TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling.

Bipolar disorder (BD) and obesity are highly comorbid. We previously performed a genome-wide association study (GWAS) for BD risk accounting for the effect of body mass index (BMI), which identified a genome-wide significant single-nucleotide polymorphism (SNP) in the gene encoding the transcription factor 7 like 2 (TCF7L2). However, the molecular function of TCF7L2 in the central nervous system (CNS) and its possible role in the BD and BMI interaction remained unclear. In the present study, we demonstrated by studying human induced pluripotent stem cell (hiPSC)-derived astrocytes, cells that highly express TCF7L2 in the CNS, that the BD-BMI GWAS risk SNP is associated with glucocorticoid-dependent repression of the expression of a previously uncharacterized TCF7L2 transcript variant. That transcript is a long non-coding RNA (lncRNA-TCF7L2) that is highly expressed in the CNS but not in peripheral tissues such as the liver and pancreas that are involved in metabolism. In astrocytes, knockdown of the lncRNA-TCF7L2 resulted in decreased expression of the parent gene, TCF7L2, as well as alterations in the expression of a series of genes involved in insulin signaling and diabetes. We also studied the function of TCF7L2 in hiPSC-derived astrocytes by integrating RNA sequencing data after TCF7L2 knockdown with TCF7L2 chromatin-immunoprecipitation sequencing (ChIP-seq) data. Those studies showed that TCF7L2 directly regulated a series of BD risk genes. In summary, these results support the existence of a CNS-based mechanism underlying BD-BMI genetic risk, a mechanism based on a glucocorticoid-dependent expression quantitative trait locus that regulates the expression of a novel TCF7L2 non-coding transcript.

Advances in RNA Viral Vector Technology to Reprogram Somatic Cells: The Paramyxovirus Wave.

Ethical issues are a significant barrier to the use of embryonic stem cells in patients due to their origin: human embryos. To further the development of stem cells in a patient application, alternative sources of cells were sought. A process referred to as reprogramming was established to create induced pluripotent stem cells from somatic cells, resolving the ethical issues, and vectors were developed to deliver the reprogramming factors to generate induced pluripotent stem cells. Early viral vectors used integrating retroviruses and lentiviruses as delivery vehicles for the transcription factors required to initiate reprogramming. However, because of the inherent risk associated with vectors that integrate into the host genome, non-integrating approaches were explored. The development of non-integrating viral vectors offers a safer alternative, and these modern vectors are reliable, efficient, and easy to use to achieve induced pluripotent stem cells suitable for direct patient application in the growing field of individualized medicine. This review summarizes all the RNA viral vectors in the field of reprogramming with a special focus on the emerging delivery vectors based on non-integrating  Paramyxoviruses, Sendai and measles viruses. We discuss their design and evolution towards being safe and efficient reprogramming vectors in generating induced pluripotent stem cells from somatic cells.

miRNA-mediated control of exogenous OCT4 during mesenchymal-epithelial transition increases measles vector reprogramming efficiency.

OCT4 is a key mediator of induced pluripotent stem cell (iPSC) reprogramming, but the mechanistic insights into the role of exogenous OCT4 and timelines that initiate pluripotency remain to be resolved. Here, using measles reprogramming vectors, we present microRNA (miRNA) targeting of exogenous OCT4 to shut down its expression during the mesenchymal to the epithelial transition phase of reprogramming. We showed that exogenous OCT4 is required only for the initiation of reprogramming and is dispensable for the maturation stage. However, the continuous expression of SOX2, KLF4, and c-MYC is necessary for the maturation stage of the iPSC. Additionally, we demonstrate a novel application of miRNA targeting in a viral vector to contextually control the vector/transgene, ultimately leading to an improved reprogramming efficiency. This novel approach could be applied to other systems for improving the efficiency of vector-induced processes.