Silencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation
Department of Neurology; Medical Scientist Training Program; Graduate School of Biomedical Sciences, MD/PhD Program; Department of Pediatrics; Lawrence Lab
Cell Biology | Congenital, Hereditary, and Neonatal Diseases and Abnormalities | Developmental Biology | Developmental Neuroscience | Molecular and Cellular Neuroscience | Nervous System Diseases | Nucleic Acids, Nucleotides, and Nucleosides
The ability of XIST to dosage compensate a trisomic autosome presents unique experimental opportunities and potentially transformative therapeutic prospects. However, it is currently thought that XIST requires the natural context surrounding pluripotency to initiate chromosome silencing. Here, we demonstrate that XIST RNA induced in differentiated neural cells can trigger chromosome-wide silencing of chromosome 21 in Down syndrome patient-derived cells. Use of this tightly controlled system revealed a deficiency in differentiation of trisomic neural stem cells to neurons, correctible by inducing XIST at different stages of neurogenesis. Single-cell transcriptomics and other analyses strongly implicate elevated Notch signaling due to trisomy 21, thereby promoting neural stem cell cycling that delays terminal differentiation. These findings have significance for illuminating the epigenetic plasticity of cells during development, the understanding of how human trisomy 21 effects Down syndrome neurobiology, and the translational potential of XIST, a unique non-coding RNA.
Down syndrome, XIST, dosage compensation, gene therapy, human pluripotent stem cells, neural differentiation, notch signaling, scRNA-seq, single-cell
DOI of Published Version
Czermiński JT, Lawrence JB. Silencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation. Dev Cell. 2020 Feb 10;52(3):294-308.e3. doi: 10.1016/j.devcel.2019.12.015. Epub 2020 Jan 23. PMID: 31978324; PMCID: PMC7055611. Link to article on publisher's site
Czerminski JT, Lawrence JB. (2020). Silencing Trisomy 21 with XIST in Neural Stem Cells Promotes Neuronal Differentiation. University of Massachusetts Medical School Faculty Publications. https://doi.org/10.1016/j.devcel.2019.12.015. Retrieved from https://escholarship.umassmed.edu/faculty_pubs/1666