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 journalArticlepeer-review

    38 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

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