Using Human iPSC-Derived Neurons to Uncover Activity-Dependent Non-Coding RNAs

Abstract

Humans are arguably the most complex organisms present on Earth with their ability to imagine, create, and problem solve. As underlying mechanisms enabling these capacities reside in the brain, it is not surprising that the brain has undergone an extraordinary increase in size and complexity within the last few million years. Human induced pluripotent stem cells (hiPSCs) can be differentiated into many cell types that were virtually inaccessible historically, such as neurons. Here, we used hiPSC-derived neurons to investigate the cellular response to activation at the transcript level. Neuronal activation was performed with potassium chloride (KCl) and its effects were assessed by RNA sequencing. Our results revealed the involvement of long non-coding RNAs and human-specific genetic variants in response to neuronal activation and help validate hiPSCs as a valuable resource for the study of human neuronal networks. In summary, we find that genes affected by KCl-triggered activation are implicated in pathways that drive cell proliferation, differentiation, and the emergence of specialized morphological features. Interestingly, non-coding RNAs of various classes are amongst the most highly expressed genes in activated hiPSC-derived neurons, thus suggesting these play crucial roles in neural pathways and may significantly contribute to the unique functioning of the human brain.

Space microgravity improves proliferation of human iPSC-derived cardiomyocytes

“…Among significantly downregulated genes (Figure 6A & Table S1), mitochondrially encoded 12S RRNA (MT-RNR1) and mitochondrially encoded 16S RRNA (MT-RNR2) are functional ncRNAs that protect cells from mitochondrial apoptosis (Bitar et al, 2017); MT-RNR1 was upregulated in hiPSC-CMs subjected to ionizing radiation during differentiation (Baljinnyam et al, 2017). Another downregulated gene, cytokine angiopoietin-2 (ANGPT2), is a promising predictor of heart disease (Po ¨ss et al, 2015) and possesses proinflammatory and apoptosis-promoting abilities (Scholz et al, 2015).…”

Modeling neuronal consequences of autism-associated gene regulatory variants with human induced pluripotent stem cells

“…Most of ~16,000 lncRNAs encoded by the human genome [30,81] have not yet been characterized, but 40% are expressed in the brain and some have been implicated in brain function [82]. For instance, lncRNAs influence neuronal versus glial fate in cortical progenitors [83], while others are upregulated in response to neuronal activity [84][85][86] and have roles in neuronal excitation and plasticity [87,88]. When mouse fibroblasts were converted directly to neurons, ~60% of differentially expressed transcripts were non-coding RNAs [24], suggesting potential roles in neuronal development.…”

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“…In total, 38 clusters were generated arising from the clustering of 76 genes in reference to maternal western diet effect on post-weaning low-fat diet fed offspring (figure 2) and 95 clusters were generated arising from the clustering of 203 genes in reference to western diet effect on post-weaning western diet fed offspring (figure 3). For the ontology analysis, a functional network illustrates the gene-gene interaction and the functional clusterization [34]. Recently, potential biomarkers were derived from functional connectivity data of Alzheimer's disease [44] and a second novel brain network was proposed via functional network organization of human brain [45].…”