Transcription profiling of cultured fibroblastic cell lines from Rett syndrome patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
SUBMITTER: Nicolas Cagnard
PROVIDER: E-MEXP-1956 | biostudies-arrayexpress |
REPOSITORIES: biostudies-arrayexpress
Publications
Rett syndrome and the urge of novel approaches to study MeCP2 functions and mechanisms of action.
Bedogni Francesco F Bedogni Francesco F Rossi Riccardo L RL Galli Francesco F Cobolli Gigli Clementina C Gandaglia Anna A Kilstrup-Nielsen Charlotte C Landsberger Nicoletta N
Neuroscience and biobehavioral reviews 20140302
Rett syndrome (RTT) is a devastating genetic disorder that worldwide represents the most common genetic cause of severe intellectual disability in females. Most cases are caused by mutations in the X-linked MECP2 gene. Several recent studies have demonstrated that RTT mimicking animal models do not develop an irreversible condition and phenotypic rescue is possible. However, no cure for RTT has been identified so far, and patients are only given symptomatic and supportive treatments. The develop ...[more]
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Project description:Rett syndrome is a human intellectual disability disorder that is associated with mutations in the X-linked MECP2 gene. Theepigenetic reader MeCP2 binds to methylated cytosines on the DNA and regulates chromatin organization. We have shownpreviously that MECP2 Rett syndrome missense mutations are impaired in chromatin binding and heterochromatinreorganization. Here, we performed a proteomics analysis of post-translational modifications of MeCP2 isolated from adult mousebrain. We show that MeCP2 carries various post-translational modifications, among them phosphorylation on S80 and S421, whichlead to minor changes in either heterochromatin binding kinetics or clustering. We found that MeCP2 is (di)methylated on severalarginines and that this modification alters heterochromatin organization. Interestingly, we identified the Rett syndrome mutationsite R106 as a dimethylation site. In addition, co-expression of protein arginine methyltransferases 1 and 6 lead to a decrease ofheterochromatin clustering. Altogether, we identified and validated novel modifications of MeCP2 in the brain and show that thesecan modulate its ability to bind as well as reorganize heterochromatin, which may play a role in the pathology of Rett syndrome.
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Project description:A unique signature of neuronal transcriptomes is the high expression of the longest genes in the genome (e.g. >100 kilobases). These genes encode proteins with essential functions in neuronal physiology, and disruption of long gene expression has been implicated in neurological disorders. DNA topoisomerases resolve topological constraints that arise on DNA and facilitate the expression of long genes in neurons. Conversely, methyl-CpG binding protein 2 (MeCP2), which is disrupted in Rett syndrome, can act as a transcriptional repressor to downregulate the expression of long genes. The molecular mechanisms underlying the regulation of long genes by these factors are not fully understood, however, and whether or not they directly influence each other is not known. Here, we identify a functional interaction between MeCP2 and Topoisomerase II-beta (TOP2β) in neurons. We show that MeCP2 and TOP2β physically interact in vivo and map protein sequences sufficient for their physical interaction in vitro. We profile TOP2β activity genome-wide in neurons and detect enrichment at regulatory regions and gene bodies of long neuronal genes, including long genes regulated by MeCP2. Further, we find that knockdown and overexpression of MeCP2 leads to altered TOP2β activity at MeCP2-regulated genes. Our findings uncover a mechanism by which MeCP2 inhibits the activity of TOP2β at long genes in neurons and suggest that this mechanism is disrupted in neurodevelopment disorders caused by mutation of MeCP2.
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