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Rank G.,Rotary Bone Marrow Research Laboratories | Cerruti L.,Rotary Bone Marrow Research Laboratories | Simpson R.J.,Ludwig Institute for Cancer Research | Moritz R.L.,Ludwig Institute for Cancer Research | And 4 more authors.
Blood | Year: 2010

Defining the molecular mechanisms underpinning fetal (γ) globin gene silencing may provide strategies for reactivation of γ-gene expression, a major therapeutic objective in patients with β-thalassemia and sickle cell disease (SCD). We have previously demonstrated that symmetric methylation of histone H4 Arginine 3 (H4R3me2s) by the protein arginine methyltransferase PRMT5 is required for recruitment of the DNA methyltransferase DNMT3A to the γ-promoter, and subsequent DNA methylation and gene silencing. Here we show in an erythroid cell line, and in primary adult erythroid progenitors that PRMT5 induces additional repressive epigenetic marks at the γ-promoter through the assembly of a multiprotein repressor complex containing the histone modifying enzymes SUV4-20h1, casein kinase 2α (CK2α), and components of the nucleosome remodeling and histone deacetylation complex. Expression of a mutant form of PRMT5 lacking methyltransferase activity or shRNA-mediated knockdown of SUV4-20h1 resulted in loss of complex binding to the γ-promoter, reversal of both histone and DNA repressive epigenetic marks, and increased γ-gene expression. The repressive H4K20me3 mark induced by SUV4-20h1 is enriched on the γ-promoter in erythroid progenitors from adult bone marrow compared with cord blood, suggesting developmental specificity. These studies define coordinated epigenetic events linked to fetal globin gene silencing, and provide potential therapeutic targets for the treatment of β-thalassemia and SCD. © 2010 by The American Society of Hematology.

Darido C.,Rotary Bone Marrow Research Laboratories | Jane S.M.,Rotary Bone Marrow Research Laboratories | Jane S.M.,University of Melbourne
Small GTPases | Year: 2010

Directional migration is a critical component of cell motility' is observed in many diverse processes including embryogenesis, immune surveillance and wound repair. A central aspect of directional migration is cellular polarity, which is established through several signaling pathways that converge on the small GTPases. These factors orchestrate precise spatial and temporal organization of the actin cytoskeleton at the leading edge of the cell, and induce polarized capture and stabilization of microtubules and their associated microtubule organizing center (MTOC). Studies of the regulation of the GTPases have predominantly focused on posttranslational mechanisms involving guanine nucleotide exchange factors (GEFs), GTPase activating proteins (GAPs), and guanine nucleotide dissociation inhibitors (GDIs). In this commentary, we examine the transcriptional regulation of these factors, focusing on the recently described regulation of RhoGEF19, an activator of RhoA, by the epidermal-specific transcription factor GRHL3, and the importance of this regulatory mechanism in wound repair. Our findings establish novel links between epidermal cell migration in wound healing and the planar cell polarity (PCP) signaling pathway, and establish a paradigm for tissue-specific regulation of Rho GTPase activity. © 2010 Landes Bioscience.

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