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User name	Arndt Benecke
Email	arndt@ihes.fr
Phone / Fax number	+33160926665 / +33160926609
Location	Institut des Hautes Etudes Scientifiques (Integrative Biology) - 35, route de Chartres - 91440 Bures sur Yvette, France

Scientific description

Non-coding (nc) RNAs are increasingly recognized to play important regulatory roles in gene expression, sometimes by directly affecting components of the transcription machinery. The essential 7SK ncRNA  is a highly abundant small stable RNA located in the cell nucleus of higher eukaryotes. 7SK RNA has been shown to negatively regulate RNA polymerase II transcription by binding to and inactivating the positive transcription elongation factor b (P-TEFb). However, P-TEFb-independent global changes in gene expression after siRNA-mediated depletion of 7SK RNA2 point to other roles for this RNA polymerase III transcript. Here we show that 7SK RNA directly affects the function of the architectural transcription factor and chromatin regulator HMGA1 in a P-TEFb-independent manner. We reveal a statistically significant set of over 1500 HMGA1-controlled genes as being also 7SK RNA targets, and demonstrate a competitive mechanism by which the RNA competes with DNA for binding to HMGA1. Our results support an important regulatory role of 7SK RNA in HMGA1-dependent cell differentiation and proliferation regulation during early development, when expression of HMGA1 is significantly increased. Furthermore, highly elevated HMGA1 expression is observed in nearly every (>99%) type of cancer, and its expression is directly correlated with the degree of malignancy and metastatic potential. Thus, the 7SK-HMGA1 interface is essential to the understanding and, potentially, to the inhibition of oncogenesis. The 7SK-HMGA1 interaction also adds a new facet in comprehending the plasticity of the basic transcription machinery.

Technical description

For microarray analyses, RNA amplification, labeling, hybridization and detection were performed following the protocols supplied by Applied Biosystems using the corresponding kits (Applied Biosystems, ProdNo: 4339628 and 4336875). The data obtained were analyzed as described previously:
1. Noth, S., Brysbaert, G., Pellay, F. X., and Benecke, A., Genomics Proteomics Bioinformatics 4 (4), 212 (2006).
2. Noth, S., Brysbaert, G., and Benecke, A., Genomics Proteomics Bioinformatics 4 (2), 90 (2006).
3. Brysbaert G, Pellay FX, Noth S, Benecke A (2010) Genomics Proteomics Bioinformatics (2010) in the press. 
4. Noth S, and Benecke A, BMC Bioinformatics. 22 (6), 307 (2005). 
5. Wilhelm E, Kornete M, Targat B, Vigneault-Edwards J, Frontini M, Tora L, Benecke A, Bell B  BMC Mol. Biol. 11:10 (2010).

References

Eilebrecht S, Brysbaert G, Wegert T, Urlaub H, Benecke A*, Benecke BJ (2010)
7SK small nuclear RNA is a direct affector of HMGA1 function in transcription regulation.

Eilebrecht S, Brysbaert G, Wegner T, Urlaub H, Benecke BJ, Benecke A (2010) 7SK small nuclear RNA directly affects HMGA1 function in transcription regulation. Nucl. Acids Res., in the press.