ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism.
The role of post-transcriptional gene regulation in human brain development and neurodevelopmental disorders remains mostly uncharacterized. ELAV-like RNA-binding proteins (RNAbps) are a family of proteins that regulate several aspects of neuronal function including neuronal excitability and synaptic transmission, both critical to the normal function of the brain in cognition and behavior. Here, we identify the downstream neuronal transcriptional and splicing networks of ELAVL2, an RNAbp with previously unknown function in the brain. Expression of ELAVL2 was reduced in human neurons and RNA-sequencing was utilized to identify networks of differentially expressed and alternatively spliced genes resulting from haploinsufficient levels of ELAVL2. These networks contain a number of autism-relevant genes as well as previously identified targets of other important RNAbps implicated in autism spectrum disorder (ASD) including RBFOX1 and FMRP. ELAVL2-regulated co-expression networks are also enriched for neurodevelopmental and synaptic genes, and include genes with human-specific patterns of expression in the frontal pole. Together, these data suggest that ELAVL2 regulation of transcript expression is critical for neuronal function and clinically relevant to ASD.
Department of Neuroscience, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, ND4.300, Dallas, TX 75390-9111, USA.
Stefano
S
Berto
Department of Neuroscience, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, ND4.300, Dallas, TX 75390-9111, USA.
Noriyoshi
N
Usui
Department of Neuroscience, University of Texas Southwestern Medical School, 5323 Harry Hines Blvd, ND4.300, Dallas, TX 75390-9111, USA Genevieve.Konopka@utsouthwestern.edu bfogel@ucla.edu.
Genevieve
G
Konopka
Program in Neurogenetics and Departments of Neurology and Human Genetics, David Geffen School of Medicine, University of California Los Angeles, 695 Charles E. Young Drive South, Gonda Room 1206, Los Angeles, CA 90095, USA Genevieve.Konopka@utsouthwestern.edu bfogel@ucla.edu.
Brent L
BL
Fogel
D000067877:Autism Spectrum Disorder / Q000235:genetics* / Q000473:pathology; D001921:Brain / Q000254:growth & development / Q000378:metabolism / Q000473:pathology; D002460:Cell Line; D000067777:ELAV-Like Protein 2 / Q000096:biosynthesis / Q000235:genetics*; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D053263:Gene Regulatory Networks / Q000235:genetics; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D009474:Neurons / Q000378:metabolism / Q000473:pathology*; D012326:RNA Splicing / Q000235:genetics; D000072260:RNA Splicing Factors / Q000235:genetics
D000067777:ELAV-Like Protein 2; D051860:Fragile X Messenger Ribonucleoprotein 1; D000072260:RNA Splicing Factors; C086811:ELAVL2 protein, human; C497683:FMR1 protein, human; C455479:RBFOX1 protein, human