The methamphetamine-induced RNA targetome of hnRNP H in Hnrnph1 mutants showing reduced dopamine release and behavior

Abstract

We previously identified Hnrnph1 (heterogeneous nuclear ribonucleoprotein H1) as a quantitative trait gene underlying reduced methamphetamine behavioral sensitivity. Mice with a heterozygous frameshift deletion in the first coding exon of Hnrnph1 showed reduced methamphetamine-induced dopamine release and behaviors. To inform the mechanism linking hnRNP H dysfunction with reduced methamphetamine-induced dopamine release and behavior, we surveyed the RNA targetome of hnRNP H via cross-linking immunoprecipitation coupled with RNA-sequencing in striatal tissue at baseline and at 30 min post-methamphetamine (2 mg/kg, i.p.). Methamphetamine induced opposite changes in RNA-binding targets of hnRNP H in Hnrnph1 mutants versus wild-types, including 3’UTR targets in mRNAs enriched for synaptic proteins involved in dopamine release and excitatory synaptic plasticity. Targetome, transcriptome, and spliceome analyses triangulated on a methamphetamine-induced upregulation of Cacna2d2 transcript and decreased 3’UTR usage in hyposensitive Hnrnph1 mutants. Our study identifies a dynamic methamphetamine-induced RNA targetome of hnRNP H that has the potential to rapidly regulate gene expression, synaptic transmission, plasticity, and behavior. HIGHLIGHTS The hnRNP H RNA targetome contains an enrichment of G-rich binding motifs within introns The hnRNP H RNA targetome reveals gene networks enriched for synaptic function Hnrnph1 mutation and methamphetamine treatment induce changes in RNA-binding targets of hnRNP H Targetome, transcriptome, and spliceome analysis triangulated on Cacna2d2 as a methamphetamine-induced regulatory target with potential physiological relevance to synaptic transmission and behavior