Project Details
Projekt
The function of long non-coding RNA-Mediator complexes in neurological disease
Applicants
Professor Dr. Ulf Andersson Orom; Dr. Heinrich Schrewe
Subject Area
Molecular Biology and Physiology of Neurons and Glial Cells
Developmental Neurobiology
Developmental Neurobiology
Term
from 2014 to 2018
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 254849966
Specification and maintenance of cell fate in multicellular organisms requires defined gene expression programs that are coordinated by precise spatio-temporal control of RNA transcription. The Mediator of polymerase II complex is part of the intricate system that regulates eukaryotic transcription by sensing and assimilating a multitude of signals and delivering a proper calibrated output to the transcriptional machinery. The MED12 subunit of Mediator has been shown to be responsible for recruiting the bulk of Mediator to DNA-bound transcription factors, and is essential for mouse development. Three human intellectual disability (ID) syndromes, Opitz-Kaveggia (FG), Lujan, and Ohdo, have been associated with missense mutations in MED12. In a recent study MED12 was shown to bind long noncoding RNAs and this interaction was demonstrated to be required for recruiting Mediator to its target genes and associated enhancers. Important for the study described in this proposal, MED12 containing FG mutations fail to associate with long noncoding RNAs. These results suggest that the loss of Mediator-ncRNA interactions is responsible for the misregulation of genes that affect brain development and neuronal plasticity in the MED12-linked ID syndromes. Using mouse models carrying ID-related MED12 mutations we aim to identify novel ncRNA Mediator interactions and the relevant ncRNA-Mediator-target assemblies. The goal is to reveal the underlying molecular mechanisms of ncRNA-Mediator regulated gene expression and connect these with the causal links to major neurological diseases.
DFG Programme
Priority Programmes
