Role of RNA modifications in brain and behavior

Abstract

Much progress in our understanding of RNA metabolism has been made since the first RNA nucleoside modification was identified in 1957. Many of these modifications are found in noncoding RNAs but recent interest has focused on coding RNAs. Here, we summarize current knowledge of cellular consequences of RNA modifications, with a special emphasis on neuropsychiatric disorders. We present evidence for the existence of an “RNA code,” similar to the histone code, that fine-tunes gene expression in the nervous system by using combinations of different RNA modifications. Unlike the relatively stable genetic code, this combinatorial RNA epigenetic code, or epitranscriptome, may be dynamically reprogrammed as a cause or consequence of psychiatric disorders. We discuss potential mechanisms linking disregulation of the epitranscriptome with brain disorders and identify potential new avenues of research.

Androgenic regulation of sexually dimorphic expression of RNA binding motif protein 48 in the developing mouse cortex and hippocampus

“…In support of this possibility, an early study observed that the hippocampal mRNA levels of two splicing factors, polypyrimidine tract‐binding protein‐associated splicing factor ( Sfpq / Psf ) and splicing factor arginine/serine‐rich 3 ( Sfrs3 / Srp20 ), were higher in male mice than in females, and hippocampus‐dependent learning tasks upregulated expression of both splicing factors differently between the sexes (Antunes‐Martins et al, 2007). Based on the growing list of neurological diseases and psychiatric disorders, in which the cortex and hippocampus are implicated, and which are linked to defects of splicing and other RNA processing mechanisms (Brinegar and Cooper, 2016; Jung and Goldman, 2018; Licatalosi and Darnell, 2006; Manning and Cooper, 2017), it has become increasingly probable that RNA binding proteins may play important roles in the regulation of neural functions served by these two brain regions. Thus, we hypothesized that during early development, sexually dimorphic expression of the genes encoding RNA binding proteins in the developing mouse cortex and hippocampus might activate a regulatory gene network to mediate the masculinizing effects of gonadal steroids on differential neural function and behavior between the sexes.…”

Small RNA modifications in Alzheimer’s disease

“…4,14,15 RNA modifications have recently been detected in the nervous system, where they are involved in the regulation of cortical differentiation, behaviour, and brain functions. 16,17 We found changes in RNA-modification profiles in the AD brain cortex in both fractions of small RNAs. While the involvement of miRNA in the pathogenesis of AD has been explored 2,3,26 , the identifications of rsRNAs and ysRNAs in a pathophysiological context has only begun to emerge 8,27,28 and has not been studied in AD.…”

The role of mRNA m6A methylation in the nervous system

“…In the emerging field of epitranscriptomic mechanisms, mRNA m 6 A modification has potential role in learning and memory [77]. It regulates physiological and stressinduced behavior in the adult mammalian brain, and augments the strength of weak memories [78][79][80]. As a newly identified element in the region-specific gene regulatory network in the mouse brain, mRNA m 6 A modification plays a vital role in the death of dopaminergic neuron [81,82].…”