Btg2 enhances retinoic acid-induced differentiation by modulating histone H4 methylation and acetylation.
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 RARalpha 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 RARalpha transcriptional complex, together with the arginine methyltransferase PRMT1 and Sin3A. Overexpressed BTG2 increases PRMT1 participation in the RARalpha protein complex on the RARbeta promoter, a target gene model, and enhances gene-specific histone H4 arginine methylation. Upon RA treatment Sin3A, BTG2, and PRMT1 detach from RARalpha 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.
Passeri
Daniela
D
Patologia Generale and Medicina Interna e Scienze Oncologiche, Dipartimento di Medicina Clinica e Sperimentale, Perugia University, Policlinico Monteluce, Perugia, Italy.
Marcucci
Antonella
A
Rizzo
Giovanni
G
Billi
Monia
M
Panigada
Maddalena
M
Leonardi
Luca
L
Tirone
Felice
F
Grignani
Francesco
F
D000107:Acetylation; D001120:Arginine / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D005786:Gene Expression Regulation; D016147:Genes, Tumor Suppressor; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics / Q000378:metabolism*; D008745:Methylation; D011401:Promoter Regions, Genetic; D011484:Protein-Arginine N-Methyltransferases / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D056264:Sin3 Histone Deacetylase and Corepressor Complex; D014158:Transcription, Genetic / Q000187:drug effects*; D014212:Tretinoin / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins
D006657:Histones; D017874:Immediate-Early Proteins; C000607071:RARA protein, human; D018168:Receptors, Retinoic Acid; D012097:Repressor Proteins; D000072482:Retinoic Acid Receptor alpha; C099683:SIN3A transcription factor; D025521:Tumor Suppressor Proteins; C070114:BTG2 protein, human; D014212:Tretinoin; D001120:Arginine; C099988:PRMT1 protein, human; D011484:Protein-Arginine N-Methyltransferases; D056264:Sin3 Histone Deacetylase and Corepressor Complex