Related Experiment Video
Updated: Jan 23, 2026
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Published on: May 22, 2019
A Non-random Mouse Model for Pharmacological Reactivation of Mecp2 on the Inactive X Chromosome
Piotr Przanowski1, Zeming Zheng1, Urszula Wasko1
1Department of Biochemistry and Molecular Genetics, University of Virginia School of Medicine.
Abstract:
X chromosome inactivation (XCI) is the random silencing of one X chromosome in females to achieve gene dosage balance between the sexes. As a result, all females are heterozygous for X-linked gene expression. One of the key regulators of XCI is Xist, which is essential for the initiation and maintenance of XCI. Previous studies have identified 13 trans acting X chromosome inactivation factors (XCIFs) using a large-scale, loss-of-function genetic screen. Inhibition of XCIFs, such as ACVR1 and PDPK1, using short-hairpin RNA or small molecule inhibitors, reactivates X chromosome-linked genes in cultured cells. But the feasibility and tolerability of reactivating the inactive X chromosome in vivo remains to be determined. Towards this goal, a XistΔ:Mecp2/Xist:Mecp2-Gfp mouse model has been generated with non-random XCI due to deletion of Xist on one X chromosome. Using this model, the extent of inactive X reactivation was quantitated in the mouse brain following treatment with XCIF inhibitors. Recently published results show, for the first time, that pharmacological inhibition of XCIFs reactivates Mecp2 from the inactive X chromosome in cortical neurons of the living mouse brain.
Insights
Scientists inhibited X chromosome inactivation factors (XCIFs) to reactivate genes on the inactive X chromosome. This study demonstrates in vivo reactivation of Mecp2 in mouse brains, a crucial step for therapeutic development.
Area of Science:
- Genetics
- Epigenetics
- Neuroscience
Background:
- X chromosome inactivation (XCI) equalizes gene dosage between sexes in females.
- Xist is essential for initiating and maintaining XCI.
- Thirteen trans-acting X chromosome inactivation factors (XCIFs) have been identified.
Purpose of the Study:
- To investigate the in vivo feasibility and tolerability of reactivating the inactive X chromosome.
- To quantitate inactive X reactivation in the mouse brain after XCIF inhibitor treatment.
Main Methods:
- Utilized a XistΔ:Mecp2/Xist:Mecp2-Gfp mouse model with non-random XCI.
- Administered XCIF inhibitors to the mouse model.
- Quantitated inactive X reactivation in the mouse brain, specifically in cortical neurons.
Main Results:
- Pharmacological inhibition of XCIFs reactivated Mecp2 from the inactive X chromosome.
- This reactivation occurred in cortical neurons within the living mouse brain.
- This is the first demonstration of in vivo reactivation of an inactive X chromosome-linked gene in mammals.
Conclusions:
- Pharmacological inhibition of XCIFs is a feasible strategy for in vivo inactive X chromosome reactivation.
- This approach holds potential for therapeutic interventions targeting X-linked gene disorders.
Related Concept Videos
02:04Polytene Chromosomes
02:31Chromosome Replication
01:51Lampbrush Chromosomes
LBCs are made up of two pairs of conjugating homologous chromatids. Each chromatid consists of alternatively positioned regions of condensed-inactive chromatin and loosely placed-active side loops, which can be contracted and extended. The loops...
02:40Chromosome Structure
The centromere is a DNA sequence that links sister chromatids. This is also where kinetochores, protein complexes to which spindle microtubules attach, are constructed after the chromosome is replicated. The kinetochores allow the spindle microtubules to move the chromosomes within the cell during cell division.
Telomeres consist of non-coding repetitive nucleotide...
01:39Chromosomal Theory of Inheritance
02:32X and Y Chromosomes
The germline cells such as egg and sperm cells carry only half the number of chromosomes, i.e., 22 autosomes and one sex chromosome. All eggs have an X chromosome, while sperm cells can carry an X or...