Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program

Hoogenkamp, Maarten; Lichtinger, Monika; Krysinska, Hanna; Lancrin, Christophe; Clarke, Deborah; Williamson, Andrew J.K.; Mazzarella, Luca; Ingram, Richard; Jørgensen, Helle F.; Fisher, Amanda G.; Tenen, Daniel G.; Kouskoff, Valérie; Lacaud, Georges; Bonifer, Constanze

doi:10.1182/blood-2008-11-191890

Cited by 103 publications

(98 citation statements)

References 66 publications

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“…Other HDAC inhibitors like PB, VPA (Nightingale et al, 2007) and trichostatin A (Paul et al, 2010) have been described to induce trimethylation of H3K4, suggesting a functional link between histone acetylation and histone methylation. The group of Constanze Bonifer described the interaction between AML1 (RUNX1) and the initiation of chromatin remodeling through trimethylation of H3K4 in pluripotent hematopoietic precursors cells, suggesting that Epigenetic regulation of LAT2 by AML1/ETO J Duque-Afonso et al the epigenetic changes of AML1/ETO target promoters may be due to modification not only in histone acetylation but also in histone methylation (Hoogenkamp et al, 2009). Others (Peterson et al, 2007, Viale et al, 2009 as well as ourselves (Berg et al, 2008) have described that p21 waf1 expression is induced by AML1/ETO.…”

Section: Discussionmentioning

confidence: 99%

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

et al. 2011

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The chromosomal translocation (8;21) fuses the hematopoietic transcription factor AML1 (RUNX1) with ETO (RUNX1T1, MTG8), resulting in the leukemia-specific chimeric protein AML1/ETO. This fusion protein has been implicated in epigenetic silencing, recruiting histone deacetylases (HDACs) and DNA methyltransferases to target promoters. Previously, we have identified a novel in vivo AML1/ETO target gene, LAT2 (NTAL/LAB/ WBSCR5), which is involved in FceR I, c-Kit, B-cell and T-cell receptor signalling. We have now addressed the molecular mechanisms of AML1/ETO-mediated LAT2 repression. In Kasumi-1 cells, where AML1/ETO bound to the LAT2 gene, small interfering RNA (siRNA)-mediated AML1/ETO depletion caused upregulation of LAT2, suggesting a possible direct mechanism of repression. Expression of AML1/ETO was associated with a decrease in acetylation of histones H3, H3K9 and H4, and an increase in H3K9 and H3K27 trimethylation. The class I-specific HDAC inhibitors entinostat (MS-275) and mocetinostat (MGCD0103) induced LAT2 expression specifically in AML1/ETO-expressing cells, resulting in induction of several activating histone marks on the LAT2 gene, including trimethylation of histone H3K4. The combination of entinostat and decitabine increased acetylation of histones H3 and H4, as well as LAT2 mRNA expression, in an at least additive fashion. In conclusion, several repressive histone modifications mark the LAT2 gene in the presence of AML1/ETO, and LAT2 gene derepression is achieved by pharmacological inhibition of HDACs.

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Section: Discussionmentioning

confidence: 99%

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

et al. 2011

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“…It was suggested that the transition of EMPs to Runx1 independence could be mediated by the onset of Runx2 and/or Runx3 expression, which could then compensate for Runx1 loss (Hoogenkamp et al, 2009). However, we demonstrated that deletion of Cbfb with Vav1-Cre, which would affect the activity of all three Runx proteins, was permissive for EMP/CFU-C function.…”

Section: Discussionmentioning

confidence: 99%

Distinct temporal requirements for Runx1 in hematopoietic progenitors and stem cells

et al. 2013

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SUMMARYThe transcription factor Runx1 is essential for the formation of yolk sac-derived erythroid/myeloid progenitors (EMPs) and hematopoietic stem cells (HSCs) from hemogenic endothelium during embryogenesis. However, long-term repopulating HSCs (LT-HSCs) persist when Runx1 is conditionally deleted in fetal liver cells, demonstrating that the requirement for Runx1 changes over time. To define more precisely when Runx1 transitions from an essential factor to a homeostatic regulator of EMPs and HSCs, and whether that transition requires fetal liver colonization, we performed conditional, timed deletions of Runx1 between E7.5 and E13.5. We determined that Runx1 loss reduces the formation or function of EMPs up through E10.5. The Runx1 requirement in HSCs ends later, as deletion up to E11.5 eliminates HSCs. At E11.5, there is an abrupt transition to Runx1 independence in at least a subset of HSCs that does not require fetal liver colonization. The transition to Runx1 independence in EMPs is not mediated by other core binding factors (Runx2 and/or Runx3); however, deleting the common non-DNA-binding β subunit (CBFβ) severely compromises LT-HSC function. Hence, the requirements for Runx1 in EMP and HSC formation are temporally distinct, and LT-HSC function is highly reliant on continued core binding factor activity.

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“…24,25 Various transcription factors can bind to the URE including PU.1 itself, Elf1, FLI-1, Runx-1 and C/EBP. 11,23,26,27 The URE regulates transcription of both sense as well as antisense non-coding transcripts and this provides an additional layer of modifying PU.1 activity via the regulation of protein translation. 28 The expression of PU.1 is regulated post-transcriptionally as the 3 0 untranslated region of PU.1 mRNA can be inhibited by the microRNA miR-155, 29 which is generated from a precursor primiR-155 encoded by the BIC gene.…”

Section: Pu1 and Its Role In Hematopoiesismentioning

confidence: 99%

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

2010

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Hematopoiesis is coordinated by a complex regulatory network of transcription factors and among them PU.1 (Spi1, Sfpi1) represents a key molecule. This review summarizes the indispensable requirement of PU.1 during hematopoietic cell fate decisions and how the function of PU.1 can be modulated by protein-protein interactions with additional factors. The mutual negative regulation between PU.1 and GATA-1 is detailed within the context of normal and leukemogenic hematopoiesis and the concept of 'differentiation therapy' to restore normal cellular differentiation of leukemic cells is discussed.

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Early chromatin unfolding by RUNX1: a molecular explanation for differential requirements during specification versus maintenance of the hematopoietic gene expression program

Cited by 103 publications

References 66 publications

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

The HDAC class I-specific inhibitor entinostat (MS-275) effectively relieves epigenetic silencing of the LAT2 gene mediated by AML1/ETO

Distinct temporal requirements for Runx1 in hematopoietic progenitors and stem cells

The role of PU.1 and GATA-1 transcription factors during normal and leukemogenic hematopoiesis

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