Compositions and methods for XI chromosome reactivation
In some aspects, the disclosure relates to the reactivation of inactive X chromosomes (Xi). In some embodiments, the disclosure provides compositions and methods for the reactivation of inactive X chromosomes. In some embodiments, the compositions and methods described by the disclosure may be useful for the treatment of dominant X-linked diseases.
1. A method of inducing expression of MECP2 in a mammalian cell having an inactive X chromosome, the method comprising
delivering to the cell an X chromosome inactivation factor (XCIF) inhibitor in an amount effective for inducing expression of MECP2,
wherein the XCIF inhibitor is (i) GSK650394 or EMD638683, (ii) an antisense oligomer comprising at least 8 nucleotides complementary to an mRNA encoded by SGK1, or (iii) an siRNA comprising a sequence that is complementary to an mRNA encoded by SGK1,
wherein the cell is of a subject having Rett Syndrome.
2. The method of claim 1 further comprising determining that the cell has a mutant allele of MECP2.
3. The method of claim 1 further comprising determining that delivery of the XCIF inhibitor to the cell results in
(i) induced expression of MECP2; or,
(ii) determining that an X-chromosome is reactivated; or
(iii) determining that there is decreased expression or activity of XIST.
4. The method of claim 1 , wherein the cell is in a subject.
5. The method of claim 1 , wherein the XCIF inhibitor is an siRNA that inhibits SGK1.
6. The method of claim 5 , wherein the XCIF inhibitor is an antisense oligomer that inhibits SGK1.
7. The method of claim 1 , wherein the antisense oligomer or the siRNA comprises one or more modified nucleotides and/or one or more modified internucleoside linkages.
8. The method of claim 1 , wherein the XCIF inhibitor is GSK650394.
9. The method of claim 1 , wherein the cell is a fibroblast, an embryonic stem cell, or a neuron.
10. The method of claim 1 , wherein the cell is in vitro.
11. The method of claim 1 , wherein the XCIF inhibitor is EMD638683.