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.
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
authors.forename: Deivid C
authors.initials: DC
authors.lastname: Rodrigues
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
authors.forename: Dae-Sung
authors.initials: DS
authors.lastname: Kim
authors.affiliation: Program in Neurosciences & Mental Health, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
authors.forename: Guang
authors.initials: G
authors.lastname: Yang
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada.
authors.forename: Kirill
authors.initials: K
authors.lastname: Zaslavsky
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada.
authors.forename: Kevin C H
authors.initials: KC
authors.lastname: Ha
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada.
authors.forename: Rebecca S F
authors.initials: RS
authors.lastname: Mok
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
authors.forename: P Joel
authors.initials: PJ
authors.lastname: Ross
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada.
authors.forename: Melody
authors.initials: M
authors.lastname: Zhao
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
authors.forename: Alina
authors.initials: A
authors.lastname: Piekna
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada.
authors.forename: Wei
authors.initials: W
authors.lastname: Wei
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Blencowe
authors.affiliation: Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada; Donnelly Center for Cellular and Biomolecular Research, University of Toronto, Toronto, ON M5S3E1, Canada.
authors.forename: Quaid
authors.initials: Q
authors.lastname: Morris
authors.affiliation: Program in Developmental & Stem Cell Biology, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A8, Canada. Electronic address: jellis@sickkids.ca.
authors.forename: James
authors.initials: J
authors.lastname: Ellis
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D063307:AU Rich Elements / Q000235:genetics; D001483:Base Sequence; D019070:Cell Lineage; D049109:Cell Proliferation; D017124:Conserved Sequence / Q000235:genetics; D005786:Gene Expression Regulation; D000066449:Human Embryonic Stem Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics* / Q000378:metabolism; D035683:MicroRNAs / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D009474:Neurons / Q000378:metabolism*; D016548:Prosencephalon / Q000196:embryology; D011485:Protein Binding / Q000235:genetics; D014176:Protein Biosynthesis; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D020413:3' Untranslated Regions; D051783:Methyl-CpG-Binding Protein 2; D035683:MicroRNAs; C471242:PUM1 protein, human; D012333:RNA, Messenger; D016601:RNA-Binding Proteins
keywords: HuC; MECP2; PUM1; RNA-binding proteins; Rett syndrome; TIA1; mRNA stability; miRNAs; post-transcriptional regulation; translational regulation