Abstract
The volume of molecular observations on human diseases in public databases is continuously increasing at accelerating rates. A bottleneck is their computational integration into a coherent description, from which researchers may derive new well-founded hypotheses. Also, the need to integrate data from different technologies (genetics, coding and regulatory RNA, proteomics) emerged in order to identify biomarkers for early diagnosis and prognosis of complex diseases and therefore facilitating the development of novel treatment approaches. We propose here a workflow for the integrative transcriptomic description of the molecular pathology in Parkinsons’s Disease (PD), including suggestions of compounds normalizing disease-induced transcriptional changes as a paradigmatic example. We integrated gene expression profiles, miRNA signatures, and publicly available regulatory databases to specify a partial model of the molecular pathophysiology of PD. Six genetic driver elements (2 genes and 4 miRNAs) and several functional network modules that are associated with PD were identified. Functional modules were assessed for their statistical significance, cellular functional homogeneity, literature evidence, and normalizing small molecules. In summary, our workflow for the joint regulatory analysis of coding and non-coding RNA, has the potential to yield clinically as well as biologically relevant information, as demonstrated here on PD data.
Highlights
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects several regions of the brain, the substania nigra (SN) dopamine neurons controlling balance and movements[1,2]
Despite these important findings based on separate analyses of gene and miRNA expression, there is a lack of studies of the associated miRNA-mRNA interactome as well as of their co-regulation mechanisms, and of their collaborative functional roles in the underlying pathogenesis of Parkinsons’s Disease (PD)
We propose a comprehensive workflow for integrating miRNA expression profiles, gene expression profiles, and publicly available regulatory databases, in order to gain a deeper understanding of the co-regulation mechanisms and the collaborative functional role of miRNAs and genes in driving disease processes
Summary
Parkinson’s disease (PD) is a progressive neurodegenerative disorder that affects several regions of the brain, the substania nigra (SN) dopamine neurons controlling balance and movements[1,2]. Transcription factors (TFs) and microRNAs (miRNAs) are key players for regulating gene expression[8] Together they play crucial roles in regulating cellular processes[9], and their malfunction can cause genetic disorders as well as complex diseases such as PD2,10,11. MiRNA expression analysis of human SN neurons showed distinct profiles that are dysregulated in PD patients[2,19,20] and suggested critical functional roles of miRNAs in SN neurons as well as in PD pathogenesis as proposed in[21,22] Despite these important findings based on separate analyses of gene and miRNA expression, there is a lack of studies of the associated miRNA-mRNA interactome as well as of their co-regulation mechanisms, and of their collaborative functional roles in the underlying pathogenesis of PD. An effective joint analysis will require the integration of a series of tools with tailored parameters for the interpretation of each dataset to reveal the regulatory mechanisms of disease pathogenesis
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