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.

Long Noncoding RNA-Directed Epigenetic Regulation of Gene Expression Is Associated With Anxiety-like Behavior in Mice

“…In agreement with these findings, lncRNAs have been implicated in neurodevelopmental disorders such as Rett syndrome (25), autism (26, 27), schizophrenia (SZ) (28, 29) and Fragile X syndrome (30). Screening of lncRNA activity has also shown links between lncRNA expression and drug abuse (31, 32), suicidal behavior (33) and potentially anxiety disorders.…”

Long non-coding RNA-dependent transcriptional regulation in neuronal development and disease

“…While useful, with few exceptions, these studies have not functionally implicated these lncRNAs in disease progression (Petazzi et al, 2013; Ziats and Rennert, 2013). Here we review the limited number of studies that directly link altered lncRNA function to the development and progression of neurological disease.…”

Rett Syndrome and MeCP2

“…Loss of MeCP2 in the cerebellum of a RTT mouse model also led to altered expression of miRNAs . The role of MeCP2 in RTT pathology through regulating the expression of miRNAs was further strengthened by the observation of altered transcriptome of long noncoding RNAs (lncRNA) and specific upregulation of AK087060 and AK081227 in the brains of Mecp2-null RTT mouse model (Petazzi et al 2013). …”