Project description:To investigate the molecular mechanisms of cardiac glycosides’ neuroprotection, we profiled transcriptomes of human iPSC-neurons after 72h of treatment with increasing doses of digoxin, oleandrin, proscillaridin A or vehicle alone (0.1% DMSO) using RNA sequencing.
Project description:MicroRNAs (miRNAs) are short RNAs that regulate fundamental biological processes. miR-132, a key miRNA with established functions in Tau homeostasis and neuroprotection, is consistently downregulated in Alzheimer’s disease (AD) and other tauopathies. miR-132 overexpression rescues neurodegenerative phenotypes in several AD models. To complement research on miRNA-mimicking oligonucleotides targeting the central nervous system, we developed a high-throughput-screen coupled high-throughput-sequencing (HTS-HTS) in human induced pluripotent stem cell (iPSC)-derived neurons to identify small molecule inducers of miR-132. We discovered that cardiac glycosides, which are canonical sodium-potassium ATPase inhibitors, selectively upregulated miR-132 in the sub-μM range. Coordinately, cardiac glycoside treatment downregulated total and phosphorylated Tau in rodent and human neurons and protected against toxicity by glutamate, N-methyl-D-aspartate, rotenone, and Aβ oligomers. In conclusion, we identified small-molecule drugs that upregulated the neuroprotective miR-132 and ameliorated neurodegenerative phenotypes. Our dataset also represents a comprehensive resource for discovering small molecules that modulate specific miRNAs for therapeutic purposes.
Project description:To determine targets of PTBP2-dependent alternative splicing, we depleted PTBP2 in human neurons derived from induced-pluripotent stem cells (iPSC-neurons) using an LNA gapmer and performed RNA-seq on untreated, negative control-treated, and knock-down samples.
Project description:We report on a comprehensive time-course study of transcription factor (TF)-induced iPSC neurons cultured in vitro through an intrinsic maturation program following neurogenesis. Combining the present RNA-seq study with immunocytochemistry and electrophysiological analyses, we determined the transcriptional and morphological sequences of key developmental events associated with postnatal brain-like transition and spinogenesis. TF-induced iPSC neurons successfully acquired structural and functional synaptic maturity, which will critically expand their utility in modeling higher brain functions and disorders.
Project description:Prostate cancer is the most common cancer in men and cardiac glycosides inhibit prostate cancer cell proliferation. In order to investigate the mechanism by which cardiac glycosides inhibit prostate cancer cells, we observed genome-wide RNA expression in prostate cancer LNCaP-abl cells, hormone resistant cells, after the cardiac glycoside treatment using RNA-Seq. In addition, we profiled LNCaP-abl cells after androgen receptor (AR) knockdown to observe whether cardiac glycoside effect on RNA expression is similar to that of AR knockdown. Observation of three cardioglycosides, Digoxin, Peruvoside and Strophanthidin, and AR knockdown regulated RNA expression in LNCaP-abl with RNA-Seq (each triplicates)