title: Mi2β-mediated silencing of the fetal γ-globin gene in adult erythroid cells.
abstract: An understanding of the human fetal to adult hemoglobin switch offers the potential to ameliorate β-type globin gene disorders such as sickle cell anemia and β-thalassemia through activation of the fetal γ-globin gene. Chromatin modifying complexes, including MBD2-NuRD and GATA-1/FOG-1/NuRD, play a role in γ-globin gene silencing, and Mi2β (CHD4) is a critical component of NuRD complexes. We observed that knockdown of Mi2β relieves γ-globin gene silencing in β-YAC transgenic murine chemical inducer of dimerization hematopoietic cells and in CD34(+) progenitor-derived human primary adult erythroid cells. We show that independent of MBD2-NuRD and GATA-1/FOG-1/NuRD, Mi2β binds directly to and positively regulates both the KLF1 and BCL11A genes, which encode transcription factors critical for γ-globin gene silencing during β-type globin gene switching. Remarkably, <50% knockdown of Mi2β is sufficient to significantly induce γ-globin gene expression without disrupting erythroid differentiation of primary human CD34(+) progenitors. These results indicate that Mi2β is a potential target for therapeutic induction of fetal hemoglobin.
authors: VCU Massey Cancer Center, Virginia Commonwealth University, 401 College St, Richmond, VA 23298, USA.
authors: Maria
authors: M
authors: Amaya
authors: Megha
authors: M
authors: Desai
authors: Merlin Nithya
authors: MN
authors: Gnanapragasam
authors: Shou Zhen
authors: SZ
authors: Wang
authors: Sheng
authors: S
authors: Zu Zhu
authors: David C
authors: DC
authors: Williams
authors: Gordon D
authors: GD
authors: Ginder
mesh_terms: D000328:Adult; D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000378:metabolism*; D002352:Carrier Proteins / Q000378:metabolism; D002454:Cell Differentiation; D002478:Cells, Cultured; D047369:Chromatin Immunoprecipitation; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D005319:Fetal Hemoglobin / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins; D055545:gamma-Globins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism
chemical_list: D001324:Autoantigens; C486563:BCL11A protein, human; C115323:CHD4 protein, human; D002352:Carrier Proteins; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C080774:erythroid Kruppel-like factor; D055545:gamma-Globins; D005319:Fetal Hemoglobin; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex