Abstract
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-isoformresolution. 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.
Highlights
Specification of differentiated cell types requires tightly coordinated execution of gene expression programs
30 UTRs exert gene-level translation to indicate the aggregate translation level the strongest effect of any feature tested on translation in syn- of all RNA molecules produced from a gene; in contrast, tranaptically active neuronal cultures, but they have a minimal ef- script-specific translation refers to an individual RNA transcript fect in human embryonic stem cells (hESCs)
Changes in ribosome profiling and RNA levels were highly correlated between cell types (Figure 2A; r = 0.89 between both hESCs and neural progenitor cells (NPCs) or NPCs and day 14 neuronal cultures), suggesting that transcriptional changes are a major influence on gene-level expression changes during differentiation
Summary
Many 30 UTRs extend dramatically during neurogenesis, sometimes by over 10 kb. Blair et al use complementary deepsequencing approaches to identify posttranscriptional regulation by UTRs in human neurons. They find that mTORC1 promotes translation of translationrelated genes in hESCs, while 30 UTRs downregulate translation selectively in active neuronal cultures. GSE100007 d mTOR signaling promotes translation of translation-related genes selectively in hESCs d 50 UTRs influence global translation; 30 UTRs control celltype-specific translation d Long 30 UTRs preferentially downregulate translation in neurons. 2017, Cell Reports 21, 2005–2016 November 14, 2017 a 2017 The Authors.
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