@article{753ffa50d8ca4cabbd97afd4090ed0c1,
title = "MECP2 Is Post-transcriptionally Regulated during Human Neurodevelopment by Combinatorial Action of RNA-Binding Proteins and miRNAs",
abstract = "A progressive increase in MECP2 protein levels is a crucial and precisely regulated event during neurodevelopment, but the underlying mechanism is unclear. We report that MECP2 is regulated post-transcriptionally during in vitro differentiation of human embryonic stem cells (hESCs) into cortical neurons. Using reporters to identify functional RNA sequences in the MECP2 3' UTR and genetic manipulations to explore the role of interacting factors on endogenous MECP2, we discover combinatorial mechanisms that regulate RNA stability and translation. The RNA-binding protein PUM1 and pluripotent-specific microRNAs destabilize the long MECP2 3' UTR in hESCs. Hence, the 3' UTR appears to lengthen during differentiation as the long isoform becomes stable in neurons. Meanwhile, translation of MECP2 is repressed by TIA1 in hESCs until HuC predominates in neurons, resulting in a switch to translational enhancement. Ultimately, 3' UTR-directed translational fine-tuning differentially modulates MECP2 protein in the two cell types to levels appropriate for normal neurodevelopment.",
keywords = "HuC, MECP2, PUM1, RNA-binding proteins, Rett syndrome, TIA1, mRNA stability, miRNAs, post-transcriptional regulation, translational regulation",
author = "Rodrigues, {Deivid C.} and Kim, {Dae Sung} and Guang Yang and Kirill Zaslavsky and Ha, {Kevin C.H.} and Mok, {Rebecca S.F.} and Ross, {P. Joel} and Melody Zhao and Alina Piekna and Wei Wei and Blencowe, {Benjamin J.} and Quaid Morris and James Ellis",
note = "Funding Information: We thank Johanna Rommens and Holly Liu for polysome-profiling resources; Freda Miller for RNA-FISH resources; the SickKids Imaging, SickKids Proteomics, Analytics Robotics & Chemical Biology Centre (SPARC), and The Centre for Applied Genomics (TCAG) Facilities for services; and Tadeo Thompson and Peter Pasceri for technical assistance. The research was supported by Canadian Institutes of Health Research (CIHR) grants (to B.J.B.; MOP-133423 and EPS-129129 to J.E.), the Ontario Brain Institute (POND network to J.E.), and the National Research Foundation, Korea (NRF-2015R1D1A1A01056649 to D.-S.K.). D.C.R. was supported by a RettSyndrome.org Mentored Fellowship and SickKids Restracomp Fellowship, D.-S.K. by a National Research Foundation of Korea Fellowship award, P.J.R. by an Ontario Stem Cell Initiative Fellowship, K.Z. by a CIHR Vanier Canada Graduate Studentship, G.Y. by Brain Canada Mental Health Fellowship, and K.H. by Ontario Graduate Scholarship and CIHR Banting and Best Doctoral Research Award. Publisher Copyright: {\textcopyright} 2016 The Author(s)",
year = "2016",
month = oct,
day = "11",
doi = "10.1016/j.celrep.2016.09.049",
language = "English",
volume = "17",
pages = "720--734",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "3",
}