Transcriptional Profiles of Cell Fate Transitions Reveal Early Drivers of Neuronal Apoptosis and Survival

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.

Cracking the Code of Neuronal Cell Fate

“…Despite little is known about the specific role of Maf in neuronal apoptosis and degeneration, recent reports suggest that over-expression of this gene can cause cell death probably through a p53-mediated signaling [122,137]. In agreement with these results, we found an early and transient peak of transcription for Maf following induction of CGNs apoptosis, while its expression decreased following treatment with NFs (Figures 1 and 3) [43]. As other oxidative stress reactive proteins, Maf has been implicated in various neurological disorders, including Alzheimer's and Parkinson's diseases, and its role is emerging as a novel target in the treatment of these disorders [138][139][140].…”

“…Several studies, in fact, have demonstrated that activation of Olig2 in response to different NFs (e.g., FGF, GDNF and PDGF) exerts protective and pro-survival effects in multiple neuronal types [155][156][157][158]. According with these findings, we observed an increased expression of Olig2 during CGNs rescue by Pacap, Igf1 and SP (Figures 1 and 3) [43]. Despite the role elicited by Olig2 in the adult cerebral cortex under pathological conditions is not yet known, its reduced expression seems to switch cell fate from differentiation to death, contributing to the development of psychiatric disorders and acute/chronic neurodegenerative diseases, including Alzheimer's disease and Amyotrophic Lateral Sclerosis, while its increased expression has been associated with different brain tumors, supporting its potential utility as therapeutic target for the treatment of both cancer and neurodegeneration [159][160][161][162][163][164][165][166][167][168][169][170][171].…”

“…Nerve growth factor receptor Ntrk1 promotes neuronal survival, proliferation and differentiation in neuronal populations, representing a clinically relevant target in neurology [56][57][58][59][60]. On the other hand, we also observed that delayed early response core set genes were, instead, enriched in different cellular processes, including cell adhesion, cytoskeleton organization, metabolic processes and oxidative damage, supporting their role as secondary effectors of the transcriptional program governing neuronal fate decision (Figure 1) [43]. Overall, these findings represent early portraits of the complex and coordinated temporal transcriptional programs underlying apoptosis and its rescue by NFs, further supporting the existence of a conserved transcriptional program governing neuronal life or death.…”

“…The potential contribution of core set genes in human pathology was further explored by directly matching the transcriptional changes of core set genes with disease-specific gene expression signatures included in the integrative Library of Integrated Network-Based Cellular Signatures (iLINCS, http://www.ilincs.org/ilincs/signatures/main) (accessed on 29 March 2023) [43]. This integrative web-based platform facilitates mining and re-analysis of user-submitted omics signatures in the context of a large collection of pre-computed disease signatures [79].…”

“…iLINCS, in fact, also includes a comprehensive large-scale drug perturbation databases containing transcriptomic profiles of dozens of cultivated cell lines treated with thousands Given the implication of core set genes in human pathology, our findings open the possibility to identify new or already existent therapeutics that are able to modulate their activity. To this regard, we performed a transcriptional signature connectivity analysis in iLINCS to explore repurposing drugs that could revert the expression of the core set genes during neuronal apoptosis, representing putatively therapeutically useful candidates [43]. iLINCS, in fact, also includes a comprehensive large-scale drug perturbation databases containing transcriptomic profiles of dozens of cultivated cell lines treated with thousands of chemical compounds serving as reference databases.…”