title: Dysregulation of the long non-coding RNA transcriptome in a Rett syndrome mouse model.
abstract: Mecp2 is a transcriptional repressor protein that is mutated in Rett syndrome, a neurodevelopmental disorder that is the second most common cause of mental retardation in women. It has been shown that the loss of the Mecp2 protein in Rett syndrome cells alters the transcriptional silencing of coding genes and microRNAs. Herein, we have studied the impact of Mecp2 impairment in a Rett syndrome mouse model on the global transcriptional patterns of long non-coding RNAs (lncRNAs). Using a microarray platform that assesses 41,232 unique lncRNA transcripts, we have identified the aberrant lncRNA transcriptome that is present in the brain of Rett syndrome mice. The study of the most relevant lncRNAs altered in the assay highlighted the upregulation of the AK081227 and AK087060 transcripts in Mecp2-null mice brains. Chromatin immunoprecipitation demonstrated the Mecp2 occupancy in the 5'-end genomic loci of the described lncRNAs and its absence in Rett syndrome mice. Most importantly, we were able to show that the overexpression of AK081227 mediated by the Mecp2 loss was associated with the downregulation of its host coding protein gene, the gamma-aminobutyric acid receptor subunit Rho 2 (Gabrr2). Overall, our findings indicate that the transcriptional dysregulation of lncRNAs upon Mecp2 loss contributes to the neurological phenotype of Rett syndrome and highlights the complex interaction between ncRNAs and coding-RNAs.
authors.affiliation: 1 Cancer Epigenetics and Biology Program (PEBC); Bellvitge Biomedical Research Institute (IDIBELL); Barcelona, Catalonia, Spain.
authors.forename: Paolo
authors.initials: P
authors.lastname: Petazzi
authors.forename: Juan
authors.initials: J
authors.lastname: Sandoval
authors.forename: Karolina
authors.initials: K
authors.lastname: Szczesna
authors.forename: Olga C
authors.initials: OC
authors.lastname: Jorge
authors.forename: Laura
authors.initials: L
authors.lastname: Roa
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.forename: Antonio
authors.initials: A
authors.lastname: Gomez
authors.forename: Dori
authors.initials: D
authors.lastname: Huertas
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
mesh_terms: D024506:5' Flanking Region; D000818:Animals; D016000:Cluster Analysis; D004195:Disease Models, Animal; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D056426:Genetic Loci; D006801:Humans; D008297:Male; D051783:Methyl-CpG-Binding Protein 2 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D062085:RNA, Long Noncoding / Q000235:genetics*; D015203:Reproducibility of Results; D015518:Rett Syndrome / Q000235:genetics*; D059467:Transcriptome
chemical_list: D051783:Methyl-CpG-Binding Protein 2; D062085:RNA, Long Noncoding
keywords: Mecp2; Rett syndrome; chromatin immunoprecipitation; mice; non-coding RNA