Abstract
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.
Highlights
Bipolar disorder (BD) is a psychiatric disease with significant morbidity and mortality [1]
We should point out the limitations of our studies, Metabolic comorbidities are highly prevalent in BD and are beginning with our use of cell line models
Disrupted insulin signaling in the more highly expressed in astrocytes than in other central nervous system (CNS) cell types brain and the hypothalamic–pituitary–adrenal axis has been and, to our knowledge, its function in human CNS cell model(s) has proposed as one explanation for the comorbidity of mood not been reported previously
Summary
Bipolar disorder (BD) is a psychiatric disease with significant morbidity and mortality [1]. We set out to characterize the molecular function of TCF7L2 in the CNS with the goal of understanding its possible role in the comorbidity of BD and obesity These studies began with a review of human brain single-nucleus and single-cell RNA-seq data for TCF7L2, results which showed that it is most highly expressed in astrocytes. We found that the “T-3” lncRNA-TCF7L2 influenced expression in astrocytes of both the parent gene and scores of other genes involved in both energy metabolism and BD risk This series of studies identified and functionally characterized a TCF7L2 lncRNA and its SNPdependent expression as a molecular mechanism related to BD-. TCF7L2 and BD risk genes To annotate TCF7L2 protein function, the RNA-seq and ChIP-seq identified TCF7L2 target genes in hiPSC-derived astrocytes were subjected to pathway enrichment analysis. BMI interaction and, as a result, illustrates the potential importance of lncRNAs for neuropsychiatry
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