Blood Journal
Leading the way in experimental and clinical research in hematology

Transcriptional regulation of the Ikzf1 locus

  1. Toshimi Yoshida1,
  2. Esther Landhuis1,
  3. Marei Dose2,
  4. Idit Hazan1,
  5. Jiangwen Zhang3,
  6. Taku Naito1,
  7. Audrey F. Jackson1,
  8. Jeffrey Wu1,
  9. Elizabeth A. Perroti1,
  10. Christoph Kaufmann1,
  11. Fotini Gounari2,
  12. Bruce A. Morgan1, and
  13. Katia Georgopoulos1,*
  1. 1 Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, United States;
  2. 2 Department of Medicine, The University of Chicago, Chicago, IL, United States;
  3. 3 Center for Genomic Research (CGR), Harvard University, Cambridge, MA, United States
  1. * Corresponding author; email: katia.georgopoulos{at}cbrc2.mgh.harvard.edu

Key points

  • Multiple enhancers identified at the Ikzf1 locus with shared and distinct epigenetic and transcriptional properties

  • Transcription factor networks that distinguish between LMPP-specific and T cell-specific Ikzf1 enhancers

Abstract

Ikaros is a critical regulator of lymphocyte development and homeostasis, thus understanding its transcriptional regulation is important from both a developmental but also clinical perspective. Using a mouse transgenic reporter approach, we functionally characterized a network of highly conserved cis-acting elements at the Ikzf1 locus. We attribute B cell and myeloid but not T cell specificity to the main Ikzf1 promoter. While this promoter was unable to counter local chromatin silencing effects, each of the six highly conserved Ikzf1 intronic enhancers alleviated silencing. Working together, the Ikzf1 enhancers provided locus control region activity, allowing reporter expression in a position and copy-independent manner. Only one of the Ikzf1 enhancers, was responsible for the progressive upregulation of Ikaros expression from hematopoietic stem cells to lymphoid-primed multipotent progenitors to T cell precursors, stages of differentiation that are dependent on Ikaros for normal outcome. Thus Ikzf1 is regulated by both epigenetic and transcriptional factors that target its enhancers in both a redundant but also specific fashion to provide for an expression profile supportive of normal lymphoid lineage progression and homeostasis. Mutations in the Ikzf1 regulatory elements and their interacting factors are likely to have adverse effects on lymphopoiesis and contribute to leukemogenesis.

  • Submitted January 4, 2013.
  • Accepted June 26, 2013.