Interleukin-5 receptor alpha subunit gene regulation in human eosinophil development: identification of a unique cis-element that acts lie an enhancer in regulating activity of the IL-5R alpha promoter.
Further functional and biochemical characterization of the nuclear factor(s) which interacts with the EOS1 enhancer-like element in the IL-5R alpha promoter is currently in progress. Since different transcription factors recognize and interact with DNA in distinct fashions and with distinct structural motifs, we have modeled potential binding of the EOS1 factor to its cis-element based upon its methylation interference pattern (Fig. 2), using a cylindrical DNA helical projection (Fig. 6). Over a length of two helical turns, all nuclear protein contacts indicated by methylation interference map to one side of the DNA helix, suggesting that EOS1 binds in the major groove, across the minor groove, and on only one side of the helix. Further review of the model also reveals a potential diad symmetry for the binding site, suggestive of binding by a homodimer and consistent with the formation of the two DNA-protein complexes in our electrophoretic mobility shift experiments that could represent interactions with monomer versus dimer. Comparison of the EOS1 binding motif to similar models for the binding of other transcription factor families for which structural crystallographic and/or binding data is available suggests a similarity of the EOS1 complex to that of the bacterial helix-turn-helix phage lambda and 434 repressor-operator complexes, and the Cys4 zinc finger glucocorticoid response element (GRE) DNA-binding motifs, all of which show similar diad symmetry and binding in the major groove on one side of the DNA. The possibility that EOS1 functions as a GRE is being investigated, especially since there is a consensus AP-1 site at bp -440 to -432 of the IL-5R alpha promoter, immediately adjacent to the EOS1 binding site (see Fig. 5 in reference [36]) and AP-1/GRE interactions have been identified for composite response elements in the regulation of a number of different genes. The identification or cloning of EOS1, a potentially novel and eosinophil lineage-active transcription factor, should enhance our understanding of the processes involved in eosinophil development in particular and myeloid lineage commitment and differentiation in general.
Sun
Z
Z
Division of Infectious Diseases, Beth Israel Hospital, Boston, MA 02215, USA.
Yergeau
D A
DA
Wong
I C
IC
Tuypens
T
T
Tavernier
J
J
Paul
C C
CC
Baumann
M A
MA
Auron
P E
PE
Tenen
D G
DG
Ackerman
S J
SJ
D000818:Animals; D001483:Base Sequence; D004742:Enhancer Elements, Genetic; D004804:Eosinophils / Q000502:physiology*; D005786:Gene Expression Regulation; D006410:Hematopoiesis / Q000235:genetics*; D006801:Humans; D008969:Molecular Sequence Data; D011401:Promoter Regions, Genetic; D018123:Receptors, Interleukin / Q000235:genetics*; D053649:Receptors, Interleukin-5
D018123:Receptors, Interleukin; D053649:Receptors, Interleukin-5