Identification of FMR1-regulated molecular networks in human neurodevelopment

• DOI: 10.1101/gr.251405.119
• Publication Date: 2020-03-16T20:29:22Z
• Authors: Meng Li; Junha Shin; Ryan D. Risgaard; Molly J. Parries; Jianyi Wang; Deborah Chasman; Shuang Liu; Sushmita Roy; Anita Bhattacharyya; Xinyu Zhao
• Keywords: Identification

RNA-binding proteins (RNA-BPs) play critical roles in development and disease to regulate gene expression. However, genome-wide identification of their targets primary human cells has been challenging. Here, we applied a modified CLIP-seq strategy identify the FMRP translational regulator 1 (FMR1), brain-enriched RNA-BP, whose deficiency leads Fragile X Syndrome (FXS), most prevalent inherited intellectual disability. We identified FMR1 dorsal ventral forebrain neural progenitors excitatory inhibitory neurons differentiated from pluripotent stem cells. In parallel, measured transcriptomes same four cell types upon deletion. discovered that preferentially binds long transcripts include genes unique associated with clinical phenotypes FXS autism. Integrative network analysis using graph diffusion multitask clustering transcriptional reveals pathways regulated by development. Our results demonstrate regulates common set among different but also operates type–specific manner targeting distinct sets neurons. By defining molecular subnetworks validating specific high-priority genes, novel components regulation program. provide new insights into neuronal RNA-BP neurodevelopment.