Ikaros drives human haemoglobin switching by facilitating active chromatin hub formation

Perkins, Andrew C., Tallack, Michael, Zhan, Ye, Papathanasiou, Peter, Goodnow, Christopher, Gaensler, Karin, Crossley, Paul M., Dekker, Job and Keys, Janelle R. (2007). Ikaros drives human haemoglobin switching by facilitating active chromatin hub formation. In: Blood. American Society of Hematology (ASH) 49th Annual Meeting, Atlanta, USA, (526A-526A). 8-11 December 2007.


Author Perkins, Andrew C.
Tallack, Michael
Zhan, Ye
Papathanasiou, Peter
Goodnow, Christopher
Gaensler, Karin
Crossley, Paul M.
Dekker, Job
Keys, Janelle R.
Title of paper Ikaros drives human haemoglobin switching by facilitating active chromatin hub formation
Conference name American Society of Hematology (ASH) 49th Annual Meeting
Conference location Atlanta, USA
Conference dates 8-11 December 2007
Proceedings title Blood   Check publisher's open access policy
Journal name Blood   Check publisher's open access policy
Place of Publication Washington, D. C., USA
Publisher American Society of Hematology
Publication Year 2007
Sub-type Published abstract
ISSN 0006-4971
1528-0020
Volume 110
Issue 11
Start page 526A
End page 526A
Total pages 1
Language eng
Abstract/Summary The human β globin locus consists of an upstream locus control region (LCR) and five functional genes arranged sequentially in the order of their expression during development: 5'--G-A- - β-3'. Haemoglobin switching entails the successive recruitment of these genes into an active chromatin hub (ACH). Although much is known about the cis elements and transcription factors involved in globin gene regulation, less is known about ACH formation. Here we show that the transcription factor Ikaros plays an essential role in both 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 (H191R), there is concomitant marked (10 fold) down-regulation of human β-globin, and up-regulation of -globin gene expression. We show Ikaros binds to a critical cis elements in the LCR near the HS3 core and upstream of the -globin gene in the β-globin locus by electormobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) and that this DNA binding activity is lost in Plast mice. This latter site is implicated in deletional hereditary persistence of fetal haemoglobin (HPFH). Furthermore, chromatin conformation capture (3C) data suggest Ikaros facilitates long range looping between the LCR and a region upstream of the -globin gene. This study provides new insights into the mechanism of adult stage-specific assembly of the β-globin ACH. In addition the findings could lead to the development of novel drugs to reactivate HbF in adults with β-thalassemia and sickle cell disease.
Subjects 1102 Cardiovascular Medicine and Haematology
Keyword Ikaros
Haemoglobin
Active chromatin hub (ACH)
Electormobility shift assay (EMSA)
Chromatin immunoprecipitation (ChIP)
Q-Index Code EX
Q-Index Status Provisional Code
Institutional Status Unknown

 
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Created: Tue, 02 Mar 2010, 12:34:01 EST by Michael Affleck on behalf of Institute for Molecular Bioscience