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Molecular and Cellular Biology, October 2007, p. 6889-6902, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00762-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Epigenetic Regulation of Protein-Coding and MicroRNA Genes by the Gfi1-Interacting Tumor Suppressor PRDM5{triangledown}

Zhijun Duan,1 Richard E. Person,1,{dagger} Hu-Hui Lee,1,{ddagger} Shi Huang,2 Jean Donadieu,3 Raffaele Badolato,4 H. Leighton Grimes,5 Thalia Papayannopoulou,6 and Marshall S. Horwitz1*

Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Box 357720, Seattle, Washington 98195,1 The Burnham Institute, La Jolla, California 92037,2 Département Sante et Environement, Institut de Veille Sanitaire, Saint Maurice 94415, France,3 Department of Pediatrics, University of Brescia, Brescia 25123, Italy,4 Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio 45229,5 Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington6

Received 1 May 2007/ Returned for modification 7 June 2007/ Accepted 9 July 2007

Gfi1 transcriptionally governs hematopoiesis, and its mutations produce neutropenia. In an effort to identify Gfi1-interacting proteins and also to generate new candidate genes causing neutropenia, we performed a yeast two-hybrid screen with Gfi1. Among other Gfi1-interacting proteins, we identified a previously uncharacterized member of the PR domain-containing family of tumor suppressors, PRDM5. PRDM5 has 16 zinc fingers, and we show that it acts as a sequence-specific, DNA binding transcription factor that targets hematopoiesis-associated protein-coding and microRNA genes, including many that are also targets of Gfi1. PRDM5 epigenetically regulates transcription similarly to Gfi1: it recruits the histone methyltransferase G9a and class I histone deacetylases to its target gene promoters and demonstrates repressor activity on synthetic reporters; on endogenous target genes, however, it functions as an activator, in addition to a repressor. Interestingly, genes that PRDM5 activates, as opposed to those it represses, are also targets of Gfi1, suggesting a competitive mechanism through which two repressors could cooperate in order to become transcriptional activators. In neutropenic patients, we identified PRDM5 protein sequence variants perturbing transcriptional function, suggesting a potentially important role in hematopoiesis.

* Corresponding author. Mailing address: Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Box 357720, Seattle, WA 98195. Phone: (206) 616-4566. Fax: (206) 897-1775. E-mail: horwitz{at}u.washington.edu

{triangledown} Published ahead of print on 16 July 2007.

{dagger} Present address: Baylor College of Medicine, Houston, TX 77030.

{ddagger} Present address: Department of Bioagricultural Science, National Chiayi University, Chiayi City, Taiwan.

Molecular and Cellular Biology, October 2007, p. 6889-6902, Vol. 27, No. 19
0270-7306/07/$08.00+0     doi:10.1128/MCB.00762-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Salipante, S. J., Rojas, M. E. B., Korkmaz, B., Duan, Z., Wechsler, J., Benson, K. F., Person, R. E., Grimes, H. L., Horwitz, M. S. (2009). Contributions to Neutropenia from PFAAP5 (N4BP2L2), a Novel Protein Mediating Transcriptional Repressor Cooperation between Gfi1 and Neutrophil Elastase. Mol. Cell. Biol. 29: 4394-4405 [Abstract] [Full Text]  
  • Velu, C. S., Baktula, A. M., Grimes, H. L. (2009). Gfi1 regulates miR-21 and miR-196b to control myelopoiesis. Blood 113: 4720-4728 [Abstract] [Full Text]  


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