Compositions and methods for treating diseases associated with an imprinting defect

Abstract

The invention provides methods for activating a repressed allele within an imprinting control region, thereby treating an imprinting associated disorder.

What is claimed is: 
     
         1 . A method of treating a subject having a disorder associated with histone 3 lysine 27 trimethylation (H3K27me3)-dependent imprinting, the method comprising administering to the subject an agent that inhibits H3K27me3 or an agent that selectively removes trimethylation at lysine 27 of histone 3, thereby treating the disorder. 
     
     
         2 . The method of  claim 1 , wherein the disorder is associated with a mutation in a gene of Table 1 or in a gene selected from the group consisting of Adamts2, Bbx, BC049762, Bmp7, C430002E04Rik, E2f3, Enc1, Epas1, Etv6, Fam198b, G730013B05Rik, Gab1, Gramd1b, Mbnl2, Otx2, Otx2os1, Phf17, Rbms1, Rbp2, Runx1, Sfmbt2, Sh3gl3, Slc38a1, Slc38a2, Slc38a4, Smoc1, Sox21, and Tle3. 
     
     
         3 . The method of  claim 1 , wherein the disorder is associated with a mutation in a gene selected from the group consisting of Sfmbt2, Bbx, C430002E04Rik, Phf17, Slc38a4, Gramd1b, Tle3, E2f3, Smoc1, Sox21, Slc38a1, Runx1, Bmp7, Rnc1, Fam198b, Rbms1, Zrsr1, Impact, and Fkbp6. 
     
     
         4 . The method of  claim 1 , wherein the disorder is associated with a mutation in a gene selected from the group consisting of Sfmbt2, Gab1, Slc38a4, and Phf17. 
     
     
         5 . The method of  claim 1 , wherein the disorder is associated with a mutation in a gene selected from the group consisting of Ev6, 17001125H03Rik, Smoc1, and Bmp7. 
     
     
         6 . The method of  claim 1 , wherein the disorder is associated with a mutation in a gene selected from the group consisting of Gab1, Phf17, Sfmbt2, Slc38a4, or Smoc1. 
     
     
         7 . The method of  claim 1 , wherein the disorder is microphthalmia with limb anomalies (MLA) associated with a mutation in Smoc1. 
     
     
         8 . The method of  claim 1 , wherein the disorder is associated with limb development associated with a mutation in Smoc1. 
     
     
         9 . The method of  claim 1 , wherein the disorder is associated with a placental defect associated with a mutation in Gab1 or Sfmbt2. 
     
     
         10 . The method of  claim 1 , wherein a cell of the subject is contacted with the agent. 
     
     
         11 . The method of  claim 10 , wherein the agent is an H3K27me3-specific demethylase. 
     
     
         12 . The method of  claim 11 , wherein the agent is lysine-specific demethylase 6A (KDM6A), lysine-specific demethylase 6B (KDM6B), or lysine-specific demethylase 6C (KDM6C). 
     
     
         13 . The method of  claim 10 , wherein the agent is an inhibitor of histone 3 lysine 27 trimethylation (H3K27me3). 
     
     
         14 . The method of  claim 13 , wherein the agent is a small molecule compound, a polypeptide, or a polynucleotide. 
     
     
         15 . The method of  claim 14 , wherein the agent is selected from the group consisting of tazemetostat, DZNep, GSK373, GSK126, El1, Epz005687, and CPI-169. 
     
     
         16 . The method of  claim 10 , wherein the cell is contacted in vitro or in vivo. 
     
     
         17 . The method of  claim 10 , wherein the cell is present in a mammalian subject undergoing pre- or post-natal development.