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Open Access Publications from the University of California

Widespread Translational Remodeling during Human Neuronal Differentiation

  • Author(s): Blair, JD
  • Hockemeyer, D
  • Doudna, JA
  • Bateup, HS
  • Floor, SN
  • et al.

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© 2017 The Authors Faithful cellular differentiation requires temporally precise activation of gene expression programs, which are coordinated at the transcriptional and translational levels. Neurons express the most complex set of mRNAs of any human tissue, but translational changes during neuronal differentiation remain incompletely understood. Here, we induced forebrain neuronal differentiation of human embryonic stem cells (hESCs) and measured genome-wide RNA and translation levels with transcript-isoform resolution. We found that thousands of genes change translation status during differentiation without a corresponding change in RNA level. Specifically, we identified mTOR signaling as a key driver for elevated translation of translation-related genes in hESCs. In contrast, translational repression in active neurons is mediated by regulatory sequences in 3′ UTRs. Together, our findings identify extensive translational control changes during human neuronal differentiation and a crucial role of 3′ UTRs in driving cell-type-specific translation. Many 3′ UTRs extend dramatically during neurogenesis, sometimes by over 10 kb. Blair et al. use complementary deep-sequencing approaches to identify post-transcriptional regulation by UTRs in human neurons. They find that mTORC1 promotes translation of translation-related genes in hESCs, while 3′ UTRs downregulate translation selectively in active neuronal cultures.

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