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Btg2 Enhances Retinoic Acid-Induced Differentiation by Modulating Histone H4 Methylation and Acetylation

Daniela Passeri,^1, Antonella Marcucci,^1, Giovanni Rizzo,¹ Monia Billi,¹ Maddalena Panigada,¹ Luca Leonardi,² Felice Tirone,² and Francesco Grignani^1*

Patologia Generale and Medicina Interna e Scienze Oncologiche, Dipartimento di Medicina Clinica e Sperimentale, Perugia University, Policlinico Monteluce, Perugia 06100, Italy,¹ Istituto di Neurobiologia e Medicina Molecolare, Consiglio Nazionale Ricerche, Fondazione St. Lucia, Via del Fosso di Fiorano 64, 00143 Rome, Italy²

Received 18 July 2005/ Returned for modification 2 September 2005/ Accepted 6 April 2006

Retinoic acid controls hematopoietic differentiation through the transcription factor activity of its receptors. They act on specific target genes by recruiting protein complexes that deacetylate or acetylate histones and modify chromatin status. The regulation of this process is affected by histone methyltransferases, which can inhibit or activate transcription depending on their amino acid target. We show here that retinoic acid treatment of hematopoietic cells induces the expression of BTG2. Overexpression of this protein increases RAR transcriptional activity and the differentiation response to retinoic acid of myeloid leukemia cells and CD34⁺ hematopoietic progenitors. In the absence of retinoic acid, BTG2 is present in the RAR transcriptional complex, together with the arginine methyltransferase PRMT1 and Sin3A. Overexpressed BTG2 increases PRMT1 participation in the RAR protein complex on the RARß promoter, a target gene model, and enhances gene-specific histone H4 arginine methylation. Upon RA treatment Sin3A, BTG2, and PRMT1 detach from RAR and thereafter BGT2 and PRMT1 are driven to the cytoplasm. These events prime histone H4 demethylation and acetylation. Overall, our data show that BTG2 contributes to retinoic acid activity by favoring differentiation through a gene-specific modification of histone H4 arginine methylation and acetylation levels.

D.P. and A.M. contributed equally to this study.

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