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LncRNAs and open chromatin regions constitute midbrain dopaminergic neuron- specific molecular signatures

ABSTRACT: LncRNAs and open chromatin regions constitute midbrain dopaminergic neuron- specific molecular signatures

PROVIDER: PRJNA430414 | ENA |

REPOSITORIES: ENA

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LncRNAs and open chromatin regions constitute midbrain dopaminergic neuron- specific molecular signatures

Project description:Midbrain dopaminergic (DA) neurons are involved in diverse neurological functions, including control of movements, emotions or reward. In return, their dysfunctions cause severe clinical manifestations in humans, such as the appearance of motor and cognitive symptoms in Parkinson’s Disease. The physiology and pathophysiology of these neurons are widely studied, mostly with respect to molecular mechanisms implicating protein-coding genes. In contrast, the contribution of non-coding elements of the genome to DA neurons function is poorly investigated. In this study, we isolated DA neurons from E14.5 ventral mesencephalons, and used RNA-seq and ATAC-seq to establish and describe the repertoires of long non-coding RNAs (lncRNAs) and putative DNA regulatory regions, such as enhancers, specific to this neuronal population. We identified 990 novel lncRNAs out of 1,363 expressed in DA neurons, and most of them were not found in hindbrain serotonergic (5-HT) neurons, indicating a high degree of cell-specificity. This feature was also observed regarding open chromatin regions, as 39% of the ATAC-seq peaks from the DA repertoire were not detected in the 5-HT neurons. Our work provides for the first time DA-specific catalogues of non-coding elements of the genome that will undoubtedly participate in deepening our knowledge regarding DA neuronal development and dysfunctions.

2019-01-09 | GSE108917 | GEO

RNA-SEQ profiling of mouse whole midbrain and dopaminergic neurons from the mouse mid-brain

Project description:RNA-SEQ profiling of mouse whole midbrain and dopaminergic neurons from the mouse mid-brain Murine whole midbrain and murine midbrain dopaminergic neurons

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ChIP-seq analysis of Foxa2 binding sites in midbrain dopaminergic progenitors

Project description:Embryonic stem (ES) cells were differentiated in culture to midbrain dopaminergic (mDA) progenitors and subjected to ChIP-seq analysis to resolve genome-wide binding sites of forkhead box protein A2 (Foxa2). Foxa2 was found to directly regulate multiple lineage pathways to specify midbrain dopaminergic and floor plate progenitor identity.

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Long non-coding RNA repertoire and open chromatin regions constitute midbrain dopaminergic neuron - specific molecular signatures.

Project description: Not available

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Single Cell RNA-seq Study of Midbrain and Dopaminergic Neuron Development in Mouse, Human, and Stem Cells

Project description:In order to get a better molecular understanding of human midbrain development, this study defines cell types of the ventral midbrain in both human and mouse as well as stem cell-derived dopaminergic neuron preparations, and reveals the temporal dynamics of key lineages across development and the adult.

2016-10-06 | GSE76381 | GEO

The Obesity-associated Fto gene regulates activity of the dopaminergic midbrain circuitry [WT]

Project description:Here we use MeRIP-Seq to analyze global adenosine methylation (m6A) in mRNAs in the midbrain and striatum of Fto-deficient mice. We find that Fto deficiency leads to increased methylation within a subset of mRNAs important for neuronal signaling, including many within the dopaminergic signaling pathway. Collectively, our results show that Fto regulates demethylation of specific mRNAs in vivo, and this activity relates to control of dopaminergic transmission. Profiling of m6A in midbrain and striatum from wild type mice

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The Obesity-associated Fto gene regulates activity of the dopaminergic midbrain circuitry [FTO KO]

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Identifying secreted biomarkers of dopaminergic ventral midbrain progenitor cells

Project description:Ventral midbrain (VM) dopaminergic progenitor cells derived from human pluripotent stem cells have the potential to replace endogenously lost dopamine neurons and are currently in preclinical and clinical development for treatment of Parkinson’s Disease (PD). However, one main challenge in the quality control of the cells is that rostral and caudal VM progenitors are extremely similar transcriptionally though only the caudal VM cells give rise to dopaminergic neurons with functionality in PD. Therefore, it is critical to develop assays which can rapidly and reliably discriminate rostral from caudal VM cells during clinical manufacturing. Here, we applied shotgun proteomics to search for novel secreted biomarkers specific for caudal VM progenitors compared to rostral VM progenitors and validated key hits by ELISA. From this, we identified novel secreted markers (CPE, LGI1 and PDGFC) significantly enriched in caudal versus rostral VM progenitor cultures, whereas the markers CNTN2 and CORIN were significantly enriched in rostral VM cultures. With this data, we suggest and test in clinical grade samples a panel of coupled ELISA assays that can be applied as a quality control tool for assessing the correct patterning of cells during clinical manufacturing.

2023-12-13 | PXD039510 | Pride

RNA-SEQ profiling of mouse whole midbrain and dopaminergic neurons from the mouse mid-brain

Project description:RNA-SEQ profiling of mouse whole midbrain and dopaminergic neurons from the mouse mid-brain

2015-07-27 | GSE64526 | GEO

Single-cell transcriptomics and in vitro lineage tracing reveals differential susceptibility of human iPSC-derived midbrain dopaminergic neurons in a cellular model of Parkinson’s disease.

Project description:Advances in stem cell technologies open up new avenues for modelling development and diseases. The success of these pursuits however rely on the use of cells most relevant to those targeted by the disease of interest, for example, midbrain dopaminergic neurons for Parkinson’s disease. In the present study, we report the generation of a human induced pluripotent stem cell (iPSC) line capable of purifying and tracing nascent midbrain dopaminergic progenitors and their differentiated progeny via the expression of a Blue Fluorescent Protein (BFP). This was achieved by CRISPR/Cas9 assisted knock-in of BFP and Cre into the safe harbour locus AAVS1 and an early midbrain dopaminergic lineage marker gene LMX1A, respectively. Immunocytochemical analysis and single cell RNA sequencing of iPSC-derived neural cultures confirms developmental recapitulation of the human fetal midbrain and high quality midbrain cells. By modelling Parkinson’s disease-related drug toxicity using 1-Methyl-4-phenylpyridinium (MPP+), we showed preferential reduction of BFP+ cells, a finding demonstrated independently by cell death assays and single cell transcriptomic analysis of MPP+ treated neural cultures. Together, these results highlight the importance of disease relevant cell type in stem cell modelling.

2023-12-08 | GSE249360 | GEO

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