Exploiting cellular heterogeneity through single cell sequencing reveals HDAC4 as a regulator of cellular phenotypes in Parkinson’s dopamine neurons
Ontology highlight
ABSTRACT:
PROVIDER: PRJEB29235 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Induced pluripotent stem cell (iPSC)-derived dopamine neurons provide an opportunity to model Parkinson’s disease (PD) but neuronal cultures are confounded by cellular heterogeneity. By applying high-resolution single cell transcriptomic analyses to Parkinson’s iPSC-derived dopamine neurons carrying the GBA-N370S risk variant, we exploited intra-culture cellular heterogeneity to identify a progressive axis of gene expression variation leading to endoplasmic reticulum stress. Analysis of genes differentially-expressed (DE) along this axis identified the transcriptional repressor histone deacetylase 4 (HDAC4) as an upstream regulator of disease progression. HDAC4 was mislocalized to the nucleus in PD iPSC-derived dopamine neurons and repressed genes early in the disease axis, leading to late deficits in protein homeostasis. Treatment of iPSC-derived dopamine neurons with compounds known to modulate HDAC4 activity upregulated genes early in the DE axis, and corrected Parkinson’s-related cellular phenotypes. Our study demonstrates how single cell transcriptomics can exploit cellular heterogeneity to reveal disease mechanisms and identify therapeutic targets.
2018-10-17 | E-MTAB-7303 | biostudies-arrayexpress
Project description:Auxilin participates in the uncoating of clathrin-coated vesicles (CCVs), thereby facilitating synaptic vesicle (SV) regeneration at presynaptic sites. Auxilin (DNAJC6/PARK19) loss-of-function mutations cause early-onset Parkinson’s disease (PD). Here, we utilized auxilin-knockout (KO) mice to elucidate the mechanisms through which auxilin deficiency and clathrin-uncoating deficits lead to PD. Auxilin KO mice display cardinal features of PD, including progressive motor deficits, α-synuclein pathology, nigral dopaminergic loss, and neuroinflammation. Significantly, treatment with L-DOPA ameliorated motor deficits. Unbiased proteomic and neurochemical analyses of auxilin KO brains indicated dopamine dys-homeostasis. We validated these findings by demonstrating slower dopamine reuptake kinetics in vivo, an effect associated with dopamine transporter misrouting into axonal membrane deformities in the dorsal striatum. Defective SV protein sorting and elevated synaptic autophagy also contribute to ineffective dopamine sequestration and compartmentalization, ultimately leading to neurodegeneration. This study advances our knowledge of how presynaptic endocytosis deficits lead to dopaminergic vulnerability and pathogenesis of PD.
2023-02-16 | PXD040141 | Pride
Project description:Hdac4 has been found to modulate symptoms in Huntington's Disease (HD) mouse models through an uknown mechanism unrelated to any enzymatic activity. We investigated the protein-protein interactions to gain insight into the role of Hdac4 in HD.
2019-05-01 | PXD011845 | Pride
Project description:Transcriptional alterations are characteristic of persistent pain states but the key regulators remain elusive. Using a conditional knockout (cKO) strategy in mice we sought to determine whether loss of the transcriptional co-repressor histone deacetylase four (HDAC4) would have implications for sensory neuron transcription and nociception. HDAC4 was found to be largely dispensable for transcriptional regulation of naïve sensory neurons but was required for transcriptional responses after injury, with Calca and Trpv1 expression consistently downregulated in HDAC4 cKO compared to littermate controls (0.2-0.44 fold). This downregulation corresponded to reduced sensitivity to capsaicin in vitro (76% +/- 4.4% wildtype capsaicin responders vs 56.9% +/- 4.7% cKO responders) and to reduced thermal hypersensitivity in the complete Freund’s adjuvant model of inflammatory pain (1.3-1.4 fold improvement). These data indicate that HDAC4 is a novel inflammatory pain mediator and may be a good therapeutic target, capable of orchestrating the regulation of multiple downstream effectors. Total RNA was extracted from HDAC4 cKO and HDAC4 fl/fl naïve adult lumbar dorsal root ganglia (n=3/group). mRNA expression was compared using Affymetrix Mouse Gene Arrays (Mouse Gene 2.0ST) run on a GeneChip Fluidics Station 450. Chips were scanned on an Affymetrix GeneChip Scanner.
2015-04-23 | E-GEOD-62405 | biostudies-arrayexpress
Project description:To identify whether Hdac4/5 were enriched in MuERVL directly, we performed Hdac4/5 ChIP-seq with anti-Hdac4/5 antibody in wildtype ESCs. we conclude that Hdac4/5 binding were enriched on MuERVL-int region and weakly enriched on MT2, suggesting a direct regulatory role of Hdac4/5 on MuERVL expression.
2022-09-05 | GSE178130 | GEO
Project description:Analysis of human dopamine (DA) from postmortem brains of 8 patients with Parkinson’s disease (PD). Results provide insight into the molecular processes perturbed in the PD substantia nigra. Human dopamine (DA) neurons from 8 PD and 9 control subjects were obtained. Double-stranded complementary DNA was made with a biotinylated T7(dT)-24 primer. Biotinylated complementary RNA was fragmented and hybridized to Affymetrix human genome U133_X3P microarrays. The Affymetrix .CEL files were normalized to “all probe sets” in a standardized matter, and scaled to 100 by the MAS5 algorithm implemented in the Bioconductor package.
2011-01-20 | E-GEOD-24378 | biostudies-arrayexpress
Project description:Reversible protein acetylation provides a central mechanism for controlling gene expression and cellular signaling events. It is governed by the antagonistic commitment of two enzymes families: the histone acetyltransferases (HATs) and the histone deacetylases (HDACs). HDAC4, like its class IIa counterparts, is a potent transcriptional repressor through interactions with tissue-specific transcription factors via its N-terminal domain. Whilst the lysine deacetylase activity of the class IIa HDACs is much less potent than that of the class I enzymes, HDAC4 has been reported to influence protein deacetylation through its interaction with HDAC3. To investigate the influence of HDAC4 on protein acetylation, we employed the unbiased AcetylScan proteomic screen. We identified many proteins known to be modified by acetylation, but found that the absence of HDAC4 had no effect on the acetylation profile of the murine neonate brain. This is consistent with the biochemical data suggesting that HDAC4 may not function as a lysine deacetylase, but these in vivo data do not support the previous report showing that the enzymatic activity of HDAC3 might be modified by its interaction with HDAC4. To complement this work, we used Affymetrix arrays to investigate the effect of HDAC4 knock-out on the transcriptional profile of the postnatal murine brain. There was no effect on global transcription, consistent with the absence of a differential histone acetylation profile. Validation of the array data by Taq-man qPCR indicated that only protamine 1 and Igfbp6 mRNA levels were increased by more than one-fold and only CamK4 was decreased. The lack of a major effect on the transcriptional profile is consistent with the cytoplasmic location of HDAC4 in the P3 murine brain. mRNA expression analysis was performed by microarray in 3-day-old HDAC4 KO pups and WT littermates. Ten samples were analysed for each genotype. Microarray quality control was performed using the software package provided on RACE (http://race.unil.ch).
2014-07-30 | E-GEOD-49383 | biostudies-arrayexpress
Project description:To explore the downstream genes of HDAC4, we performed RNA-seq to screen after knocking down HDAC4 in 5-8F cells, a nasopharyngeal carcinoma cell line.
2022-01-28 | GSE125744 | GEO
Project description:Electromagnetic fields (EMF) are physical energy generated by electrically charged objects that can influence numerous biologic processes, including control of cell fate and plasticity. In this study, we show that magnetic gold nanoparticles in the presence of EMF can facilitate efficient direct lineage reprogramming to induced dopamine neurons both in vitro and in vivo. Remarkably, electromagnetic stimulation leads to the specific activation of the histone acetyl transferase Brd2, resulting in H3K27 acetylation and robust activation of neuronal-specific gene expression. In vivo reprogramming in conjunction with EMF stimulation efficiently alleviated symptoms in a mouse model of Parkinson’s disease (PD) in a noninvasive and controllable manner. These studies provide a proof of principle that EMF-based approaches may represent a viable and safe therapeutic strategy facilitating in vivo lineage conversion for neurodegenerative disorders.
2018-04-10 | GSE86051 | GEO
Project description:Electromagnetic fields (EMF) are physical energy generated by electrically charged objects that can influence numerous biologic processes, including control of cell fate and plasticity. In this study, we show that magnetic gold nanoparticles in the presence of EMF can facilitate efficient direct lineage reprogramming to induced dopamine neurons both in vitro and in vivo. Remarkably, electromagnetic stimulation leads to the specific activation of the histone acetyl transferase Brd2, resulting in H3K27 acetylation and robust activation of neuronal-specific gene expression. In vivo reprogramming in conjunction with EMF stimulation efficiently alleviated symptoms in a mouse model of Parkinson’s disease (PD) in a noninvasive and controllable manner. These studies provide a proof of principle that EMF-based approaches may represent a viable and safe therapeutic strategy facilitating in vivo lineage conversion for neurodegenerative disorders.
2018-04-10 | GSE86050 | GEO