Scientists Make Important Discovery in Gene Regulation
ScienceDaily (Mar. 11, 2010) — Scientists at the University of Essex have a greater understanding of how our genes are controlled following a major research project.
Proteins at work. (Credit: Image courtesy of University of Essex)
The findings of the study, which looked at how proteins work as teams to control genes in the cells, could also help to unravel the mechanisms of disease such as cancer.
The five-year research, funded by the Medical Research Council, has been published in Molecular and Cellular Biology.
The research team, led by Dr Elena Klenova from the Department of Biological Sciences, looked at the protein called CTCF, which was previously identified as a key 'controller' of many of our genes, making them either active or inactive.
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Molecular and Cellular Biology, March 2010, p. 1199-1216, Vol. 30, No. 5
0270-7306/10/$12.00+0 doi:10.1128/MCB.00827-09
Copyright © 2010, American Society for Microbiology. All Rights Reserved.
Mutational Analysis of the Poly(ADP-Ribosyl)ation Sites of the Transcription Factor CTCF Provides an Insight into the Mechanism of Its Regulation by Poly(ADP-Ribosyl)ation ,Dawn Farrar,1 Sushma Rai,1, Igor Chernukhin,1 Maja Jagodic,2, Yoko Ito,2Samer Yammine,3 Rolf Ohlsson,3 Adele Murrell,2 and Elena Klenova1*
Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, United Kingdom,1 CRUK Cambridge Research Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, United Kingdom,2 Box 280, Karolinska Institute, SE-171 77 Stockholm, Sweden3
Received 25 June 2009/ Returned for modification 2 August 2009/ Accepted 10 December 2009
Poly(ADP-ribosyl)ation of the conserved multifunctional transcription factor CTCF was previously identified as important to maintain CTCF insulator and chromatin barrier functions. However, the molecular mechanism of this regulation and also the necessityof this modification for other CTCF functions remain unknown. In this study, we identified potential sites of poly(ADP-ribosyl)ation within the N-terminal domain of CTCF and generated a mutant deficient in poly(ADP-ribosyl)ation. Using this CTCF mutant, we demonstrated the requirement of poly(ADP-ribosyl)ation for optimal CTCF function in transcriptional activation of the p19ARF promoter and inhibition of cell proliferation. By using a newlygenerated isogenic insulator reporter cell line, the CTCF insulator function at the mouse Igf2-H19 imprinting control region (ICR) was found to be compromised by the CTCF mutation. The association and simultaneous presence of PARP-1 and CTCF at the ICR, confirmed by single and serial chromatin immunoprecipitation assays, were found to be independent of CTCF poly(ADP-ribosyl)ation. These results suggest a model of CTCF regulation by poly(ADP-ribosyl)ation whereby CTCF and PARP-1 form functional complexes at sites along the DNA, producing a dynamic reversible modification of CTCF. By using bioinformatics tools, numerous sites of CTCF and PARP-1 colocalization were demonstrated, suggesting that such regulation of CTCF may take place at the genome level.
* Corresponding author. Mailing address: Department of Biological Sciences, University of Essex, Wivenhoe Park, Colchester, Essex CO4 3SQ, United Kingdom. Phone: 44-1206874868. Fax: 44-1206872592. E-mail:klenovae@essex.ac.uk
Published ahead of print on 28 December 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Present address: Helen Rollason Research Laboratory, SAW 106, Sawyers Building, Anglia Ruskin University, Rivermead Campus, Bishop Hall Lane, CM1 1SQ Chelmsford, Essex, United Kingdom.
Present address: Department of Clinical Neuroscience, Karolinska Institutet, Neuroimmunology Unit, Center for Molecular Medicine, Karolinska Hospital at Solna, Stockholm, Sweden.
Molecular and Cellular Biology, March 2010, p. 1199-1216, Vol. 30, No. 5
0270-7306/10/$12.00+0 doi:10.1128/MCB.00827-09Copyright © 2010, American Society for Microbiology. All Rights Reserved.
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