RT Journal Article
SR Electronic
T1 Loss of MECP2 leads to telomere dysfunction and neuronal stress
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 130401
DO 10.1101/130401
A1 M Ohashi
A1 P Lee
A1 D Allen
A1 K Fu
A1 B Vargas
A1 J Cinkornpumin
A1 C Salas
A1 J Park
A1 I Germanguz
A1 K Chronis
A1 E Kuoy
A1 T Wu
A1 K Lin
A1 AZ Xiao
A1 L Chen
A1 S Tran
A1 G Xiao
A1 L Lin
A1 P Jin
A1 M Pellegrini
A1 K Plath
A1 WE Lowry
YR 2017
UL http://biorxiv.org/content/early/2017/04/24/130401.abstract
AB 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.