Role of the GATA-1/FOG-1/NuRD pathway in the expression of human beta-like globin genes.
The human beta-globin genes are expressed in a developmentally controlled fashion. Studies on the molecular mechanisms underlying the stage-specific regulation of globin genes have been fueled by the clinical benefit of elevated fetal gamma-globin expression in patients with sickle cell anemia and thalassemia. Recent reports suggested a role of the hematopoietic transcription factor GATA-1, its cofactor FOG-1, and the associated chromatin remodeling complex NuRD in the developmental silencing of HBG1 and HBG2 gene expression. To examine whether FOG-1 via NuRD controls HBG1 and HBG2 silencing in vivo, we created mice in which the FOG-1/NuRD complex is disrupted (A. Miccio et al., EMBO J. 29:442-456, 2010) and crossed these with animals carrying the entire human beta-globin gene locus as a transgene. We found that the FOG-1/NuRD interaction is dispensable for the silencing of human HBG1 and HBG2 expression. In addition, mutant animals displayed normal silencing of the endogenous embryonic globin genes. In contrast, a significant reduction of adult-type human and murine globin gene expression was found in adult bone marrows of mutant animals. These results suggest that, unexpectedly, NuRD is required for FOG-1-dependent activation of adult-type globin gene expression but is dispensable for human gamma-globin silencing in vivo.
Miccio
Annarita
A
Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Blobel
Gerd A
GA
D000818:Animals; D001483:Base Sequence; D018244:Chromosomes, Artificial, Yeast / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D005260:Female; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D006801:Humans; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D055544:beta-Globins / Q000235:genetics / Q000378:metabolism; D055545:gamma-Globins / Q000235:genetics* / Q000378:metabolism
D017931:DNA Primers; D050982:GATA1 Transcription Factor; C494689:Gata1 protein, mouse; D009687:Nuclear Proteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D014157:Transcription Factors; C107310:Zfpm1 protein, mouse; D055544:beta-Globins; D055545:gamma-Globins; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex