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Ikaros and Aiolos directly regulate AP-1 transcriptional complexes and are essential for natural killer cell development [ChIP-seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE247280 | GEO | 2023/11/08

REPOSITORIES: GEO

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Ikaros and Aiolos directly regulate AP-1 transcriptional complexes and are essential for natural killer cell development [RNA-seq]

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

Ikaros and Aiolos directly regulate AP-1 transcriptional complexes and are essential for natural killer cell development [CUT&Run]

2023-11-08 | GSE247281 | GEO

Ikaros and Aiolos directly regulate AP-1 transcriptional complexes and are essential for natural killer cell development [ATAC-seq]

2023-11-08 | GSE247279 | GEO

RUNX proteins desensitize multiple myeloma to lenalidomide via protecting IKZFs from degradation

Project description:Ikaros family zinc finger protein 1 and 3 (IKZF1 and IKZF3) are transcription factors that promote multiple myeloma (MM) proliferation. The immunomodulatory imide drug (IMiD) lenalidomide promotes myeloma cell death via Cereblon (CRBN)-dependent ubiquitylation and proteasome-dependent degradation of IKZF1 and IKZF3. Although IMiDs have been used as first-line drugs for MM, the overall survival of refractory MM patients remains poor and demands the identification of novel agents to potentiate the therapeutic effect of IMiDs. Using an unbiased screen based on mass spectrometry, we identified the Runt-related transcription factor 1 and 3 (RUNX1 and RUNX3) as interactors of IKZF1 and IKZF3. Interaction with RUNX1 and RUNX3 inhibits CRBN-dependent binding, ubiquitylation and degradation of IKZF1 and IKZF3 upon lenalidomide treatment. Inhibition of RUNXs, via genetic ablation or a small molecule (AI-10-104), results in sensitization of myeloma cell lines and primary tumors to lenalidomide. Thus, RUNX inhibition represents a valuable therapeutic opportunity to potentiate IMiDs therapy for the treatment of multiple myeloma.

2020-04-13 | GSE123660 | GEO

The AP-1 Transcription Factor c-Jun Prevents Stress-Imposed Maladaptive Remodeling of the Heart

Project description:Systemic hypertension increases cardiac workload and subsequently induces signaling networks in heart that underlie myocyte growth (hypertrophic response) through expansion of sarcomeres with the aim to increase contractility. However, conditions of increased workload can induce both adaptive and maladaptive growth of heart muscle. Previous studies implicate two members of the AP-1 transcription factor family, junD and fra-1, in regulation of heart growth during hypertrophic response. In this study, we investigate the function of the AP-1 transcription factors, c-jun and c-fos, in heart growth. Using pressure overload-induced cardiac hypertrophy in mice and targeted deletion of Jun or Fos in cardiomyocytes, we show that c-jun is required for adaptive cardiac hyphertrophy, while c-fos is dispensable in this context. c-jun promotes expression of sarcomere proteins and suppresses expression of extracellular matrix proteins. Capacity of cardiac muscle to contract depends on organization of principal thick and thin filaments, myosin and actin, within the sarcomere. In line with decreased expression of sarcomere-associated proteins, Jun-deficient cardiomyocytes present disarrangement of filaments in sarcomeres and actin cytoskeleton disorganization. Moreover, Jun-deficient hearts subjected to pressure overload display pronounced fibrosis and increased myocyte apoptosis finally resulting in dilated cardiomyopathy. In conclusion, c-jun but not c-fos is required to induce a transcriptional program aimed at adapting heart growth upon increased workload. Microarrays were used to identify specific genes that might be globally affected in the absence of c-jun in cardiomyocytes. Total RNA was extracted from the hearts of 10 weeks old Junf/f (n=2) and Jun delta mu (n=2) mice using TRIzol Reagent.

2013-09-19 | E-GEOD-47898 | biostudies-arrayexpress

Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [scRNA-seq]

Project description:Intestinal intraepithelial lymphocytes (IEL) are capable of rapid innate-like responses to microenvironmental cues. While poised to activation, IEL effector functions must be stringently controlled. Aiolos is an Ikaros zinc finger (IKZF) family member encoded by Ikzf3 that promotes histone deacetylation. Here, we found that Aiolos is a crucial regulator of IEL activation. Ikzf3–/– CD8αα+ IEL expressed high levels of innate NK receptors, cytotoxic enzymes, cytokines and chemokines. Single cell RNAseq of IEL revealed that Ikzf3 deficiency mostly amplified the effector machinery of a CD8αα+ IEL subset characterized by high expression CD122, the receptor for IL-15. Furthermore, Ikzf3 deficiency increased IEL responsiveness to IL-15. Aiolos binding sites were close to those for STAT5 and RUNX transcription factors that promote IL-15 signaling and cytolytic programs, respectively; lack of Ikzf3 increased accessibility and histone acetylation of these chromatin regions. Ikzf3 deficiency increased susceptibility to colitis, demonstrating the functional relevance of Aiolos-mediated regulation of IEL effector functions.

2023-10-20 | GSE220028 | GEO

Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [CUT&RUN]

2023-10-20 | GSE220022 | GEO

Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [ATAC-seq]

2023-10-20 | GSE220021 | GEO

Aiolos modulates IL-15 responsiveness of intestinal intraepithelial lymphocytes [RNA-seq]

2023-10-20 | GSE220020 | GEO

Liver cancer development driven by the AP-1/c-Jun~Fra2 dimer through c-Myc

Project description:Hepatocellular carcinoma (HCC) is a leading cause of cancer-related death. HCC incidence is on the rise, while treatment options remain limited. Thus, a better understanding of the molecular pathways involved in HCC development has become a priority to guide future therapies. While previous studies implicated the AP-1 (Fos/Jun) transcription factor family members c-Fos and c-Jun in HCC formation, the contribution of Fos-related antigens 1 and 2 (Fra-1/2) is unknown. Here we show that hepatocyte-restricted expression of a single chain c-Jun~Fra-2 protein, which functionally mimics the c-Jun/Fra-2 AP-1 dimer, results in spontaneous HCC formation in c-Jun~Fra-2hep mice. Several hallmarks of human HCC, such as cell cycle dysregulation and the expression of HCC markers are observed in liver tumors arising in c-Jun~Fra-2hep mice. Tumorigenesis occurs in the context of mild inflammation, low-grade fibrosis and Pparg-driven dyslipidemia. Subsequent analyses revealed increased expression of c-Myc, evidently directly regulated by AP-1 through a conserved distal 3’ enhancer. Importantly, c-Jun~Fra-2-induced tumors revert upon switching off transgene expression, suggesting oncogene addiction to the c-Jun~Fra-2 transgene. Tumors escaping reversion maintained c-Myc and c-Myc target gene expression, likely due to increased c-Fos. Interfering with c-Myc in established tumors using the BET bromodomain inhibitor JQ-1 diminished liver tumor growth in c-Jun~Fra-2 mutant mice. Thus, our data establish c-Jun~Fra-2hep mice as a novel model to study liver tumorigenesis and identify the c-Jun/Fra-2-Myc interaction as a potential target to improve HCC patient stratification and/or therapy.

2024-04-22 | GSE261005 | GEO

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