Abstract
miRNA regulates the expression of protein coding genes and plays a regulatory role in human development and disease. The human iPSCs and their differentiated progenies provide a unique opportunity to identify these miRNA-mediated regulatory mechanisms. To identify miRNA–mRNA regulatory interactions in human nervous system development, well characterized NSCs were differentiated from six validated iPSC lines and analyzed for differentially expressed (DE) miRNome and transcriptome by RNA sequencing. Following the criteria, moderated t statistics, FDR-corrected p-value ≤ 0.05 and fold change—absolute (FC-abs) ≥2.0, 51 miRNAs and 4033 mRNAs were found to be significantly DE between iPSCs and NSCs. The miRNA target prediction analysis identified 513 interactions between 30 miRNA families (mapped to 51 DE miRNAs) and 456 DE mRNAs that were paradoxically oppositely expressed. These 513 interactions were highly enriched in nervous system development functions (154 mRNAs; FDR-adjusted p-value range: 8.06 × 10−15–1.44 × 10−4). Furthermore, we have shown that the upregulated miR-10a-5p, miR-30c-5p, miR23-3p, miR130a-3p and miR-17-5p miRNA families were predicted to down-regulate several genes associated with the differentiation of neurons, neurite outgrowth and synapse formation, suggesting their role in promoting the self-renewal of undifferentiated NSCs. This study also provides a comprehensive characterization of iPSC-generated NSCs as dorsal neuroepithelium, important for their potential use in in vitro modeling of human brain development and disease.
Highlights
The cell fate determination during embryonic development and adult tissue homeostasis is orchestrated by global changes in the cellular transcriptome and proteome—a complex but tightly regulated process involving diverse regulatory mechanisms
The six induced pluripotent stem cells (iPSCs) lines used in this study were previously reprogrammed from lymphoblastoid cells lines established in-vitro using blood samples of our San Antonio Mexican American Family Study (SAMAFS) participants, who were originally recruited in our San Antonio Family Heart Study (SAFHS), and provided appropriate written consent
A detailed description of iPSC reprogramming and validation methodology used in reprogramming of six iPSC lines and their validation can found in our previous publications [18,19]
Summary
The cell fate determination during embryonic development and adult tissue homeostasis is orchestrated by global changes in the cellular transcriptome and proteome—a complex but tightly regulated process involving diverse regulatory mechanisms. The binding of the miRNA with cognate mRNAs typically results in either the destabilization or suppressed translation of the mRNA targets [3,4]. This complementary nature of the miRNA–mRNA interaction is being exploited to computationally predict and identify miRNAs regulatory targets [5,6,7,8]. Single miRNAs can regulate the expression of numerous genes and a single protein coding gene can be a target of multiple miRNAs. The miRNAs spatial and temporal expression is tightly regulated by cellular developmental and physiological state, indicating a key role that miRNAs play in regulating cell fate and differentiation [3,9]. MiRNA expression is highly cell- and tissue-specific [3,10,11]
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