ELAVL2-regulated transcriptional and splicing networks in human neurons link neurodevelopment and autism

Abstract

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.

Genome-wide meta-analysis of depression identifies 102 independent variants and highlights the importance of the prefrontal brain regions

“…CELF4 plays a key role in coordinating the synaptic function in excitatory neurons 37 with dynamic changes in expression during brain development 38 and deletions in the surrounding region (18q.12.2) associated with autism spectrum disorder 39 and developmental and behavioural disorders 40 . ELAVL2 potentially aids in the regulation of gene expression pathways in human neurodevelopment 41 and disruption of related pathways may be a factor in neurodevelopmental disorders 42 . Improving our understanding of the genetic similarities and differences between neuroticism and depression may provide a route to determining the biological aspects that underpin a more permanent personality trait or a depressive state.…”

Defining the Genetic, Genomic, Cellular, and Diagnostic Architectures of Psychiatric Disorders

“…FMR1 in particular interacts with the mRNA of many ASD-and SCZ-risk genes (Iossifov et al, 2014;Parikshak et al, 2013; Schizophrenia Working Group of the Psychiatric Genomics Consortium, 2014). Analysis of transcriptional (Cotney et al, 2015;Sugathan et al, 2014), splicing (Berto et al, 2016;Fogel et al, 2012;Weyn-Vanhentenryck et al, 2014), or signaling (Tian et al, 2014) networks indicates that at least some of the rare major gene forms of psychiatric disorders impact pathways that are more generally related to risk in the population. This further highlights the relevance of rare forms of psychiatric disorders to understanding common genetic variation.…”

Coverage-dependent bias creates the appearance of binary splicing in single cells

“…Our filter based on the number of recovered mRNA molecules and the expected splice junction reads was able to remove potentially spurious binary observations, as shown for alternatively spliced exon 8 of Cadm1, a cell adhesion factor that is differentially spliced in neurogenesis [22,23]. Single-cell data showed an apparent bimodal distribution of Cadm1 splicing throughout differentiation, with no clear pattern of differential splicing ( Figure 3d,e).…”