TCF7L2 lncRNA: a link between bipolar disorder and body mass index through glucocorticoid signaling
| Autor: | Huanyao Gao, Brandon J. Coombes, Duan Liu, Richard M. Weinshilboum, Daniel C. Kim, Zhenqing Ye, Tamas Ordog, Mark A. Frye, Jeong Heon Lee, Thanh Thanh L. Nguyen, Brenna Sharp, Huaizhi Huang, Liewei Wang, Joanna M. Biernacka |
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| Rok vydání: | 2021 |
| Předmět: |
endocrine system
Bipolar Disorder endocrine system diseases Induced Pluripotent Stem Cells Genome-wide association study Biology Polymorphism Single Nucleotide Transcription Factor 7-Like 2 Body Mass Index Cellular and Molecular Neuroscience Humans SNP Induced pluripotent stem cell Glucocorticoids Molecular Biology Gene Gene knockdown nutritional and metabolic diseases Psychiatry and Mental health Diabetes Mellitus Type 2 Expression quantitative trait loci Cancer research RNA Long Noncoding Transcription Factor 7-Like 2 Protein TCF7L2 Genome-Wide Association Study |
| Zdroj: | Molecular Psychiatry. 26:7454-7464 |
| ISSN: | 1476-5578 1359-4184 |
| DOI: | 10.1038/s41380-021-01274-z |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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