Abstract
Neuronal apoptosis and survival are regulated at the transcriptional level. To identify key genes and upstream regulators primarily responsible for these processes, we overlayed the temporal transcriptome of cerebellar granule neurons following induction of apoptosis and their rescue by three different neurotrophic factors. We identified a core set of 175 genes showing opposite expression trends at the intersection of apoptosis and survival. Their functional annotations and expression signatures significantly correlated to neurological, psychiatric and oncological disorders. Transcription regulatory network analysis revealed the action of nine upstream transcription factors, converging pro-apoptosis and pro-survival-inducing signals in a highly interconnected functionally and temporally ordered manner. Five of these transcription factors are potential drug targets. Transcriptome-based computational drug repurposing produced a list of drug candidates that may revert the apoptotic core set signature. Besides elucidating early drivers of neuronal apoptosis and survival, our systems biology-based perspective paves the way to innovative pharmacology focused on upstream targets and regulatory networks.
Highlights
Neuronal apoptosis and survival are regulated by cell fate decision processes that ensure the correct development of the central nervous system and its homeostasis throughout adulthood
Our analysis offers for the first time a systems biology-based perspective of the complex and coordinated temporal transcriptional programs underlying apoptosis and its rescue by neurotrophic factors, further sustaining that, acting through different upstream signaling pathways, the growth factors (GFs)-mediated survival effects were propagated by common transcriptional regulatory cascades
Besides elucidating the common mechanism and key genes by which neurotrophic factors elicit neuronal survival, we identify potential transcription factors that act as master regulatory switches to control neuronal apoptosis and survival in a temporally ordered manner
Summary
Neuronal apoptosis and survival are regulated by cell fate decision processes that ensure the correct development of the central nervous system and its homeostasis throughout adulthood. Mediated by specific receptors and intracellular second messengers, the survival effects of Pituitary adenylate cyclase-activating polypeptide (Pacap) and insulin-like growth factor-1 (Igf1) were propagated by common transcriptional cascades [21]. These findings represent the first glimpse of how a neuron orchestrates its destruction/survival, the dynamic spectrum of physical and biological elements (hardware) that execute these processes is mostly unknown. The instruction set (software) that tells the hardware how to implement neuronal apoptosis or survival is still unexplored
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