Ulf Orom & Heiner Schrewe

The role of long noncoding RNA for the function of the Mediator complex subunit 12

Ulf Andersson Ørom

Max Planck Institute for Molecular Genetics
Long non-coding RNA

Ihnestrasse 63-73 14195 Berlin - Germany

Phone : 030-8413-1664
Fax : --

E-Mail : oerom@molgen.mpg.de

Web : See online here

1st. Financiation

Heinrich Schrewe

Max Planck Institute for Molecular Genetics
Department of Developm

Ihnestrasse 63-73 14195 Berlin - Germany

Phone : 030-8413-1302
Fax : --

E-Mail : schrewe@molgen.mpg.de

Web : See online here

The 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 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. MED12 is a 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, 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 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 regulation and connect these with the causal links to major neurological diseases.

Key technologies:

- RNA sequencing
- Mouse development and organogenesis
- Mouse embryonic stem cells (establishment, modification, differentiation)
- Classical gene targeting (knock-out, knock-in)
- CRISPR/cas gene editing
Transgenic techniques

Last Publications

- Ørom UA, Derrien T, Beringer M, Gumireddy K, Gardini A, Bussotti G, Lai F, Zytnicki M, Notredame C, Huang Q, Guigo R, and Shiekhattar R. (2010). Long noncoding RNAs with enhancer-like function in human cells. Cell 143, 46-58.

- Lai F, Ørom UA, Cesaroni M, Beringer M, Taatjes DJ, Blobel GA, and Shiekhattar R. (2013). Activating RNAs associate with Mediator to enhance chromatin architecture and transcription. Nature 494, 497–501 .

- Rocha, PP, Scholze, M, Bleiß, W, and Schrewe, H. (2010). Med12 is essential for early mouse development and for canonical Wnt and Wnt/PCP signaling. Development 137, 2723-2731.

- Rocha, PP, Bleiß, W, and Schrewe, H. (2010). Mosaic expression of Med12 in female mice leads to exencephaly, spina bifida and craniorachischisis. Birth Defects Res. A Clin. Mol. Teratol. 88, 626-632.

- Vogl, MR, Reiprich, S, Kosian, T, Schrewe, H, Nave, KA, and Wegner, M. (2013). Sox10 cooperates with the Mediator subunit 12 during terminal differentiation of myelinating glia. J. Neuroscience 33, 6679-6690.