%0 Journal Article %A M Ohashi %A P Lee %A D Allen %A K Fu %A B Vargas %A J Cinkornpumin %A C Salas %A J Park %A I Germanguz %A K Chronis %A E Kuoy %A T Wu %A K Lin %A AZ Xiao %A L Chen %A S Tran %A G Xiao %A L Lin %A P Jin %A M Pellegrini %A K Plath %A WE Lowry %T Loss of MECP2 leads to telomere dysfunction and neuronal stress %D 2017 %R 10.1101/130401 %J bioRxiv %P 130401 %X To determine the role for mutations of MECP2 in Rett Syndrome, we generated isogenic lines of human iPSCs (hiPSCs), neural progenitor cells (NPCs), and neurons from patient fibroblasts with and without MECP2 expression in an attempt to recapitulate disease phenotypes in vitro. Molecular profiling uncovered a reduction of 5hmC, increased expression of subtelomeric genes including TERRA (a long non-coding RNA), and shortening of telomeres in the absence of MECP2 in hiPSCs, NPCs, and Neurons. Neurons made without MECP2 show signs of stress, including induction of gamma-H2aX, p53, and senescence, which are typical molecular responses to telomere shortening. The induction of p53 appeared to affect dendritic branching in Rett neurons, as p53 inhibition restored dendritic complexity. Examination of Rett patient brains uncovered similar molecular phenotypes suggesting that our disease-in-a-dish model yielded insights into human Rett Syndrome patient phenotypes and point towards a role for MECP2 in regulating telomere function. %U https://www.biorxiv.org/content/biorxiv/early/2017/04/24/130401.full.pdf