Abstract
While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. RNA-binding proteins play central roles in RNA regulation, including translation and turnover. Here we show that the RNA-binding protein CSDE1 (cold shock domain containing E1) is highly expressed in hESCs to maintain their undifferentiated state and prevent default neural fate. Notably, loss of CSDE1 accelerates neural differentiation and potentiates neurogenesis. Conversely, ectopic expression of CSDE1 impairs neural differentiation. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis. Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. Thus, our results uncover CSDE1 as a central post-transcriptional regulator of hESC identity and neurogenesis.
Highlights
While the transcriptional network of human embryonic stem cells has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function
Besides LIN28A, we found that all the cold shock domain (CSD) and CSD-like proteins detected in our proteomics assay are significantly increased in hESCs (Supplementary Table 1 and Supplementary Data 1)
Since LIN28A and DHX8 levels are linked to ESC function, we performed a shRNA screen against other CSDcontaining proteins to identify potential novel regulators of hESC function. hESCs were infected with shRNA-expressing lentivirus and selected for puromycin resistance
Summary
While the transcriptional network of human embryonic stem cells (hESCs) has been extensively studied, relatively little is known about how post-transcriptional modulations determine hESC function. We find that CSDE1 post-transcriptionally modulates core components of multiple regulatory nodes of hESC identity, neuroectoderm commitment and neurogenesis Among these key pro-neural/neuronal factors, CSDE1 binds fatty acid binding protein 7 (FABP7) and vimentin (VIM) mRNAs, as well as transcripts involved in neuron projection development regulating their stability and translation. CSDE1 post-transcriptionally regulates numerous mRNAs by different mechanisms depending on its interaction with other proteins, the target transcript and the region within the transcript where CSDE1 primarily binds in a dynamic process associated with the specific cell type and state. A comprehensive study combining individual-nucleotide resolution crosslinking immunoprecipitation sequencing (iCLIP-seq), RNA sequencing and ribosome profiling unveiled CSDE1 targets in human melanoma[16] In these cells, CSDE1 protein expression is often increased and regulates the levels of pro-oncogenic factors such as vimentin (VIM) or RAC1 as well as tumor suppressors (e.g., PTEN)[16]. This study demonstrated that CSDE1 binds to mRNAs encoding regulatory proteins involved in development and neuron projection guidance in melanoma cells[16]
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