title: Transcriptional regulation of the Ikzf1 locus.
abstract: Ikaros is a critical regulator of lymphocyte development and homeostasis; thus, understanding its transcriptional regulation is important from both developmental and clinical perspectives. Using a mouse transgenic reporter approach, we functionally characterized a network of highly conserved cis-acting elements at the Ikzf1 locus. We attribute B-cell and myeloid but not T-cell specificity to the main Ikzf1 promoter. Although this promoter was unable to counter local chromatin silencing effects, each of the 6 highly conserved Ikzf1 intronic enhancers alleviated silencing. Working together, the Ikzf1 enhancers provided locus control region activity, allowing reporter expression in a position and copy-independent manner. Only 1 of the Ikzf1 enhancers was responsible for the progressive upregulation of Ikaros expression from hematopoietic stem cells to lymphoid-primed multipotent progenitors to T-cell precursors, which are stages of differentiation dependent on Ikaros for normal outcome. Thus, Ikzf1 is regulated by both epigenetic and transcriptional factors that target its enhancers in both redundant and specific fashions to provide an expression profile supportive of normal lymphoid lineage progression and homeostasis. Mutations in the Ikzf1 regulatory elements and their interacting factors are likely to have adverse effects on lymphopoiesis and contribute to leukemogenesis.
authors.affiliation: Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA;
authors.forename: Toshimi
authors.initials: T
authors.lastname: Yoshida
authors.forename: Esther
authors.initials: E
authors.lastname: Landhuis
authors.forename: Marei
authors.initials: M
authors.lastname: Dose
authors.forename: Idit
authors.initials: I
authors.lastname: Hazan
authors.forename: Jiangwen
authors.initials: J
authors.lastname: Zhang
authors.forename: Taku
authors.initials: T
authors.lastname: Naito
authors.forename: Audrey F
authors.initials: AF
authors.lastname: Jackson
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Wu
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Perotti
authors.forename: Christoph
authors.initials: C
authors.lastname: Kaufmann
authors.forename: Fotini
authors.initials: F
authors.lastname: Gounari
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Morgan
authors.forename: Katia
authors.initials: K
authors.lastname: Georgopoulos
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D001483:Base Sequence; D001665:Binding Sites / Q000235:genetics; D001921:Brain / Q000378:metabolism; D004742:Enhancer Elements, Genetic / Q000235:genetics*; D044127:Epigenesis, Genetic; D005434:Flow Cytometry; D053263:Gene Regulatory Networks; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D051740:Ikaros Transcription Factor / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008957:Models, Genetic; D008969:Molecular Sequence Data; D022423:Myeloid Cells / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D013601:T-Lymphocytes / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D015533:Transcriptional Activation
chemical_list: C497239:IKZF1 protein, human; D014157:Transcription Factors; C497238:Zfpn1a1 protein, mouse; D049452:Green Fluorescent Proteins; D051740:Ikaros Transcription Factor