Unknown,Transcriptomics,Genomics,Proteomics

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Selective Functions of Individual Zinc Fingers Within the DNA-Binding Domain of Ikaros (ChIP-seq: Thymocytes)


ABSTRACT: The C2H2 zinc finger is the most prevalent DNA-binding motif in the mammalian proteome, with DNA-binding domains usually containing more tandem fingers than are needed for stable sequence-specific DNA recognition. To examine the reason for the frequent presence of multiple zinc fingers, we generated mice lacking finger 1 or finger 4 of the 4-finger DNA-binding domain of Ikaros, a critical regulator of lymphopoiesis and leukemogenesis. Each mutant strain exhibited a specific subset of the phenotypes observed with Ikaros null mice. Of particular relevance, fingers 1 and 4 contributed to distinct stages of B- and T-cell development and finger 4 was selectively required for tumor suppression in thymocytes and in a new model of BCR-ABL+ acute lymphoblastic leukemia. These results, combined with transcriptome profiling (this GEO submission: RNA-Seg of whole thymus from wt and the two ZnF mutants), reveal that different subsets of fingers within multi-finger transcription factors can regulate distinct target genes and biological functions, and they demonstrate that selective mutagenesis can facilitate efforts to elucidate the functions and mechanisms of action of this prevalent class of factors. Ikaros ChIP-Seq from Whole Thymus comparing wt, Ikaros-ZnF1-/- mutant and Ikaros-ZnF4-/- mutant

ORGANISM(S): Mus musculus

SUBMITTER: Hilde Schjerven 

PROVIDER: E-GEOD-33679 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Selective regulation of lymphopoiesis and leukemogenesis by individual zinc fingers of Ikaros.

Schjerven Hilde H   McLaughlin Jami J   Arenzana Teresita L TL   Frietze Seth S   Cheng Donghui D   Wadsworth Sarah E SE   Lawson Gregory W GW   Bensinger Steven J SJ   Farnham Peggy J PJ   Witte Owen N ON   Smale Stephen T ST  

Nature immunology 20130908 10


C2H2 zinc fingers are found in several key transcriptional regulators in the immune system. However, these proteins usually contain more fingers than are needed for sequence-specific DNA binding, which suggests that different fingers regulate different genes and functions. Here we found that mice lacking finger 1 or finger 4 of Ikaros exhibited distinct subsets of the hematological defects of Ikaros-null mice. Most notably, the two fingers controlled different stages of lymphopoiesis, and finger  ...[more]

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