Beta-globin active chromatin Hub formation in differentiating erythroid cells and in p45 NF-E2 knock-out mice.
Expression of the beta-globin genes proceeds from basal to exceptionally high levels during erythroid differentiation in vivo. High expression is dependent on the locus control region (LCR) and coincides with more frequent LCR-gene contacts. These contacts are established in the context of an active chromatin hub (ACH), a spatial chromatin configuration in which the LCR, together with other regulatory sequences, loops toward the active beta-globin-like genes. Here, we used recently established I/11 cells as a model system that faithfully recapitulates the in vivo erythroid differentiation program to study the molecular events that accompany and underlie ACH formation. Upon I/11 cell induction, histone modifications changed, the ACH was formed, and the beta-globin-like genes were transcribed at rates similar to those observed in vivo. The establishment of frequent LCR-gene contacts coincided with a more efficient loading of polymerase onto the beta-globin promoter. Binding of the transcription factors GATA-1 and EKLF to the locus, although previously shown to be required, was not sufficient for ACH formation. Moreover, we used knock-out mice to show that the erythroid transcription factor p45 NF-E2, which has been implicated in beta-globin gene regulation, is dispensable for beta-globin ACH formation.
Kooren
Jurgen
J
Department of Cell Biology, Erasmus Medical Center, P. O. Box 2040, 3000 CA Rotterdam, The Netherlands.
Palstra
Robert-Jan
RJ
Klous
Petra
P
Splinter
Erik
E
von Lindern
Marieke
M
Grosveld
Frank
F
de Laat
Wouter
W
D000818:Animals; D002454:Cell Differentiation / Q000502:physiology*; D002478:Cells, Cultured; D002843:Chromatin / Q000378:metabolism; D042002:Chromatin Assembly and Disassembly / Q000502:physiology*; D041905:Erythroid Cells / Q000166:cytology / Q000378:metabolism*; D050982:GATA1 Transcription Factor / Q000378:metabolism; D005914:Globins / Q000096:biosynthesis* / Q000235:genetics; D006657:Histones / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000378:metabolism; D019901:Locus Control Region / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D050984:NF-E2 Transcription Factor, p45 Subunit / Q000172:deficiency / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000502:physiology; D040641:Quantitative Trait Loci / Q000502:physiology
D002843:Chromatin; D050982:GATA1 Transcription Factor; D006657:Histones; D051741:Kruppel-Like Transcription Factors; D050984:NF-E2 Transcription Factor, p45 Subunit; C494693:Nfe2 protein, mouse; C080774:erythroid Kruppel-like factor; D005914:Globins