Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression in Drosophila dissects recognition of multiple PPAR-γ associated gene regulation
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens Drosophila melanogaster
PROVIDER: GSE175556 | GEO | 2021/08/02
REPOSITORIES: GEO
Similar Datasets
Project description: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.
| S-EPMC8563805 | biostudies-literature
Project description:PURPOSE: The transcriptional repressor PARIS (ZNF746) was initially identified as a pathogenic co-substrate of PINK1 and parkin that leads to Parkinson’s disease (PD) by disrupting mitochondrial biogenesis through PPARγ coactivator -1α (PGC-1α) suppression. Later, accumulation of PARIS in dopamine (DA) neurons that cause neurotoxicity has been studied widely and growing evidence has linked defective mitochondrial biogenesis to PD pathogenesis. Yet, the mechanistic underpinnings of this link remain elusive. METHODS: We performed a global, model-based analysis of PARIS genomic occupancy using chromatin immune-precipitation followed by sequencing (ChIP-seq) on SHSY-5Y in human cell line. The dataset is composed of PARIS and control samples, each with one replicate only. For each sample, after quality control as mentioned above, reads were separately aligned to the latest human genome (NCBI; GRCh38) using Bowtie with the parameter “-m 1” to retain uniquely mapped reads only. The R packages ChIPQC v1.20.0 and PhantomPeakQualTools v1.2.2 were used to confirm the quality of the aligned bam files based on the ChIP-seq guidelines by ENCODE consortium (NSC >= 1.05; RSC >= 0.8, Qtag={-2,-1,0,1,2}). QC-confirmed bam files were subject to differential peak calling using MACS v1.4.220 with the following parameters: -t Sample.sam -c Control.sam --format SAM -g hs -B -S --call-subpeaks. Peak annotation and visualization were done using the R packages ChIPseeker v1.20.0 and clusterProfiler v3.12.0, respectively. RESULTS: We showed that PPARγ acts as a master regulator of transcriptomic changes induced by PARIS in the clusters of Drosophila dopaminergic neurons. Also, we revealed that PARIS directly modulates expression of PPARγ target genes by physically binding to the promoter regions. And finally, we observed a PARIS binding motif at the promoter proximal site of PPARγ, implying a direct regulatory effect of PARIS on PPARγ expression profile. CONCLUSION: PARIS displays adverse effects on modulation of PPARγ associated gene clusters. Our work revealed a pivotal role of PPARγ in PARIS-driven neurodegeneration.
2021-08-02 | GSE175555 | GEO
Project description:PURPOSE: The transcriptional repressor PARIS (ZNF746) was initially identified as a pathogenic co-substrate of PINK1 and parkin that leads to Parkinson’s disease (PD) by disrupting mitochondrial biogenesis through PPARγ coactivator -1α (PGC-1α) suppression. Later, accumulation of PARIS in dopamine (DA) neurons that cause neurotoxicity has been studied widely and growing evidence has linked defective mitochondrial biogenesis to PD pathogenesis. Yet, the mechanistic underpinnings of this link remain elusive. METHODS: We employed translating ribosome affinity purification (TRAP) followed by RNA sequencing (TRAP-seq) for transcriptome profiling of DA neurons in transgenic Drosophila lines we generated expressing human PARIS or human PARIS mutant (C571A). Together with TRAP control and whole brain samples, this data set is composed of a total of 10 (3, 3, 3, and 1 respectively) replicate samples representing 4 different treatment groups for a set of gene-level (a parametric F-test) and transcript-level (a Wald test or a likelihood ratio test) differential expression analysis. RESULTS: Firstly, we identified differentially expressed genes by human PARIS in fly DA neurons successfully. Then, we showed that PPARγ acts as a master regulator of transcriptomic changes induced by PARIS in the clusters of Drosophila dopaminergic neurons. Also, we validated this finding in human neuroblastoma cell line. CONCLUSION: PPARγ plays a crucial regulatory role in PARIS phenotype. Drosophila models of PARIS-induced neurodegeneration used in this work to represent PD phenotype and our TRAP-seq protocol serve as a paradigm for future studies to unravel mechanistic underpinnings of PARIS biology.
2021-08-02 | GSE175554 | GEO
Project description:Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression in Drosophila dissects recognition of multiple PPAR-γ associated gene regulation
| PRJNA732708 | ENA
Project description:Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression dissects recognition of multiple PPAR-γ associated gene regulation (ChIP-Seq).
| PRJNA732784 | ENA
Project description:Integrative genome-wide analysis of dopaminergic neuron-specific PARIS expression dissects recognition of multiple PPAR-γ associated gene regulation (TRAP-Seq).
| PRJNA732783 | ENA
Project description:Peroxisome proliferator activated receptor-gamma (PPAR gamma) regulates metabolic homeostasis and adipocyte differentiation, and it is activated by oxidized and nitrated fatty acids. Here we report the crystal structure of the PPAR gamma ligand binding domain bound to nitrated linoleic acid, a potent endogenous ligand of PPAR gamma. Structural and functional studies of receptor-ligand interactions reveal the molecular basis of PPAR gamma discrimination of various naturally occurring fatty acid derivatives.
| S-EPMC2538624 | biostudies-literature
Project description:Mushroom body (MB)-dependent olfactory learning in Drosophila provides a powerful model to investigate memory mechanisms. MBs integrate olfactory conditioned stimulus (CS) inputs with neuromodulatory reinforcement (unconditioned stimuli, US), which for aversive learning is thought to rely on dopaminergic (DA) signaling to DopR, a D1-like dopamine receptor expressed in MBs. A wealth of evidence suggests the conclusion that parallel and independent signaling occurs downstream of DopR within two MB neuron cell types, with each supporting half of memory performance. For instance, expression of the Rutabaga (Rut) adenylyl cyclase in ? neurons is sufficient to restore normal learning to rut mutants, whereas expression of Neurofibromatosis 1 (NF1) in ?/? neurons is sufficient to rescue NF1 mutants. DopR mutations are the only case where memory performance is fully eliminated, consistent with the hypothesis that DopR receives the US inputs for both ? and ?/? lobe traces. We demonstrate, however, that DopR expression in ? neurons is sufficient to fully support short- and long-term memory. We argue that DA-mediated CS-US association is formed in ? neurons followed by communication between ? and ?/? neurons to drive consolidation.
| S-EPMC3326180 | biostudies-literature
Project description:Activation of the forkhead box transcription factor FoxO is suggested to be involved in dopaminergic (DA) neurodegeneration in a Drosophila model of Parkinson's disease (PD), in which a PD gene product LRRK2 activates FoxO through phosphorylation. In the current study that combines Drosophila genetics and biochemical analysis, we show that cyclic guanosine monophosphate (cGMP)-dependent kinase II (cGKII) also phosphorylates FoxO at the same residue as LRRK2, and Drosophila orthologues of cGKII and LRRK2, DG2/For and dLRRK, respectively, enhance the neurotoxic activity of FoxO in an additive manner. Biochemical assays using mammalian cGKII and FoxO1 reveal that cGKII enhances the transcriptional activity of FoxO1 through phosphorylation of the FoxO1 S319 site in the same manner as LRRK2. A Drosophila FoxO mutant resistant to phosphorylation by DG2 and dLRRK (dFoxO S259A corresponding to human FoxO1 S319A) suppressed the neurotoxicity and improved motor dysfunction caused by co-expression of FoxO and DG2. Nitric oxide synthase (NOS) and soluble guanylyl cyclase (sGC) also increased FoxO's activity, whereas the administration of a NOS inhibitor L-NAME suppressed the loss of DA neurons in aged flies co-expressing FoxO and DG2. These results strongly suggest that the NO-FoxO axis contributes to DA neurodegeneration in LRRK2-linked PD.
| S-EPMC3290610 | biostudies-literature
Project description:Amyotrophic Lateral Sclerosis (ALS) is a progressive neuromuscular disease for which there is no cure. We have previously developed a Drosophila model of ALS based on TDP-43 that recapitulates several aspects of disease pathophysiology. Using this model, we designed a drug screening strategy based on the pupal lethality phenotype induced by TDP-43 when expressed in motor neurons. In screening 1200 FDA-approved compounds, we identified the PPARγ agonist pioglitazone as neuroprotective in Drosophila. Here, we show that pioglitazone can rescue TDP-43-dependent locomotor dysfunction in motor neurons and glia but not in muscles. Testing additional models of ALS, we find that pioglitazone is also neuroprotective when FUS, but not SOD1, is expressed in motor neurons. Interestingly, survival analyses of TDP or FUS models show no increase in lifespan, which is consistent with recent clinical trials. Using a pharmacogenetic approach, we show that the predicted Drosophila PPARγ homologs, E75 and E78, are in vivo targets of pioglitazone. Finally, using a global metabolomic approach, we identify a set of metabolites that pioglitazone can restore in the context of TDP-43 expression in motor neurons. Taken together, our data provide evidence that modulating PPARγ activity, although not effective at improving lifespan, provides a molecular target for mitigating locomotor dysfunction in TDP-43 and FUS but not SOD1 models of ALS in Drosophila. Furthermore, our data also identify several 'biomarkers' of the disease that may be useful in developing therapeutics and in future clinical trials.
| S-EPMC4381760 | biostudies-literature