MECP2 Is Post-transcriptionally Regulated during Human Neurodevelopment by Combinatorial Action of RNA-Binding Proteins and miRNAs
2016
Summary A progressive increase in
MECP2protein levels is a crucial and precisely regulated event during neurodevelopment, but the underlying mechanism is unclear. We report that
MECP2is 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
MECP23′ 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
PUM1and pluripotent-specific microRNAs destabilize the long
MECP23′ UTR in hESCs. Hence, the 3′ UTR appears to lengthen during differentiation as the long isoform becomes stable in neurons. Meanwhile, translation of
MECP2is repressed by
TIA1in hESCs until HuC predominates in neurons, resulting in a switch to translational enhancement. Ultimately, 3′ UTR-directed translational fine-tuning differentially modulates
MECP2protein in the two cell types to levels appropriate for normal neurodevelopment.
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