title: 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. RNAi-mediated 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.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan 48202, USA
authors.forename: Leonard
authors.initials: L
authors.lastname: Lipovich
authors.forename: Fabien
authors.initials: F
authors.lastname: Dachet
authors.forename: Juan
authors.initials: J
authors.lastname: Cai
authors.forename: Shruti
authors.initials: S
authors.lastname: Bagla
authors.forename: Karina
authors.initials: K
authors.lastname: Balan
authors.forename: Hui
authors.initials: H
authors.lastname: Jia
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Loeb
mesh_terms: D001921:Brain / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000235:genetics; D002460:Cell Line; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D053263:Gene Regulatory Networks; D006801:Humans; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D022661:RNA, Untranslated; D014158:Transcription, Genetic; D059467:Transcriptome
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D062085:RNA, Long Noncoding; D012333:RNA, Messenger; D022661:RNA, Untranslated