Enhancer Rna's In Brain Function and Disease

Abstract

Distal enhancer elements in DNA enable higher-order chromatin interactions that regulate gene expression programs critical for cellular development, phenotype, and function. The vast majority of genetic variants linked to human health and disease by genome-wide association studies are located in non-coding regions of the genome, with putative enhancers containing more disease-linked single-nucleotide polymorphisms than all other genetic loci combined. This is especially relevant to intellectual and neuropsychiatric disorders, as sequence variations in enhancer regions have been linked to depression, schizophrenia, bipolar disorder, and autism spectrum disorders. In neuronal systems, enhancer elements are subject to widespread, bidirectional transcription that yields non-coding enhancer RNA (eRNA). However, the precise function of eRNAs has remained controversial, with different models proposing unique regulatory functions. This presentation will examine the biogenesis, localization, and function of eRNAs arising from enhancers that regulate activity-responsive immediate early genes known to be involved in cognitive functions. We show that eRNA expression from these loci are dynamically modulated by neuronal activity in an RNA PolII-dependent manner, resulting in non-polyadenylated transcripts with exclusive localization in the cell nucleus. Enhancer RNA knockdown results in impaired mRNA expression from linked genes, whereas eRNA upregulation or targeting with CRISPR-dCas9 tools results in increased expression of linked genes. Finally, we show that eRNAs interact with key epigenetic modifiers and are correlated with specific chromatin states. Together, these results suggest that RNAs transcribed from neuronal enhancers are important contributors to epigenetic landscapes and gene regulatory mechanisms. This growing link between enhancer activity and brain function strongly highlights the need to better understand the specific interactions that regulate enhancer function at the molecular level, and also suggests that enhancers could be attractive targets for a new generation of disease therapeutics.