The Expression of CNS-Specific PPARGC1A Transcripts Is Regulated by Hypoxia and a Variable GT Repeat Polymorphism

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.

Dysregulation of PGC-1α-Dependent Transcriptional Programs in Neurological and Developmental Disorders: Therapeutic Challenges and Opportunities

“…PGC-1α expression can also be enhanced in striatal SPNs in response to cocaine exposure, with changes being selective for neurons expressing dopamine receptor Drd1 [ 87 ]. Accumulating evidence also indicates the existence of brain-specific splice variants of PGC-1α [ 88 ] that are responsive to cellular stimuli, such as hypoxia [ 89 ], although the cell-type-specific distribution of these variants has not yet been determined. The cell-type-specific expression patterns of PGC-1α as well as its potential non-mitochondrial roles in neuron function are important to acknowledge when assessing therapeutic overexpression or targeting of PGC-1α for neuroprotection (see below).…”

Mutations on a novel brain-specific isoform of PGC1α leads to extensive upregulation of neurotransmitter-related genes and sexually dimorphic motor deficits in mice

“…Our understanding of the function of PGC1α in the brain is still emerging. Despite findings describing multiple and uniquely regulated transcriptional PGC1α isoforms in the brain (Soyal et al, 2020;Soyal et al, 2012;Soyal et al, 2019), their function remain largely unknown. Full body and CNS-conditional Pgc1α KO mice were generated over a decade ago and found to have neurological phenotypes, including altered behaviour, but inconsistent data has been reported by different groups (Dougherty et al, 2014;Leone et al, 2005;Lin et al, 2004;Lucas et al, 2012;Lucas et al, 2010;Lucas et al, 2014b;McMeekin et al, 2018).…”

“…Lastly, HIF1α was recently shown to activate transcription from the human B1 promoter, which corresponds to the SSR promoter in the mouse, by selectively interacting with it and not the reference promoter for the gene (Soyal et al, 2020). While the role of HIF1α in the brain has previously been limited to hypoxic insult, a recent study has shown that crucial polarity-controlled events in neuronal determination and cerebellar germinal zone exit -including spindle orientation during neural stem cell division, axon-dendrite specification, or adhesive events that promote synaptogenesis (Singh et al, 2016;Singh and Solecki, 2015;Uzquiano et al, 2018) are also regulated through HIF1α-dependent pathways, and, consequently, are sensitive to O2 tension (Kullmann et al, 2020).…”

“…and motor performance. Soyal and co-workers (Soyal et al, 2020) recently demonstrated crosstalk between the Pgc1α B1 and the reference promoter in the brain. Whereas they found that some stimuli activated both, which in turn seemed to co-activate each other, hypoxia was shown to engage the B1 but not the reference promoter.…”

“…Conversely, in ALS mouse models the B1-B4 isoform seems downregulated (Bayer et al, 2017). More recently, the B1 promoter was shown to be activated by transcription factors, such as HIF1α, that do not act on the Pgc1α reference promoter (Soyal et al, 2020), demonstrating distinct transcriptional regulation of the brain isoforms. Finally, haplotypes encompassing the human region of the B1 promoter were associated with the age of onset of HD (Soyal et al, 2012) and with protection against PD (Soyal et al, 2019), collectively suggesting that sequence variations in brain isoforms of Pgc1α may contribute to disease.…”