Alternative splicing and/or transcriptional initiation represent another level of control that results in gain or loss of domains interacting with signaling targets. The truncated NT-PGC1α resulting from alternative splicing contains the Nterminal activation and nuclear interaction domains and displays functional differences in comparison to the full-length protein [11, 12]. We recently described several distinct CNS-specific PPARGC1A mRNAs that are transcribed from a novel promoter located ~ 586 kbp upstream of the reference promoter. These transcripts are more abundant than reference gene (RG) mRNAs in human post-mortem brain samples and are partially conserved in rodents [16]
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