Transcriptome level analysis in Rett syndrome using human samples from different tissues

Abstract

The mechanisms of neuro-genetic disorders have been mostly investigated in the brain, however, for some pathologies, transcriptomic analysis in multiple tissues represent an opportunity and a challenge to understand the consequences of the genetic mutation. This is the case for Rett Syndrome (RTT): a neurodevelopmental disorder predominantly affecting females that is characterised by a loss of purposeful movements and language accompanied by gait abnormalities and hand stereotypies. Although the genetic aetiology is largely associated to Methyl CpG binding protein 2 (MECP2) mutations, linking the pathophysiology of RTT and its clinical symptoms to direct molecular mechanisms has been difficult.One approach used to study the consequences of MECP2 dysfunction in patients, is to perform transcriptomic analysis in tissues derived from RTT patients or Induced Pluripotent Stem cells. The growing affordability and efficiency of this approach has led to a far greater understanding of the complexities of RTT syndrome but is also raised questions about previously held convictions such as the regulatory role of MECP2, the effects of different molecular mechanisms in different tissues and role of X Chromosome Inactivation in RTT.In this review we consider the results of a number of different transcriptomic analyses in different patients-derived preparations to unveil specific trends in differential gene expression across the studies. Although the analyses present limitations- such as the limited sample size- overlaps exist across these studies, and they report dysregulations in three main categories: dendritic connectivity and synapse maturation, mitochondrial dysfunction, and glial cell activity.These observations have a direct application to the disorder and give insights on the altered mechanisms in RTT, with implications on potential diagnostic criteria and treatments.

Beyond Pathway Analysis: Identification of Active Subnetworks in Rett Syndrome

“…MECP2 was generally regarded as a repressor, however its role as genetic activator has also been confirmed (Chahrour et al, 2008). In previous studies, a loss of function in MECP2 due to a mutation has been found to influence a variety of pathways and biological processes, including pathways related to not only neuron development and function, but also to the immune system, transcription, and translation related processes (which were identified mainly by transcriptome analysis, Colantuoni et al, 2001; Bedogni et al, 2014; Ehrhart et al, 2018; Shovlin and Tropea, 2018). The affected pathways identified with our study closely match the results previously found by Ehrhart et al (2018), in which human brain tissue data of Rett syndrome patients (published by Deng et al, 2007) was analyzed.…”

“…In the past 10 years, omics data analysis on the level of genome, transcriptome, or proteome saw an increase in importance, to analyse and understand the holistic impact of MECP2, respectively, the impact of an impaired MECP2. Shovlin and Tropea (2018) recently reviewed the available transcriptomics studies on Rett syndrome and came to the conclusion that the most researched impact of MECP2 dysfunction lies with dendritic connectivity and synapse maturation, mitochondrial dysfunction, and glial cell activity. Recent pathway analysis results of single and integrated studies identified changes in intracellular signaling, including EIF2 (eukaryotic translation initiation) signaling, cytoskeleton, and cell metabolism including mitochondrial function (Bedogni et al, 2014; Ehrhart et al, 2018).…”

Genome‐wide transcriptomic and proteomic studies of Rett syndrome mouse models identify common signaling pathways and cellular functions as potential therapeutic targets

“…This then raises the question as to whether we can learn anything new from previously conducted studies through comparing existing data sets and ultimately extracting valuable information by conducting meta‐analysis. A notable example of utilizing omic data within the Rett syndrome research field is the recent study by Shovlin and Tropea () that delineated transcriptomic data from human Rett syndrome patient samples, to present trends in differential gene expression for investigating broader research questions.…”

Establishing a transcriptome-based drug discovery paradigm for neurodevelopmental disorders

“…Conditionally ablating MECP2 from the mouse brain recapitulates several findings in patients with Rett Syndrome, such as uncoordinated gait and repetitive movements 37,38 . Gene expression profiling of mouse models as well as human brain tissue has revealed widespread changes in gene expression across brain regions [39][40][41] , consistent with MECP2's role in modulating chromatin topology.…”