A mechanism for Ikaros regulation of human globin gene switching.
The human beta globin locus consists of an upstream LCR and functional genes arranged sequentially in the order of their expression during development: 5'-HBE1, HBG2, HBG1, HBD, HBB-3'. Haemoglobin switching entails the successive recruitment of these genes into an active chromatin hub (ACH). Here we show that the transcription factor Ikaros plays a major role in the formation of the beta-globin ACH, and in haemoglobin switching. In Plastic mice, where the DNA-binding region of Ikaros is disrupted by a point mutation, there is concomitant marked down-regulation of HBB, and up-regulation of HBG expression. We show for the first time Ikaros and its family member Eos, bind to critical cis elements implicated in haemoglobin switching and deletional hereditary persistence of fetal haemoglobin (HPFH). Chromatin conformation capture (3C) data demonstrated that Ikaros facilitates long-distance DNA looping between the LCR and a region upstream of HBD. This study provides new insights into the mechanism of stage-specific assembly of the beta-globin ACH, and HPFH.
Keys
Janelle R
JR
Institute for Molecular Bioscience, Queensland Bioscience Precinct, University of Queensland, Queensland, Australia.
Tallack
Michael R
MR
Zhan
Ye
Y
Papathanasiou
Peter
P
Goodnow
Christopher C
CC
Gaensler
Karin M
KM
Crossley
Merlin
M
Dekker
Job
J
Perkins
Andrew C
AC
D000818:Animals; D002843:Chromatin / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D005319:Fetal Hemoglobin / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D005812:Genes, Switch; D005914:Globins / Q000235:genetics*; D006801:Humans; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods
D002843:Chromatin; D004268:DNA-Binding Proteins; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D005914:Globins; D005319:Fetal Hemoglobin