Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression in Drosophila dissects recognition of multiple PPAR-γ associated gene regulation

Abstract

The transcriptional repressor called parkin interacting substrate (PARIS; ZNF746) was initially identified as a novel co-substrate of parkin and PINK1 that leads to Parkinson’s disease (PD) by disrupting mitochondrial biogenesis through peroxisome proliferator-activated receptor gamma (PPARγ) coactivator -1α (PGC-1α) suppression. Since its initial discovery, growing evidence has linked PARIS to defective mitochondrial biogenesis observed in PD pathogenesis. Yet, dopaminergic (DA) neuron-specific mechanistic underpinnings and genome-wide PARIS binding landscape has not been explored. We employed conditional translating ribosome affinity purification (TRAP) followed by RNA sequencing (TRAP-seq) for transcriptome profiling of DA neurons in transgenic Drosophila lines expressing human PARIS wild type (WT) or mutant (C571A). We also generated genome-wide maps of PARIS occupancy using ChIP-seq in human SH-SY5Y cells. The results demonstrated that PPARγ functions as a master regulator of PARIS-induced molecular changes at the transcriptome level, confirming that PARIS acts primarily on PGC-1α to lead to neurodegeneration in PD. Moreover, we identified that PARIS actively modulates expression of PPARγ target genes by physically binding to the promoter regions. Together, our work revealed how PARIS drives adverse effects on modulation of PPAR-γ associated gene clusters in DA neurons.

Obesity-induced PARIS (ZNF746) accumulation in adipose progenitor cells leads to attenuated mitochondrial biogenesis and impaired adipogenesis

“…Our in vitro study showed that the PARIS accumulated in APCs decreased adipogenesis by suppressing the expression of Pparg and Cebpa , without suppressing the expression of their upstream transcription factors. In support of these results, Yazar and colleagues reported that there is a PARIS binding motif in the promoter region of Pparg and that PARIS directly represses its expression in neurons of Drosophila 29 . Therefore, the impairment of differentiation in APCs with high levels of PARIS may be caused by the direct repression of Pparg expression by PARIS.…”

Mitochondrial Dysfunction in Parkinson’s Disease: From Mechanistic Insights to Therapy

“…The biogenesis of a large number of functional mitochondria may reduce the production of ROS. A genome-wide study showed that the expression of PGC-1α, the main controller of mitochondrial biogenesis, was reduced in PD models compared with controls, which confirmed the role of mitochondrial biogenesis in the pathogenesis of PD ( Imam et al, 2013 ; Yazar et al, 2021 ). A recent study showed that parkin-knockout DA neurons had mitophagy defects that mainly resulted from mitochondrial biogenesis defects driven by parkin interacting substrate (PARIS) upregulation and subsequent PGC-1α downregulation ( Pirooznia et al, 2020 ).…”

Realizing the Potential of Social Determinants Data: A Scoping Review of Approaches for Screening, Linkage, Extraction, Analysis and Interventions

“…However, it also demonstrates a concerted effort towards more comprehensive patient care. The prevalence of home-grown tools [32,34,39,43] indicates a trend towards customization, tailored to specific patient populations and healthcare settings. This is likely due to the unique needs and circumstances of different patient demographics.…”