Painting a picture of RNA editing in the brain

Noel-Marie Plonski¹, Madeline Fredrick², Gabriella Amato², Caroline Nitirahardjo², Helen Piontkivska^1,2

1. School of Biomedical Sciences, Kent State University, Kent OH 44242
2. Department of Biology, Kent State University, Kent OH 44242

Adenosine deaminase acting on RNA (ADAR) enzyme deaminates adenosine (A) to inosine (I) in a double stranded RNA (dsRNA), which can result in a codon or splice site change. Of 3 ADAR loci, ADAR1p150 isoform is of particular interest because of its connection to the innate immune response through interferon alpha (IFNA) pathway controlled expression.  Regulation of ADAR1p150 expression also plays an important role in controlling RNA editing events during neuro-development.  This phenomenon is in major part responsible for increased neural transcriptome diversity, with its nuanced spatio-temporal control of ion channel permeability, speed of nerve cell conduction as well as neurotransmitter packaging, trafficking and release.  Such fine-tuning of nerve cell signaling contributes to higher functioning cognitive brain development seen in primates compared to the other vertebrates.  The current goals in our lab are to understand the links between RNA editing, neural development and host-pathogen interactions, including the evolution of regulatory elements in ADAR genes. Here we examine the conservation of genomic sequences of interferon-stimulated response element (ISRE) found in the promoter region of ADAR1p150 across multiple species.  The results show the higher conservation of the promoter region in primates compared to other vertebrates.  Once we understand the regulation of ADAR1p150, the next step is to understand how its expression affects RNA editing patterns.  Using publically available RNA-seq datasets and a custom computational pipeline, we demonstrate the correlation between expression of all three ADAR genes and A to G editing sites in early neuro-development as well as the differential editing patterns seen in the development of the human brain.  Once the normal spatio-temporal RNA editing patterns are mapped, they can then be compared to RNA patterns observed in neurological diseases and disorders to determine genes or pathways potentially involved in the mechanisms of pathology. Congenital Zika syndrome (CZS) is one example where the observed breadth of clinical sequelae can potentially be attributed to ADAR editing dysregulation, where symptoms such as microcephaly, ventriculomegaly, calcium deposits and hydrocephalus can be explained in part by changes in ratios of variant isoforms of ion channels, most notably of glutamate receptors.  By combing multiple computational and comparative genomics strategies, our ultimate goal is to decipher the role of ADAR-mediated transcriptome diversity in neural development and subsequent neurological diseases of vertebrates.