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

@article{citeulike:2770890, 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.}, address = {Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.}, author = {Duan, Z. and Person, R. E. and Lee, H. H. and Huang, S. and Donadieu, J. and Badolato, R. and Grimes, H. L. and Papayannopoulou, T. and Horwitz, M. S. }, citeulike-article-id = {2770890}, doi = {http://dx.doi.org/10.1128/MCB.00762-07}, issn = {0270-7306}, journal = {Molecular and cellular biology}, keywords = {gfi1, microrna, prdm5}, month = {October}, number = {19}, pages = {6889--6902}, posted-at = {2008-05-09 16:25:27}, priority = {2}, title = {Epigenetic regulation of protein-coding and microRNA genes by the Gfi1-interacting tumor suppressor PRDM5.}, url = {http://dx.doi.org/10.1128/MCB.00762-07}, volume = {27}, year = {2007} }

TY - JOUR ID - citeulike:2770890 L3 - citeulike-article-id:2770890 TI - Epigenetic regulation of protein-coding and microRNA genes by the Gfi1-interacting tumor suppressor PRDM5. JF - Molecular and cellular biology VL - 27 IS - 19 SP - 6889 EP - 6902 AD - Division of Medical Genetics, Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA. SN - 0270-7306 N2 - 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. KW - gfi1 KW - microrna KW - prdm5 AU - Duan, Z AU - Person, RE AU - Lee, HH AU - Huang, S AU - Donadieu, J AU - Badolato, R AU - Grimes, HL AU - Papayannopoulou, T AU - Horwitz, MS PY - 2007/10// UR - http://dx.doi.org/10.1128/MCB.00762-07 ER -