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Blood disease–causing and –suppressing transcriptional enhancers: general principles and GATA2 mechanisms

Emery H. Bresnick and Kirby D. Johnson

Article Figures & Data

Figures

  • Figure 1.

    Essential enhancers governing Gata2 expression and hematopoiesis. (A) The −77 and +9.5 enhancers reside 77 and 9.5 kb upstream and downstream, respectively, of the Gata2 transcriptional start site. These evolutionarily conserved enhancers control mouse and human Gata2 transcription in specific biological contexts and vital steps in hematopoiesis (depicted with brackets). (B) The photomicrographs depict Giemsa-stained myeloerythroid progeny resulting from ex vivo differentiation of −77+/+ or −77−/− fetal liver progenitor cells. AGM, aorta gonad mesonephros region of the embryo proper.

  • Figure 2.

    Mouse and human +9.5 enhancer alleles. The wild-type mouse +9.5 configuration is depicted, with 3 mutant mouse alleles below. Ets-only and GATA-only mutants fail to support developmental hematopoiesis and are both embryonic lethal. The Ets motif point mutant that models the human single-nucleotide mutation exhibits largely normal developmental hematopoiesis yet is incompetent to support regeneration of the hematopoietic system postmyeloablation. Human alleles identified in patients with GATA2-deficiency syndrome are depicted. Black arrow extending from +9.5 to promoter, transcriptional activation; gray arrow, partial activation; absence of an arrow, severely attenuated enhancer activity. E, E-box-binding protein.

  • Figure 3.

    Corrupting, creating, and expropriating enhancers through mutation or chromosomal aberrations. By destroying cis-element integrity and impairing factor binding, mutations corrupt enhancer function. Corruption may involve a complete loss of activity (if the factor affected is essential), partial loss of activity (if the remaining enhancer components can confer some degree of transcriptional activation), or acquisition of ectopic activity distinct from that of the wild-type enhancer. Mutations may generate cis elements that permit transcription factor binding, following by binding of additional transcription factors and coregulators to generate an enhancer at a site normally lacking an enhancer. Chromosomal inversions or translocations can expropriate a gene’s enhancer, transferring it to another gene, thus creating an ectopic gene-regulatory mechanism. A, gene normally controlled by enhancer; B, gene that expropriates the enhancer.