A mechanism for Ikaros regulation of human globin gene switching

Janelle R. Keys, Michael R. Tallack, Ye Zhan, Peter Papathanasiou, Christopher C. Goodnow, Karin M. Gaensler, Merlin Crossley, Job Dekker, Andrew C. Perkins

Research output: Contribution to journalArticleResearchpeer-review

32 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)398-406
Number of pages9
JournalBritish Journal of Haematology
Volume141
Issue number3
DOIs
Publication statusPublished - May 2008
Externally publishedYes

Keywords

  • ACH
  • Eos
  • Globin
  • HPFH
  • Ikaros

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