Multiple hematopoietic defects and delayed globin switching in Ikaros null mice.
We have previously reported the structure of a chromatin remodeling complex (PYR complex) with Ikaros as its DNA binding subunit that is specifically present in adult murine and human hematopoietic cells. We now show that homozygous Ikaros "knockout" (null) mice lack the PYR complex, demonstrating the requirement for Ikaros in the formation of the complex on DNA. Heterozygous Ikaros null mice have about half as much PYR complex, indicating a dosage effect for both Ikaros and PYR complex. We also show that Ikaros null mice have multiple hematopoietic cell defects including anemia and megakaryocytic abnormalities, in addition to previously reported lymphoid and stem cell defects. The null mice also have a delay in murine embryonic to adult beta-globin switching and a delay in human gamma to beta switching, consistent with a previously suggested role for PYR complex in this process. Lastly, cDNA array analyses indicate that several hematopoietic cell-specific genes in all blood lineages are either up- or down-regulated in 14-day embryos from Ikaros null as compared with wild-type mice. These results indicate that Ikaros and PYR complex function together in vivo at many adult hematopoietic cell-specific genes and at intergenic sites, affecting their expression and leading to pleiotropic hematopoietic defects.
Lopez
Rocio A
RA
Department of Genetics and Development, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
Schoetz
Stuti
S
DeAngelis
Kathryn
K
O'Neill
David
D
Bank
Arthur
A
D000740:Anemia / Q000235:genetics / Q000473:pathology; D000818:Animals; D001665:Binding Sites / Q000235:genetics; D004268:DNA-Binding Proteins; D015870:Gene Expression; D005812:Genes, Switch; D005914:Globins / Q000235:genetics*; D006410:Hematopoiesis / Q000235:genetics* / Q000502:physiology; D006801:Humans; D051740:Ikaros Transcription Factor; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D013922:Thrombocytosis / Q000235:genetics / Q000473:pathology; D014157:Transcription Factors / Q000172:deficiency* / Q000235:genetics* / Q000502:physiology; D015533:Transcriptional Activation
D004268:DNA-Binding Proteins; C497239:IKZF1 protein, human; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D051740:Ikaros Transcription Factor; D005914:Globins