RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity

Cellot, Sonia; Hope, Kristin J.; Chagraoui, Jalila; Sauvageau, Martin; Deneault, Éric; MacRae, Tara; Mayotte, Nadine; Wilhelm, Brian T.; Landry, Josette Renée; Ting, Stephen B.; Krošl, Jana; Humphries, R. Keith; Thompson, Alexander; Sauvageau, Guy

doi:10.1182/blood-2013-04-496281

Cited by 59 publications

(58 citation statements)

References 41 publications

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“…This is fully compatible with the involvement of the HoxA family in stem cell expansion and leukemogenesis. [35][36][37][38] Using RNA interference-based functional screening, Cellot et al 39 identified the H3K4 demethylase JARID1B as a negative regulator of HSC functions among the Jumonji domain-containing family of histone demethylases. The shRNA-mediated knockdown of JARID1B leads to the in vitro expansion of HSCs, which is accompanied by the upregulation of HoxA7, HoxA9, and HoxA10, with preserved long-term reconstitution potential.…”

Section: Discussionmentioning

confidence: 99%

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Wada

Koyama

Kikuchi

et al. 2015

Blood

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Key Points• LSD1 is barely expressed in normal hematopoietic stem cells, but is overexpressed in leukemias especially those of a T-cell origin.• LSD1 overexpression forms preleukemic stem cells with an increased self-renewal potential in a transgenic mice model.Recent investigations indicate that epigenetic regulators act at the initial step of myeloid leukemogenesis by forming preleukemic hematopoietic stem cells (HSCs), which possess the increased self-renewal potential but retain multidifferentiation ability, and synergize with genetic abnormalities in later stages to develop full-blown acute myeloid leukemias. However, it is still unknown whether this theory is applicable to other malignancies. In this study, we demonstrate that lysine-specific demethylase 1 (LSD1) overexpression is a founder abnormality for the development of T-cell lymphoblastic leukemia/ lymphoma (T-LBL) using LSD1 transgenic mice. LSD1 expression is tightly regulated via alternative splicing and transcriptional repression in HSCs and is altered in most leukemias, especially T-LBL. Overexpression of the shortest isoform of LSD1, which is specifically repressed in quiescent HSCs and demethylates histone H3K9 more efficiently than other isoforms, increases self-renewal potential via upregulation of the HoxA family but retains multidifferentiation ability with a skewed differentiation to T-cell lineages at transcriptome levels in HSCs. Transgenic mice overexpressing LSD1 in HSCs did not show obvious abnormalities but developed T-LBL at very high frequency after g-irradiation. LSD1 overexpression appears to be the first hit in T-cell leukemogenesis and provides an insight into novel strategies for early diagnosis and effective treatment of the disease. (Blood. 2015;125(24):3731-3746)

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Section: Discussionmentioning

confidence: 99%

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Wada

Koyama

Kikuchi

et al. 2015

Blood

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“…The demethylase LSD1 has July 2015 been shown to maintain endothelium-dependent relaxation. 8 For JARID2, an important role of endocardial-driven cardiac development has been reported. 9,10 The function of the other JARID enzymes in the cardiovascular system has not been studied.…”

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confidence: 99%

“…14,15 Through this function, JARID1B is involved in the repression of transcription during embryonic development and in embryonic and hematopoietic stem cells. 5,8,11,12,16,17 Therefore, genetic deletion of JARID1B impairs mouse and porcine embryonic development. [18][19][20][21] Considering its effect on gene regulation, we hypothesized that JARID1B affects the expression of endothelial genes and examined the consequences on angiogenesis in human umbilical vein ECs (HUVECs), tamoxifen-inducible conditional, and in the endothelial-specific Jarid1b knockout mouse.…”

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confidence: 99%

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Fork

Hitzel

et al. 2015

ATVB

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Objective-Altering endothelial biology through epigenetic modifiers is an attractive novel concept, which is, however, just in its beginnings. We therefore set out to identify chromatin modifiers important for endothelial gene expression and contributing to angiogenesis. Approach and Results-To identify chromatin modifying enzymes in endothelial cells, histone demethylases were screened by microarray and polymerase chain reaction. The histone 3 lysine 4 demethylase JARID1B was identified as a highly expressed enzyme at the mRNA and protein levels. Knockdown of JARID1B by shRNA in human umbilical vein endothelial cells attenuated cell migration, angiogenic sprouting, and tube formation. Similarly, pharmacological inhibition and overexpression of a catalytic inactive JARID1B mutant reduced the angiogenic capacity of human umbilical vein endothelial cells. To identify the in vivo relevance of JARID1B in the vascular system, Jarid1b knockout mice were studied. As global knockout results in increased mortality and developmental defects, tamoxifen-inducible and endothelial-specific knockout mice were generated. Acute knockout of Jarid1b attenuated retinal angiogenesis and endothelial sprout outgrowth from aortic segments. To identify the underlying mechanism, a microarray experiment was performed, which led to the identification of the antiangiogenic transcription factor HOXA5 to be suppressed by JARID1B. Importantly, downregulation or inhibition of JARID1B, but not of JARID1A and JARID1C, induced HOXA5 expression in human umbilical vein endothelial cells. Consistently, chromatin immunoprecipitation revealed that JARID1B occupies and reduces the histone 3 lysine 4 methylation levels at the HOXA5 promoter, demonstrating a direct function of JARID1B in endothelial HOXA5 gene regulation. Conclusions-JARID1B, by suppressing HOXA5, maintains the endothelial angiogenic capacity in a demethylasedependent manner.

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“…A search of the Oncomine database (59,60) showed that JARID1B is up-regulated in multiple types of leukemia (46). JARID1B is important for hematopoietic stem cell renewal (47,48) and is overex- pressed in acute myeloid leukemia. Our data demonstrated a strong increase in expression of JARID1B in B-ALL as compared with normal bone marrow.…”

Section: Discussionmentioning

confidence: 99%

“…Molecular inhibition of JARID1B using siRNA has shown that JARID1B is important for hematopoietic stem cell renewal (47,48). Here, we tested the effect of pharmacological inhibition of JARID1B on the proliferation of leukemia cells.…”

Section: Inhibition Of Ck2 Restores Ikaros-mediated Repression Of Jarmentioning

confidence: 99%

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

Wang

Song

Ding

et al. 2016

Journal of Biological Chemistry

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Impaired function of the Ikaros (IKZF1) protein is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL). The mechanisms of Ikaros tumorsuppressor activity in leukemia are unknown. Ikaros binds to the upstream regulatory elements of its target genes and regulates their transcription via chromatin remodeling. Here, we report that Ikaros represses transcription of the histone H3K4 demethylase, JARID1B (KDM5B). Transcriptional repression of JARID1B is associated with increased global levels of H3K4 trimethylation. Ikaros-mediated repression of JARID1B is dependent on the activity of the histone deacetylase, HDAC1, which binds to the upstream regulatory element of JARID1B in complex with Ikaros. In leukemia, JARID1B is overexpressed, and its inhibition results in cellular growth arrest. Ikaros-mediated repression of JARID1B in leukemia is impaired by pro-oncogenic casein kinase 2 (CK2). Inhibition of CK2 results in increased binding of the Ikaros-HDAC1 complex to the promoter of JARID1B, with increased formation of trimethylated histone H3 lysine 27 and decreased histone H3 Lys-9 acetylation. In cases of high-risk B-ALL that carry deletion of one Ikaros (IKZF1) allele, targeted inhibition of CK2 restores Ikaros binding to the JARID1B promoter and repression of JARID1B. In summary, the presented data suggest a mechanism through which Ikaros and HDAC1 regulate the epigenetic signature in leukemia: via regulation of JARID1B transcription. The presented data identify JARID1B as a novel therapeutic target in B-ALL and provide a rationale for the use of CK2 inhibitors in the treatment of high-risk B-ALL.IKZF1 encodes the Ikaros DNA-binding zinc finger protein (1-4). Ikaros is essential for normal hematopoiesis and acts as a tumor suppressor (5, 6). In humans, deletion of a single Ikaros allele is associated with the development of high-risk B-cell precursor acute lymphoblastic leukemia (B-ALL) 3 that is characterized by resistance to chemotherapy and poor prognosis (7-9). Alterations in the Ikaros have also been associated with T cell ALL (10, 11) and myeloid leukemias (12-16). Ikaros regulates transcription of its target genes via chromatin remodeling (9). Ikaros has been shown to directly bind histone deacetylases HDAC1 and HDAC2 and to associate with the chromatin remodeling complex NuRD through interaction with the Mi-2 protein (9, 17).Ikaros is hypothesized to recruit chromatin remodeling complexes to the regulatory elements of its target genes, resulting in chromatin modifications (primarily histone deacetylation) and transcriptional repression or activation of its target genes (18 -20). Mechanisms of Ikaros-mediated repression that are independent of histone deacetylase have also been described (18, 3 The abbreviations used are: B-ALL, B-cell precursor acute lymphoblastic leukemia; CK2, casein kinase 2; TSS, transcriptional start site; ALL, acute lymphoblastic leukemia; TBB, 4,5,6,7-tetrabromobenzotriazole; IK haploid , Ikaros haploinsufficiency; Ikaros-CTS, C terminus o...

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RNAi screen identifies Jarid1b as a major regulator of mouse HSC activity

Cited by 59 publications

References 41 publications

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Overexpression of the shortest isoform of histone demethylase LSD1 primes hematopoietic stem cells for malignant transformation

Epigenetic Regulation of Angiogenesis by JARID1B-Induced Repression of HOXA5

Transcriptional Regulation of JARID1B/KDM5B Histone Demethylase by Ikaros, Histone Deacetylase 1 (HDAC1), and Casein Kinase 2 (CK2) in B-cell Acute Lymphoblastic Leukemia

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