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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE108917 | GEO | 2019/01/09

REPOSITORIES: GEO

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Project description:While microRNAs (miRNAs) have recently emerged as critical post-transcriptional modulators of gene expression in neuronal development, very little is known regarding the roles of miRNA-mediated regulation in the specification of cell-type specific dendritic complexity. The dendritic arborization (da) sensory neurons of the Drosophila PNS offer an excellent model system for elucidating the molecular mechanisms governing class specific dendrite morphogenesis and for exploring miRNA-mediated control of this process. To facilitate functional analyses of miRNA regulation in da neurons, we have conducted whole-genome miRNA expression profiling as well as mRNA expression profiling of three distinct classes of da neurons, thereby generating a comprehensive molecular gene expression signature within these individual subclasses of da neurons. To further validate the role of these expressed miRNAs in directing dendritic architecture, we conducted a genome-wide UAS-miRNA phenotypic screen using live-image confocal microscopy followed by semi-automated neurometric quantification, to directly assess the effect of over/mis-expression of individual and clustered miRNAs on neurons of varying dendritic complexity. Through this approach, we have identified numerous miRNAs with previously unknown functions in dendritic development. Gain-of-function and loss-of-function analyses revealed an endogenous role miR-2b and miR-13b (members of the K-box family) and miR-12/283/304 in dendritic patterning in da neuron subclasses. Moreover, using an integrative bioinformatic analysis approach involving inverse correlation between miRNA and mRNA expression profiling data in combination with existing target prediction algorithms, we have identified putative target of these miRNAs in regulating da neuron dendritic development. Validation of these predicted miRNA-target relationships via phenotypic analyses as well as QPCR, revealed the regulatory effect of these molecules in restricting dendritic branching in da neurons.

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

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