Activity-Dependent Human Brain Coding/Noncoding Gene Regulatory Networks

Abstract

While most gene transcription yields RNA transcripts that code for proteins, a sizable proportion of the genome generates RNA transcripts that do not code for proteins, but may have important regulatory functions. The brain-derived neurotrophic factor (BDNF ) gene, a key regulator of neuronal activity, is overlapped by a primate-specific, antisense long noncoding RNA (lncRNA) called BDNFOS. We demonstrate reciprocal patterns of BDNF and BDNFOS transcription in highly active regions of human neocortex removed as a treatment for intractable seizures. A genome-wide analysis of activity-dependent coding and noncoding human transcription using a custom lncRNA microarray identified 1288 differentially expressed lncRNAs, of which 26 had expression profiles that matched activity-dependent coding genes and an additional 8 were adjacent to or overlapping with differentially expressed protein-coding genes. The functions of most of these protein-coding partner genes, such as ARC, include long-term potentiation, synaptic activity, and memory. The nuclear lncRNAs NEAT1, MALAT1, and RPPH1, composing an RNAse P-dependent lncRNA-maturation pathway, were also upregulated. As a means to replicate human neuronal activity, repeated depolarization of SY5Y cells resulted in sustained CREB activation and produced an inverse pattern of BDNF-BDNFOS co-expression that was not achieved with a single depolarization. RNAimediated knockdown of BDNFOS in human SY5Y cells increased BDNF expression, suggesting that BDNFOS directly downregulates BDNF. Temporal expression patterns of other lncRNA-messenger RNA pairs validated the effect of chronic neuronal activity on the transcriptome and implied various lncRNA regulatory mechanisms. lncRNAs, some of which are unique to primates, thus appear to have potentially important regulatory roles in activity-dependent human brain plasticity.T HE availability of mammalian genome sequences has made it possible to delineate the boundaries and structures of all genes in a genome and has demonstrated an abundance of non-protein-coding transcriptional units that rivals the numbers of known protein-coding genes (reviewed in Carninci and Hayashizaki 2007). Complex and potentially functional regulatory relationships between protein-coding and noncoding genes, including noncoding RNA genes that are poorly conserved across different species, have recently been delineated (Katayama et al. 2005;Engstrom et al. 2006). These long noncoding RNA (lncRNA) genes can be defined by four fundamental criteria: encoding transcripts that lack any open reading frames (ORFs) .100 amino acids or possessing protein database homologies (Dinger et al. 2008); being within the known range of lengths of mammalian mRNAs; support by transcript-to-genome alignments from complementary DNA (cDNA) data; and absence of matches to any known noncoding-RNA classes. Functionally, lncRNAs can have regulatory effects on coding mRNAs through a number of mechanisms, including those involving endogenous antisense lncRNA transcripts that repress ...

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