Foxp3 depends on Ikaros for control of regulatory T cell gene expression and function [ATAC-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE200176 | GEO | 2024/03/28
REPOSITORIES: GEO
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Project description:We investigated the role of Ikaros in regulatory Tcell identity and function during stimulation using RNA-seq, ATAC-seq, and H3K27ac/Foxp3/Ikzf1 ChIP-seq
2024-03-28 | GSE200178 | GEO
Project description:We investigated the role of Ikaros in regulatory Tcell identity and function during stimulation using RNA-seq, ATAC-seq, and H3K27ac/Foxp3/Ikzf1 ChIP-seq
2024-03-28 | GSE200177 | GEO
Project description:Ikaros is an essential regulator of lymphopoiesis. Here, we studied the B-cell-specific function of Ikaros by conditional Ikzf1 inactivation in pro-B cells. B-cell development was arrested at an aberrant ‘pro-B’ cell stage characterized by increased cell adhesion and loss of pre-B cell receptor signaling. Ikaros was found to activate genes coding for pre-BCR signal transducers and to repress genes involved in the downregulation of pre-BCR signaling and upregulation of the integrin signaling pathway. Unexpectedly, derepression of Aiolos expression could not compensate for the loss of Ikaros in pro-B cells. Ikaros differentially controlled active chromatin at promoters and enhancers of repressed and activated target genes. Notably, Ikaros binding and target gene expression was dynamically regulated at distinct stages of early B-lymphopoiesis. 16 RNA-Seq samples in pre-proB cells (4 replicates, for each 2 controls and 2 experimental samples); 4 RNA-Seq samples in pro-B cells in Rag2-/- backgrounds (Ikzf1 deleted versus non deleted, 2 replicates each); 4 RNA-Seq samples in c-Kit high pro-B cells (Ikzf1 deleted versus non deleted, 2 replicates each); 4 RNA-Seq samples in pro-B cells (Ikzf1 deleted versus non deleted, 2 replicates each); 2 RNA-Seq samples pre-B cells wild type; 8 chromatin ChIP-Seq samples (4x H3K9ac, 4x H3K4me3, Ikzf1 deleted/non deleted, two replicates each).; 4 Transcription factor ChIP-Seq samples in pro-B cells; 1 Transcription factor ChIP-Seq samples in DP-T cells; 1 Transcription factor ChIP-Seq samples in pre-pro-B cells; 2 Mi-2b Chip-Seq samples (Ikzf1 deleted versus non deleted); 1 ChIP-Seq input track for pro-B cells; 1 ChIP-Seq input track for DP-T cells
2014-02-09 | E-GEOD-53595 | biostudies-arrayexpress
Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
2023-10-25 | GSE238149 | GEO
Project description:Temporal identity factors regulate competence of neural progenitors to generate specific cell types in a time-dependent manner, but how they operate remains poorly defined. In the developing mouse retina, the Ikaros zinc-finger transcription factor Ikzf1 regulates production of early-born cell types, except cone photoreceptors. In this study we show that, during early stages of retinal development, another Ikaros family protein, Ikzf4, functions redundantly with Ikzf1 to regulate cone photoreceptor production. Using CUT&RUN and functional assays, we show that Ikzf4 binds and represses genes involved in late-born rod photoreceptor specification, hence favoring cone production. At late stages, when Ikzf1 is no longer expressed in progenitors, we show that Ikzf4 re-localizes to target genes involved in gliogenesis and is required for Müller glia production. We report that Ikzf4 regulates Notch signaling genes and is sufficient to activate the Hes1 promoter through two Ikzf GGAA-binding motifs, suggesting a mechanism by which Ikzf4 may influence gliogenesis. These results uncover a combinatorial role for Ikaros family members during nervous system development and provide mechanistic insights on how they temporally regulate cell fate output.
2022-12-22 | GSE189590 | GEO
Project description:Deletion of the Ikaros DNA-binding domain generates dominant-negative isoforms that interfere with Ikaros family activity and correlate with poor prognosis in human precursor B cell acute lymphoblastic leukemias (B-ALL). Here, we show that conditional inactivation of the Ikaros DNA binding domain in early pre-B cells arrests their differentiation at a stage where integrin-dependent niche adhesion augments mitogen-activated protein kinase signaling, proliferation, and self-renewal, and attenuates pre-B cell receptor signaling and differentiation. Transplantation of polyclonal Ikzf1 mutant pre-B cells results in long-latency oligoclonal pre-B-ALL, demonstrating that loss of Ikaros contributes to multistep B-leukemogenesis. These results explain how normal pre-B cells transit from a highly proliferative and stromal-dependent to a stromal-independent phase where differentiation is enabled, providing potential therapeutic strategies for IKZF1 mutant B-ALL. One of the analyses described in this manuscript is the differential gene expression of large preB cells sorted from the bone marrow of WT and IKDN mice. The RNASeq method and Deseq analysis algorithm were employed
2014-02-09 | E-GEOD-53401 | biostudies-arrayexpress
Project description:The zinc-finger transcription factor Ikaros (Ikzf1) modulates key gene expression programs important for hematopoietic development, and coding mutations in IKZF1 are found in patients with immunodeficiency, leukemia, and autoimmunity. While Ikaros has a well-established function in hematopoiesis, its role in other cell types is less well defined. Here, we uncover new functions for Ikaros in thymic epithelial lineage development and show that Ikzf1 expression in medullary thymic epithelial cells (mTECs) is required for both Autoimmune Regulator positive (Aire+) mTEC development and tissue-specific antigen (TSA) gene expression. Accordingly, TEC-specific deletion of Ikzf1 in mice results in a profound decrease in Aire+ mTECs, a global loss of TSA gene expression, and the development of autoimmunity. Moreover, Ikaros shapes thymic mimetic cell diversity and its deletion results in a dramatic expansion of thymic tuft cells and muscle-like mTECs and a loss of other Aire-dependent mimetic populations. Single-cell analysis reveals Ikaros modulates core transcriptional programs in TECs that correlate with the observed cellular changes. Our findings highlight a previously undescribed role for Ikaros in regulating epithelial lineage development and function, and suggest that failed thymic central tolerance could contribute to the autoimmunity seen in humans with IKZF1 mutations.
2023-10-25 | GSE241742 | GEO
Project description:Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological malignancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis is unknown. Here we used gene inactivation to reveal that NK cell-expression of Ikaros is essential for normal NK lymphopoiesis. Mechanistically, IKZF1 directly repressed Cish and Socs2, known negative regulators of IL-15R resulting in impaired IL-15 signaling in Ikzf1-null NK cells. Bcl2l11/BIM levels and apoptosis were increased in Ikzf1-null NK cells which in part accounted for the NK lymphopenia since both apoptosis and NK cell frequency were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes (Fos/Jun members) and a compensatory increase in Ikzf2 and Ikzf3. Both IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in a further reduction in Jun/Fos expression and a complete loss of peripheral NK cells in mice. Consistently, IKZF1 bound Jun/Fos genes at the same locations in activated B cells identifying a novel and conserved role for IKZF1 in Jun/Fos regulation. Collectively we show the Ikaros-family are novel regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity required for NK cell development and function.
2023-11-08 | GSE247282 | GEO
Project description:Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological malignancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis is unknown. Here we used gene inactivation to reveal that NK cell-expression of Ikaros is essential for normal NK lymphopoiesis. Mechanistically, IKZF1 directly repressed Cish and Socs2, known negative regulators of IL-15R resulting in impaired IL-15 signaling in Ikzf1-null NK cells. Bcl2l11/BIM levels and apoptosis were increased in Ikzf1-null NK cells which in part accounted for the NK lymphopenia since both apoptosis and NK cell frequency were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes (Fos/Jun members) and a compensatory increase in Ikzf2 and Ikzf3. Both IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in a further reduction in Jun/Fos expression and a complete loss of peripheral NK cells in mice. Consistently, IKZF1 bound Jun/Fos genes at the same locations in activated B cells identifying a novel and conserved role for IKZF1 in Jun/Fos regulation. Collectively we show the Ikaros-family are novel regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity required for NK cell development and function.
2023-11-08 | GSE247279 | GEO
Project description:Ikaros family transcription factors regulate lymphocyte biology and are targets of the immunomodulatory imide drugs (IMiDs) for hematological malignancies. Ikaros (Ikzf1/IKZF1) is the most broadly expressed family member in lymphocytes, yet its role in innate lymphopoiesis is unknown. Here we used gene inactivation to reveal that NK cell-expression of Ikaros is essential for normal NK lymphopoiesis. Mechanistically, IKZF1 directly repressed Cish and Socs2, known negative regulators of IL-15R resulting in impaired IL-15 signaling in Ikzf1-null NK cells. Bcl2l11/BIM levels and apoptosis were increased in Ikzf1-null NK cells which in part accounted for the NK lymphopenia since both apoptosis and NK cell frequency were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with a striking reduction in expression of genes encoding AP-1 transcriptional complexes (Fos/Jun members) and a compensatory increase in Ikzf2 and Ikzf3. Both IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in a further reduction in Jun/Fos expression and a complete loss of peripheral NK cells in mice. Consistently, IKZF1 bound Jun/Fos genes at the same locations in activated B cells identifying a novel and conserved role for IKZF1 in Jun/Fos regulation. Collectively we show the Ikaros-family are novel regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity required for NK cell development and function.
2023-11-08 | GSE247281 | GEO