This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Supplemental material
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrowReprints and Permissions
Right arrow Copyright Information
Right arrow Books from ASM Press
Right arrow MicrobeWorld
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Sripathy, S. P.
Right arrow Articles by Schultz, D. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Sripathy, S. P.
Right arrow Articles by Schultz, D. C.

 Previous Article  |  Next Article 

Molecular and Cellular Biology, November 2006, p. 8623-8638, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00487-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

The KAP1 Corepressor Functions To Coordinate the Assembly of De Novo HP1-Demarcated Microenvironments of Heterochromatin Required for KRAB Zinc Finger Protein-Mediated Transcriptional Repression{triangledown} ,{dagger}

Smitha P. Sripathy, Jessica Stevens, and David C. Schultz*

Case Western Reserve University, Department of Pharmacology and Case Comprehensive Cancer Center, 10900 Euclid Avenue, Cleveland, Ohio 44106-4965

Received 20 March 2006/ Returned for modification 1 May 2006/ Accepted 27 August 2006

KAP1/TIF1ß is proposed to be a universal corepressor protein for the KRAB zinc finger protein (KRAB-zfp) superfamily of transcriptional repressors. To characterize the role of KAP1 and KAP1-interacting proteins in transcriptional repression, we investigated the regulation of stably integrated reporter transgenes by hormone-responsive KRAB and KAP1 repressor proteins. Here, we demonstrate that depletion of endogenous KAP1 levels by small interfering RNA (siRNA) significantly inhibited KRAB-mediated transcriptional repression of a chromatin template. Similarly, reduction in cellular levels of HP1{alpha}/ß/{gamma} and SETDB1 by siRNA attenuated KRAB-KAP1 repression. We also found that direct tethering of KAP1 to DNA was sufficient to repress transcription of an integrated transgene. This activity is absolutely dependent upon the interaction of KAP1 with HP1 and on an intact PHD finger and bromodomain of KAP1, suggesting that these domains function cooperatively in transcriptional corepression. The achievement of the repressed state by wild-type KAP1 involves decreased recruitment of RNA polymerase II, reduced levels of histone H3 K9 acetylation and H3K4 methylation, an increase in histone occupancy, enrichment of trimethyl histone H3K9, H3K36, and histone H4K20, and HP1 deposition at proximal regulatory sequences of the transgene. A KAP1 protein containing a mutation of the HP1 binding domain failed to induce any change in the histone modifications associated with DNA sequences of the transgene, implying that HP1-directed nuclear compartmentalization is required for transcriptional repression by the KRAB/KAP1 repression complex. The combination of these data suggests that KAP1 functions to coordinate activities that dynamically regulate changes in histone modifications and deposition of HP1 to establish a de novo microenvironment of heterochromatin, which is required for repression of gene transcription by KRAB-zfps.

* Corresponding author. Present address: The Wistar Institute, 3601 Spruce Street, Philadelphia, PA 19104. Phone: (215) 495-6885. Fax: (215) 898-3929. E-mail: dschultz{at}wistar.org.

{triangledown} Published ahead of print on 5 September 2006.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

Molecular and Cellular Biology, November 2006, p. 8623-8638, Vol. 26, No. 22
0270-7306/06/$08.00+0     doi:10.1128/MCB.00487-06
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Jiang, W.-Q., Zhong, Z.-H., Nguyen, A., Henson, J. D., Toouli, C. D., Braithwaite, A. W., Reddel, R. R. (2009). Induction of alternative lengthening of telomeres-associated PML bodies by p53/p21 requires HP1 proteins. JCB 185: 797-810 [Abstract] [Full Text]  
  • Barde, I., Laurenti, E., Verp, S., Groner, A. C., Towne, C., Padrun, V., Aebischer, P., Trumpp, A., Trono, D. (2009). Regulation of Episomal Gene Expression by KRAB/KAP1-Mediated Histone Modifications. J. Virol. 83: 5574-5580 [Abstract] [Full Text]  
  • Briers, S., Crawford, C., Bickmore, W. A., Sutherland, H. G. (2009). KRAB zinc-finger proteins localise to novel KAP1-containing foci that are adjacent to PML nuclear bodies. J. Cell Sci. 122: 937-946 [Abstract] [Full Text]  
  • Brower-Toland, B., Riddle, N. C., Jiang, H., Huisinga, K. L., Elgin, S. C. R. (2009). Multiple SET Methyltransferases Are Required to Maintain Normal Heterochromatin Domains in the Genome of Drosophila melanogaster. Genetics 181: 1303-1319 [Abstract] [Full Text]  
  • Riclet, R., Chendeb, M., Vonesch, J.-L., Koczan, D., Thiesen, H.-J., Losson, R., Cammas, F. (2009). Disruption of the Interaction between Transcriptional Intermediary Factor 1{beta} and Heterochromatin Protein 1 Leads to a Switch from DNA Hyper- to Hypomethylation and H3K9 to H3K27 Trimethylation on the MEST Promoter Correlating with Gene Reactivation. Mol. Biol. Cell 20: 296-305 [Abstract] [Full Text]  
  • Quenet, D., Gasser, V., Fouillen, L., Cammas, F., Sanglier-Cianferani, S., Losson, R., Dantzer, F. (2008). The histone subcode: poly(ADP-ribose) polymerase-1 (Parp-1) and Parp-2 control cell differentiation by regulating the transcriptional intermediary factor TIF1{beta} and the heterochromatin protein HP1{alpha}. FASEB J. 22: 3853-3865 [Abstract] [Full Text]  
  • Wolf, D., Cammas, F., Losson, R., Goff, S. P. (2008). Primer Binding Site-Dependent Restriction of Murine Leukemia Virus Requires HP1 Binding by TRIM28. J. Virol. 82: 4675-4679 [Abstract] [Full Text]  
  • Li, X., Lee, Y.-K., Jeng, J.-C., Yen, Y., Schultz, D. C., Shih, H.-M., Ann, D. K. (2007). Role for KAP1 Serine 824 Phosphorylation and Sumoylation/Desumoylation Switch in Regulating KAP1-mediated Transcriptional Repression. J. Biol. Chem. 282: 36177-36189 [Abstract] [Full Text]  
  • Wiznerowicz, M., Jakobsson, J., Szulc, J., Liao, S., Quazzola, A., Beermann, F., Aebischer, P., Trono, D. (2007). The Kruppel-associated Box Repressor Domain Can Trigger de Novo Promoter Methylation during Mouse Early Embryogenesis. J. Biol. Chem. 282: 34535-34541 [Abstract] [Full Text]  
  • Wang, C., Rauscher, F. J. III, Cress, W. D., Chen, J. (2007). Regulation of E2F1 Function by the Nuclear Corepressor KAP1. J. Biol. Chem. 282: 29902-29909 [Abstract] [Full Text]  
  • Mascle, X. H., Germain-Desprez, D., Huynh, P., Estephan, P., Aubry, M. (2007). Sumoylation of the Transcriptional Intermediary Factor 1beta (TIF1beta), the Co-repressor of the KRAB Multifinger Proteins, Is Required for Its Transcriptional Activity and Is Modulated by the KRAB Domain. J. Biol. Chem. 282: 10190-10202 [Abstract] [Full Text]  
  • White, D. E., Negorev, D., Peng, H., Ivanov, A. V., Maul, G. G., Rauscher, F. J. III (2006). KAP1, a Novel Substrate for PIKK Family Members, Colocalizes with Numerous Damage Response Factors at DNA Lesions. Cancer Res. 66: 11594-11599 [Abstract] [Full Text]  


Copyright © 2009 by the American Society for Microbiology.   For an alternate route to Journals.ASM.org, visit: http://intl-journals.asm.org | More Info»