Transcriptional regulation of the Ikzf1 locus

Yoshida, Toshimi; Landhuis, Esther; Dose, Marei; Hazan, Idit; Zhang, Jiangwen; Naito, Taku; Jackson, Andrew; Wu, Jeffrey H.; Perotti, Elizabeth A.; Kaufmann, Christoph; Gounari, Fotini; Morgan, Bruce; Georgopoulos, Katia

doi:10.1182/blood-2013-01-474916

Cited by 34 publications

(50 citation statements)

References 40 publications

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“…Interestingly, the later set of genes contained multiple active enhancers within their gene bodies in DKO1 cells, and these same enhancers were methylated in HCT116 cells. Intronic enhancers have been previously described to regulate the genes they reside within [23,[31][32][33]. Here, we have identified several hundred genes that may be controlled by increases in active histones at intragenic enhancers.…”

Section: Discussionmentioning

confidence: 86%

Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes

et al. 2014

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Background: Gene expression is epigenetically regulated by a combination of histone modifications and methylation of CpG dinucleotides in promoters. In normal cells, CpG-rich promoters are typically unmethylated, marked with histone modifications such as H3K4me3, and are highly active. During neoplastic transformation, CpG dinucleotides of CG-rich promoters become aberrantly methylated, corresponding with the removal of active histone modifications and transcriptional silencing. Outside of promoter regions, distal enhancers play a major role in the cell type-specific regulation of gene expression. Enhancers, which function by bringing activating complexes to promoters through chromosomal looping, are also modulated by a combination of DNA methylation and histone modifications.

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Section: Discussionmentioning

confidence: 86%

Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes

et al. 2014

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“…Ikzf1 enhancers feature enrichment sites for several key transcriptional regulators of the hematopoietic and lymphoid system. Occupancy of Ikzf1 enhancers by the Ebox proteins (E2A and HEB), RUNX1, and TCF-1 indicates that these may contribute to IKAROS induction in the HSCs, with changes in their expression likely contributing to changes in Ikzf1 transcription during differentiation (Yoshida et al 2013). Still, it remains unclear whether and how these factors impact Ikzf1 expression.…”

Section: Expression and Immune Cell Phenotypesmentioning

confidence: 99%

“…IKAROS (Ikzf1) is strongly expressed from the HSCs to mature T and B effector cells and is the only family member that is necessary at both the onset and later stages of lymphocyte differentiation. There is an extensive redundancy of regulatory elements at the Ikzf1 locus, with two promoters and six enhancers providing locus control region activity during hemolymphopoiesis (Yoshida et al 2013;Perotti et al 2015). Ikzf1 enhancers feature enrichment sites for several key transcriptional regulators of the hematopoietic and lymphoid system.…”

Section: Expression and Immune Cell Phenotypesmentioning

confidence: 99%

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Georgopoulos

2017

Genes Dev.

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Lymphocyte differentiation is set to produce myriad immune effector cells with the ability to respond to multitudinous foreign substances. The uniqueness of this developmental system lies in not only the great diversity of cellular functions that it can generate but also the ability of its differentiation intermediates and mature effector cells to expand upon demand, thereby providing lifelong immunity. Surprisingly, the goals of this developmental system are met by a relatively small group of DNA-binding transcription factors that work in concert to control the timing and magnitude of gene expression and fulfill the demands for cellular specialization, expansion, and maintenance. The cellular and molecular mechanisms through which these lineage-promoting transcription factors operate have been a focus of basic research in immunology. The mechanisms of development discerned in this effort are guiding clinical research on disorders with an immune cell base. Here, I focus on IKAROS, one of the earliest regulators of lymphoid lineage identity and a guardian of lymphocyte homeostasis.

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“…Mouse studies suggest that the transcription of IKZF1 during normal hematopoiesis is regulated by a complex network. 18 However, Ikaros protein is expressed at high levels in most hematopoietic cells, and posttranslational modifications are hypothesized to play a critical role in regulating Ikaros activity. 19 Several groups have shown that phosphorylation, [19][20][21][22][23][24] sumoylation, 25 and ubiquitination 22 can regulate Ikaros function as a transcriptional repressor.…”

Section: Introductionmentioning

confidence: 99%

Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia

Song

Gowda

Pan

et al. 2015

Blood

159

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• Ikaros controls cellular proliferation by repressing genes that regulate cell cycle progression and the PI3K pathway in leukemia.• CK2 inhibitor restores Ikaros tumor suppressor function in high-risk B-ALL with IKZF1 deletion and has a strong therapeutic effect in vivo.Ikaros (IKZF1) is a tumor suppressor that binds DNA and regulates expression of its target genes. The mechanism of Ikaros activity as a tumor suppressor and the regulation of Ikaros function in leukemia are unknown. Here, we demonstrate that Ikaros controls cellular proliferation by repressing expression of genes that promote cell cycle progression and the phosphatidylinositol-3 kinase (PI3K) pathway. We show that Ikaros function is impaired by the pro-oncogenic casein kinase II (CK2), and that CK2 is overexpressed in leukemia. CK2 inhibition restores Ikaros function as transcriptional repressor of cell cycle and PI3K pathway genes, resulting in an antileukemia effect. In high-risk leukemia where one IKZF1 allele has been deleted, CK2 inhibition restores the transcriptional repressor function of the remaining wild-type IKZF1 allele. CK2 inhibition demonstrated a potent therapeutic effect in a panel of patient-derived primary high-risk B-cell acute lymphoblastic leukemia xenografts as indicated by prolonged survival and a reduction of leukemia burden. We demonstrate the efficacy of a novel therapeutic approach for high-risk leukemia: restoration of Ikaros tumor suppressor activity via inhibition of CK2. These results provide a rationale for the use of CK2 inhibitors in clinical trials for high-risk leukemia, including cases with deletion of one IKZF1 allele. (Blood. 2015;126(15):1813-1822 Introduction Ikaros (IKZF1) activity is essential for normal hematopoiesis and immune development. [1][2][3][4] Ikaros knockout mice have severely impaired hematopoiesis, 5-7 whereas mice with the heterozygous loss of Ikaros develop T-cell leukemia. 8 In humans, impaired Ikaros activity due to the deletion or inactivating mutation of a single IKZF1 allele results in high-risk B-cell leukemia that is resistant to treatment.9-14 Ikaros regulates transcription of target genes via chromatin remodeling. [15][16][17] Ikaros activity is controlled through multiple mechanisms. Mouse studies suggest that the transcription of IKZF1 during normal hematopoiesis is regulated by a complex network. 18 However, Ikaros protein is expressed at high levels in most hematopoietic cells, and posttranslational modifications are hypothesized to play a critical role in regulating Ikaros activity. 19 Several groups have shown that phosphorylation, [19][20][21][22][23][24] sumoylation, 25 and ubiquitination 22 can regulate Ikaros function as a transcriptional repressor. However, the role of posttranslational modification in the regulation of Ikaros tumor suppressor activity in leukemia is unknown.Despite extensive global analyses of Ikaros DNA binding in normal murine hematopoietic cells, 26-28 the molecular mechanisms by which Ikaros exerts its tumor suppressor effects in human leukemia ...

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Transcriptional regulation of the Ikzf1 locus

Abstract: Key Points Multiple enhancers identified at the Ikzf1 locus with shared and distinct epigenetic and transcriptional properties. Transcription factor networks that distinguish between LMPP-specific and T cell–specific Ikzf1 enhancers.

Cited by 34 publications

References 40 publications

Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes

Global loss of DNA methylation uncovers intronic enhancers in genes showing expression changes

The making of a lymphocyte: the choice among disparate cell fates and the IKAROS enigma

Targeting casein kinase II restores Ikaros tumor suppressor activity and demonstrates therapeutic efficacy in high-risk leukemia

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