MECP2 Is Post-transcriptionally Regulated during Human Neurodevelopment by Combinatorial Action of RNA-Binding Proteins and miRNAs

Deivid C. Rodrigues, Dae-Sung Kim, Guang Yang, Kirill Zaslavsky, Kevin C.H. Ha, Rebecca S.F. Mok, P. Joel Ross, Melody Zhao, Alina Piekna, Wei Wei, Benjamin J. Blencowe, Quaid Morris, James Ellis

Research output: Contribution to journalArticlepeer-review

21 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)720-734
Number of pages15
JournalCell Reports
Volume17
Issue number3
DOIs
Publication statusPublished - 2016 Oct 11
Externally publishedYes

Keywords

  • HuC
  • MECP2
  • miRNAs
  • mRNA stability
  • post-transcriptional regulation
  • PUM1
  • Rett syndrome
  • RNA-binding proteins
  • TIA1
  • translational regulation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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