TY - JOUR
T1 - A mechanism for Ikaros regulation of human globin gene switching
AU - Keys, Janelle R.
AU - Tallack, Michael R.
AU - Zhan, Ye
AU - Papathanasiou, Peter
AU - Goodnow, Christopher C.
AU - Gaensler, Karin M.
AU - Crossley, Merlin
AU - Dekker, Job
AU - Perkins, Andrew C.
PY - 2008/5
Y1 - 2008/5
N2 - The human β 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 β-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 β-globin ACH, and HPFH.
AB - The human β 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 β-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 β-globin ACH, and HPFH.
KW - ACH
KW - Eos
KW - Globin
KW - HPFH
KW - Ikaros
UR - http://www.scopus.com/inward/record.url?scp=42049103528&partnerID=8YFLogxK
U2 - 10.1111/j.1365-2141.2008.07065.x
DO - 10.1111/j.1365-2141.2008.07065.x
M3 - Article
SN - 0007-1048
VL - 141
SP - 398
EP - 406
JO - British Journal of Haematology
JF - British Journal of Haematology
IS - 3
ER -