Abstract
Noncoding RNAs such as miRNAs and piRNAs have long-lasting effects on the regulation of gene expression involved in long-term synaptic changes. To characterize gene regulation mediated by small noncoding RNAs associated with long-term memory in Aplysia, we consider two noncoding RNAs stimulated by 5-HT into a gene regulatory network motif model, including miR-124 that binds to and inhibits the mRNA of CREB1 and piR-F that facilitates serotonin-dependent DNA methylation to lead to repression of CREB2. Codimension-1 and -2 bifurcation analyses of 5-HT regulating both miR-124 and piR-F and a negative feedback strength for oscillation reveal rich dynamical properties of bistability and oscillations robust to variations in all other parameters. More importantly, we verify three stimulus protocols of 5-HT in experiments by our model and find that application of five pulses of 5-HT leads to a transient decrease of miR-124 but increase of piR-F concentrations, which matters sustained high level of CREB1 concentration associated with long-term memory. Furthermore, we perform bifurcation analyses for the concentrations of miR-124 and piR-F as two parameters to explore dynamical mechanisms underlying the epigenetic regulation in long-term memory formation. This study provides insights into revealing regulatory roles of epigenetic changes in gene expression involving noncoding RNAs associated with synaptic plasticity.
Highlights
Learning and memory are two of the most critical brain functions for acquiring new knowledge from experience and retaining that knowledge over time [1,2,3]
In Aplysia, cyclic AMP- response elementbinding proteins (CREBs) as transcription factors (TFs) are crucial for the regulation of the gene expression required for neuronal plasticity and formation of long-term memory (LTM) [6]
We construct a mathematical model characterizing epigenetic regulation of gene expression by two noncoding RNAs related to LTM in Aplysia, in which miR124 inhibits the mRNA of CREB1 and piR-F facilitates serotonin-dependent DNA methylation of CREB2 and silences it
Summary
Learning and memory are two of the most critical brain functions for acquiring new knowledge from experience and retaining that knowledge over time [1,2,3]. Hao et al establish a network model of the regulation between CREB1 and miR-124 stimulated by 5-HT, which is associated with long-term memory formation in Aplysia [26]. We construct a mathematical model characterizing epigenetic regulation of gene expression by two noncoding RNAs related to LTM in Aplysia, in which miR124 inhibits the mRNA of CREB1 and piR-F facilitates serotonin-dependent DNA methylation of CREB2 and silences it.
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