Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity
| العنوان: | Pluripotent stem cell-derived models of neurological diseases reveal early transcriptional heterogeneity |
|---|---|
| المؤلفون: | Cynthia C. Hession, Walaa Oweis, Lisa M. Ellerby, Mahmoud A. Pouladi, Xiaohong Xu, Malka Nissim-Rafinia, Matan Sorek, Xian Adiconis, Neville E. Sanjana, Congyi Lu, Xi Shi, Moria Maman, Jen Q. Pan, Eran Meshorer, Sean Simmons, Shahar Simon, Joshua Z. Levin, Feng Zhang |
| المصدر: | Genome Biology, Vol 22, Iss 1, Pp 1-25 (2021) Genome Biology |
| بيانات النشر: | BMC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Adult, Pluripotent Stem Cells, lcsh:QH426-470, Smart-seq2, Stem cell model, Disease, Biology, Models, Biological, Genetic Heterogeneity, Huntington's disease, Gene expression, scRNA-seq, medicine, Transcriptional regulation, Humans, Gene Regulatory Networks, Genetic Predisposition to Disease, Single cell, RNA-Seq, Progenitor cell, Induced pluripotent stem cell, lcsh:QH301-705.5, Research, Gene Expression Profiling, Neurodegenerative diseases, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, Human genetics, lcsh:Genetics, Gene Expression Regulation, lcsh:Biology (General), Transcriptional heterogeneity, Mutation, Single-Cell Analysis, Genetic Background, Neuroscience, Neurological diseases, Huntington’s disease |
| الوصف: | Background Many neurodegenerative diseases develop only later in life, when cells in the nervous system lose their structure or function. In many forms of neurodegenerative diseases, this late-onset phenomenon remains largely unexplained. Results Analyzing single-cell RNA sequencing from Alzheimer’s disease (AD) and Huntington’s disease (HD) patients, we find increased transcriptional heterogeneity in disease-state neurons. We hypothesize that transcriptional heterogeneity precedes neurodegenerative disease pathologies. To test this idea experimentally, we use juvenile forms (72Q; 180Q) of HD iPSCs, differentiate them into committed neuronal progenitors, and obtain single-cell expression profiles. We show a global increase in gene expression variability in HD. Autophagy genes become more stable, while energy and actin-related genes become more variable in the mutant cells. Knocking down several differentially variable genes results in increased aggregate formation, a pathology associated with HD. We further validate the increased transcriptional heterogeneity in CHD8+/− cells, a model for autism spectrum disorder. Conclusions Overall, our results suggest that although neurodegenerative diseases develop over time, transcriptional regulation imbalance is present already at very early developmental stages. Therefore, an intervention aimed at this early phenotype may be of high diagnostic value. |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::a0dffc651b829a6bba15f6016b6ffd44Test https://doaj.org/article/ef6b9f08c22b4b3bb7ae4a84695c552bTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....a0dffc651b829a6bba15f6016b6ffd44 |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |