title: Regulation of gene expression dynamics during developmental transitions by the Ikaros transcription factor.
abstract: The DNA-binding protein Ikaros is a potent tumor suppressor and hematopoietic regulator. However, the mechanisms by which Ikaros functions remain poorly understood, due in part to its atypical DNA-binding properties and partnership with the poorly understood Mi-2/NuRD complex. In this study, we analyzed five sequential stages of thymocyte development in a mouse strain containing a targeted deletion of Ikaros zinc finger 4, which exhibits a select subset of abnormalities observed in Ikaros-null mice. By examining thymopoiesis in vivo and in vitro, diverse abnormalities were observed at each developmental stage. RNA sequencing revealed that each stage is characterized by the misregulation of a limited number of genes, with a strong preference for stage-specific rather than lineage-specific genes. Strikingly, individual genes rarely exhibited Ikaros dependence at all stages. Instead, a consistent feature of the aberrantly expressed genes was a reduced magnitude of expression level change during developmental transitions. These results, combined with analyses of the interplay between Ikaros loss of function and Notch signaling, suggest that Ikaros may not be a conventional activator or repressor of defined sets of genes. Instead, a primary function may be to sharpen the dynamic range of gene expression changes during developmental transitions via atypical molecular mechanisms that remain undefined.
authors: Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90095, USA;
authors: Teresita L
authors: TL
authors: Arenzana
authors: Department of Laboratory Medicine, University of California at San Francisco, San Francisco, California 94143, USA.
authors: Hilde
authors: H
authors: Schjerven
authors: Department of Microbiology, Immunology, and Molecular Genetics, University of California at Los Angeles, Los Angeles, California 90095, USA;
authors: Stephen T
authors: ST
authors: Smale
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D059447:Cell Cycle Checkpoints; D002454:Cell Differentiation / Q000235:genetics*; D002478:Cells, Cultured; D004268:DNA-Binding Proteins; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics*; D051740:Ikaros Transcription Factor / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D017423:Sequence Analysis, RNA; D060168:Thymocytes / Q000166:cytology*
chemical_list: D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D009419:Nerve Tissue Proteins; D051881:Receptor, Notch1; C497238:Zfpn1a1 protein, mouse; C118760:Zfpn1a4 protein, mouse; D051740:Ikaros Transcription Factor
keywords: Ikaros; gene regulation; leukemogenesis; lymphocyte development; transcription