Histone arginine methylation keeps RUNX1 target genes in an intermediate state

Herglotz, Julia; Kuvardina, Olga N.; Kolodziej, Stephan; Kumar, Ashok; Hussong, Helge; Grez, Manuel; Lausen, Jörn

doi:10.1038/onc.2012.274

Cited by 50 publications

(68 citation statements)

References 56 publications

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“…These functions agree with the nuclear localization of Prmt6 (25). To date, many target genes of Prmt6 have been reported, including HoxA2 (17), thrombospondin-1 (26), p21 (20), p27 (27), p53 (21), Oct4 and Nanog (28), CD41 (29), and IL-6 (24).…”

supporting

confidence: 82%

Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

Zhao

Zhang

et al. 2016

Journal of Biological Chemistry

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Histone lysine methylation is important in early zebrafish development; however, the role of histone arginine methylation in this process remains unclear. H3R2me2a, generated by protein arginine methyltransferase 6 (Prmt6), is a repressive mark. To explore the role of Prmt6 and H3R2me2a during zebrafish embryogenesis, we identified the maternal characteristic of prmt6 and designed two prmt6-specific morpholino-oligos (MOs) to study its importance in early development, application of which led to early epiboly defects and significantly reduced the level of H3R2me2a marks. prmt6 mRNA could rescue the epiboly defects and the H3R2me2a reduction in the prmt6 morphants. Functionally, microarray data demonstrated that growth arrest and DNA damage-inducible, ␣, a (gadd45␣a) was a significantly up-regulated gene in MO-treated embryos, the activity of which was linked to the activation of the p38/JNK pathway and apoptosis. Importantly, gadd45␣a MO and p38/ JNK inhibitors could partially rescue the defect of prmt6 morphants, the downstream targets of Prmt6, and the apoptosis ratios of the prmt6 morphants. Moreover, the results of ChIP quantitative real time PCR and luciferase reporter assay indicated that gadd45␣a is a repressive target of Prmt6. Taken together, these results suggest that maternal Prmt6 is essential to early zebrafish development by directly repressing gadd45␣a.

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supporting

confidence: 82%

Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

Zhao

Zhang

et al. 2016

Journal of Biological Chemistry

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“…As these genes are all downregulated during the transition from MPP to GMP but upregulated in the absence of Runx1, we predict that C/ebpa-Runx1-occupied cis-regulatory elements may actively repress transcription, likely by recruiting strong repressors or corepressors, such as Gfi1, Sin3a, or protein arginine methyltransferases. 77,78 In summary, we have identified a critical role of Runx1 in suppressing what may be considered the default lineage choice in HSC development, ie, the amplification and lineage skewing of progenitors destined to form Megs, essential for producing platelets that repair disrupted endothelium and inhibit excessive bleeding. We postulate that the biased differentiation toward the Meg lineage occurs at the level of the HSC/MPP but manifests itself in an amplified Meg progenitor compartment and aberrant GMPs.…”

Section: Identification Of Runx1-binding Sites In Gmp-like Cells and mentioning

confidence: 97%

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

Behrens

Triviai

Schwieger

et al. 2016

Blood

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• Runx1 is a key determinant of megakaryocyte cell-fate decisions in multipotent progenitors.• Runx1 downregulates celladhesion factors that promote residency of stem cells and megakaryocytes in their bone marrow niche.Disrupting mutations of the RUNX1 gene are found in 10% of patients with myelodysplasia (MDS) and 30% of patients with acute myeloid leukemia (AML). Previous studies have revealed an increase in hematopoietic stem cells (HSCs) and multipotent progenitor (MPP) cells in conditional Runx1-knockout (KO) mice, but the molecular mechanism is unresolved. We investigated the myeloid progenitor (MP) compartment in KO mice, arguing that disruptions at the HSC/MPP level may be amplified in downstream cells. We demonstrate that the MP compartment is increased by more than fivefold in Runx1 KO mice, with a prominent skewing toward megakaryocyte (Meg) progenitors. Runx1-deficient granulocyte-macrophage progenitors are characterized by increased cloning capacity, impaired development into mature cells, and HSC and Meg transcription signatures. An HSC/MPP subpopulation expressing Meg markers was also increased in Runx1-deficient mice. Rescue experiments coupled with transcriptome analysis and Runx1 DNA-binding assays demonstrated that granulocytic/monocytic (G/M) commitment is marked by Runx1 suppression of genes encoding adherence and motility proteins (Tek, Jam3, Plxnc1, Pcdh7, and Selp) that support HSC-Meg interactions with the BM niche. In vitro assays confirmed that enforced Tek expression in HSCs/MPPs increases Meg output. Interestingly, besides this key repressor function of Runx1 to control lineage decisions and cell numbers in progenitors, our study also revealed a critical activating function in erythroblast differentiation, in addition to its known importance in Meg and G/M maturation. Thus both repressor and activator functions of Runx1 at multiple hematopoietic stages and lineages likely contribute to the tumor suppressor activity in MDS and AML. (Blood. 2016;127(26):3369-3381)

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“…Upon binding of cis-regulatory elements, strong repressors/corepressors, e.g. Gfi1, Sin3a, or protein arginine methyltransferase 6 (PRMT6), may be recruited [34].…”

Section:  Functional Properties Of Runx1mentioning

confidence: 99%

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

Schlegelberger

Heller

2017

Seminars in Hematology

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In this review, we discuss disease-causing alterations of RUNT-related transcription factor 1 (RUNX1), a master regulator of hematopoietic differentiation. Familial platelet disorder with predisposition to myeloid leukemia (FPDMM) typically present with 1) mild to moderate thrombocytopenia with normal-sized platelets; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL.Hematological neoplasms in carriers of a germline RUNX1 mutation need additional secondary mutations or chromosome aberrations to develop. If a disease-causing mutation is known in the family, it is important to prevent hematopoietic stem cell transplantation from a sibling or other relative carrying the familial mutation. First experiments introducing a wild-type copy of RUNX1 into iPSC lines from patients with FPDMM appear to demonstrate that by gene correction reversal of the phenotype may be possible.  Definition of RUNX1 deficiency/ FPDMMRUNT-related transcription factor 1 (RUNX1), previously named core binding factor A2 (CBFA2) and acute myeloid leukemia 1 (AML1), is a master regulator of hematopoiesis [1]. It is involved in the most frequent chromosome translocations in leukemia (i.e. t(12;21)/RUNX1/ETV6 in pediatric acute lymphoblastic leukemia, t(8;21)/RUNX1/RUNX1T1 in acute myeloid leukemia (AML), and t(3;21)/RUNX1/EVI1 in therapy-related AML or chronic myeloid leukemia in blast phase [2,3]. Moreover, somatic RUNX1 mutations have recently been identified as recurrent abnormalities in myelodysplastic syndromes (MDS) and AML [4]. These somatic changes are associated with poor prognosis in AML and MDS indicating an increased resistance against exposure to genotoxic agents. RUNX1 mutations seem to trigger progression into MDS and AML in Fanconi anemia and severe congenital neutropenia [5,6]. Song et al. (1999) were the first to describe heterozygous germline RUNX1 mutations in six families, each carrying a different mutation. Individuals carrying germline RUNX1 may be asymptomatic throughout lifetime or develop familial platelet disorder with myeloid malignancies (i.e. FPDMM, OMIM 601399). Characteristic features are 1) mild to moderate thrombocytopenia; 2) functional platelets defects leading to prolonged bleeding; and 3) an increased risk to develop MDS, AML or T-ALL. There is a great phenotypic heterogeneity. FPDMM is inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity.  Diagnostic criteria to identify persons at riskSince the diagnosis of FPDMM in a patient with leukemia carries important critical implications for the patient and also for her/his family, it is important to recognize clinical features pointing to this genetic predisposition [7]. An important clinical feature is persisting thrombocytopenia or aspirin-like platelet disorder, which are not explained by other reasons.Thorough pedigree analysis may identify first or second degree relatives with bleeding tendency or hematological neoplasms. It has to be kept i...

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Histone arginine methylation keeps RUNX1 target genes in an intermediate state

Cited by 50 publications

References 56 publications

Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

Protein Arginine Methyltransferase 6 (Prmt6) Is Essential for Early Zebrafish Development through the Direct Suppression of gadd45αa Stress Sensor Gene

Runx1 downregulates stem cell and megakaryocytic transcription programs that support niche interactions

RUNX1 deficiency (familial platelet disorder with predisposition to myeloid leukemia, FPDMM)

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