GATA-1 utilizes Ikaros and polycomb repressive complex 2 to suppress Hes1 and to promote erythropoiesis.
The transcription factor Hairy Enhancer of Split 1 (HES1), a downstream effector of the Notch signaling pathway, is an important regulator of hematopoiesis. Here, we demonstrate that in primary erythroid cells, Hes1 gene expression is transiently repressed around proerythroblast stage of differentiation. Using mouse erythroleukemia cells, we found that the RNA interference (RNAi)-mediated depletion of HES1 enhances erythroid cell differentiation, suggesting that this protein opposes terminal erythroid differentiation. This is also supported by the decreased primary erythroid cell differentiation upon HES1 upregulation in Ikaros-deficient mice. A comprehensive analysis led us to determine that Ikaros favors Hes1 repression in erythroid cells by facilitating recruitment of the master regulator of erythropoiesis GATA-1 alongside FOG-1, which mediates Hes1 repression. GATA-1 is then necessary for the chromatin binding of the NuRD remodeling complex ATPase MI-2, the transcription factor GFI1B, and the histone H3K27 methyltransferase EZH2 along with Polycomb repressive complex 2. We show that EZH2 is required for the transient repression of Hes1 in erythroid cells. In aggregate, our results describe a mechanism whereby GATA-1 utilizes Ikaros and Polycomb repressive complex 2 to promote Hes1 repression as an important step in erythroid cell differentiation.
Maisonneuve-Rosemont Hospital Research Center and Faculty of Medicine, University of Montreal, Montreal, Quebec, Canada.
Julie
J
Ross
Lionel
L
Mavoungou
Emery H
EH
Bresnick
Eric
E
Milot
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D019556:COS Cells; D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D002522:Chlorocebus aethiops; D002843:Chromatin / Q000378:metabolism; D000071221:Enhancer of Zeste Homolog 2 Protein; D004920:Erythropoiesis; D050982:GATA1 Transcription Factor / Q000378:metabolism*; D005786:Gene Expression Regulation; D006657:Histones / Q000378:metabolism; D018398:Homeodomain Proteins / Q000378:metabolism*; D051740:Ikaros Transcription Factor / Q000378:metabolism*; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex / Q000378:metabolism; D051379:Mice; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D063146:Polycomb-Group Proteins / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D012097:Repressor Proteins / Q000378:metabolism; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; D014158:Transcription, Genetic; D015533:Transcriptional Activation
D051792:Basic Helix-Loop-Helix Proteins; D002843:Chromatin; D000071221:Enhancer of Zeste Homolog 2 Protein; D050982:GATA1 Transcription Factor; D006657:Histones; D018398:Homeodomain Proteins; D051740:Ikaros Transcription Factor; D056245:Mi-2 Nucleosome Remodeling and Deacetylase Complex; D009687:Nuclear Proteins; D063151:Polycomb Repressive Complex 2; D063146:Polycomb-Group Proteins; D011518:Proto-Oncogene Proteins; D034741:RNA, Small Interfering; D012097:Repressor Proteins; D000072056:Transcription Factor HES-1; D014157:Transcription Factors; C494689:Gata1 protein, mouse; C486395:Gfi1b protein, mouse; C489734:Hes1 protein, mouse; C107310:Zfpm1 protein, mouse; C497238:Zfpn1a1 protein, mouse; C498410:Ezh2 protein, mouse