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Publication : Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells.

First Author  Mira-Bontenbal H Year  2022
Journal  Stem Cell Reports Volume  17
Issue  3 Pages  693-706
PubMed ID  35148843 Mgi Jnum  J:326514
Mgi Id  MGI:7314109 Doi  10.1016/j.stemcr.2022.01.008
Citation  Mira-Bontenbal H, et al. (2022) Genetic and epigenetic determinants of reactivation of Mecp2 and the inactive X chromosome in neural stem cells. Stem Cell Reports 17(3):693-706
abstractText  Rett syndrome may be treated by reactivating the silent copy of Mecp2 from the inactive X chromosome in female cells. Most studies that model Mecp2 reactivation have used mouse fibroblasts rather than neural cells, which would be critical for phenotypic reversal, and rely on fluorescent reporters that lack adequate sensitivity. Here, we present a mouse model based on a dual bioluminescent and fluorescent reporter to assess the level of reactivation of Mecp2 and the inactive X chromosome by treating neural stem cells with 5-azacytidine and Xist knockdown. We show that reactivation of Mecp2 and other X-linked genes correlates with CpG density, with distance from escapees, and, very strongly, with the presence of short interspersed nuclear elements. In addition, X-linked genes reactivated in neural stem cells overlap substantially with early reactivating genes by induced pluripotent stem cell reprogramming of fibroblasts or neuronal progenitors, indicating that X chromosome reactivation follows similar paths regardless of the technique or cell type used.
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