Epigenetic regulation of protein-coding and microRNA genes by the Gfi1-interacting tumor suppressor PRDM5.

Abstract

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.

• Authors: Zhijun Duan, Richard E Person, Hu-Hui Lee, Shi Huang, Jean Donadieu, Raffaele Badolato, H Leighton Grimes, Thalia Papayannopoulou, Marshall S Horwitz
• Journal: Molecular and cellular biology (Mol Cell Biol) Vol. 27 Issue 19 Pg. 6889-902 (Oct 2007) ISSN: 0270-7306 [Print] United States
• PMID: 17636019 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA-Binding Proteins
• GFI1 protein, human
• MicroRNAs
• PRDM5 protein, human
• Transcription Factors
• Histone Methyltransferases
• Protein Methyltransferases
• Histone-Lysine N-Methyltransferase
• HDAC1 protein, human
• Histone Deacetylase 1
• Histone Deacetylases

Topics

• Cell Cycle (physiology)
• Cell Line
• DNA-Binding Proteins (genetics, metabolism)
• Epigenesis, Genetic
• Gene Expression Regulation
• Hematopoiesis (physiology)
• Histone Deacetylase 1
• Histone Deacetylases (genetics, metabolism)
• Histone Methyltransferases
• Histone-Lysine N-Methyltransferase (metabolism)
• Humans
• MicroRNAs (genetics, metabolism)
• Molecular Sequence Data
• Neutropenia (genetics, metabolism)
• Promoter Regions, Genetic
• Protein Methyltransferases
• RNA Interference
• Transcription Factors (genetics, metabolism)
• Transcription, Genetic
• Two-Hybrid System Techniques
• Zinc Fingers