Regulation of Hoxb2 by APL-associated PLZF protein

Ivins, Sarah; Pemberton, Kieran D.; Guidez, Fabien; Howell, Louise; Krumlauf, Robb; Zelent, Arthur

doi:10.1038/sj.onc.1206328

Cited by 39 publications

(48 citation statements)

References 67 publications

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“…ZBTB16 is a negative regulator of cell division in embryogenesis and controls skeletal patterning through repression of HOX, BMP, and Sonic Hedge Hog (Shh) expression. Deletion of ZBTB16 in mice leads to severe skeletal deformities due to impaired limb and axial skeleton patterning leading to transformation of anterior skeletal elements into posterior structures [41][42][43]. ZBTB16 is required for stylopod and zeugopod formation during early stages of limb development, before the initiation of cartilage condensation [44].…”

Section: Discussionmentioning

confidence: 99%

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Hemming

Cakouros

Vandyke

et al. 2016

Stem Cells and Development

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Histone three lysine 27 (H3K27) methyltransferase enhancer of zeste homolog 2 (EZH2) is a critical epigenetic modifier, which regulates gene transcription through the trimethylation of the H3K27 residue leading to chromatin compaction and gene repression. EZH2 has previously been identified to regulate human bone marrow-derived mesenchymal stem cells (MSC) lineage specification. MSC lineage specification is regulated by the presence of EZH2 and its H3K27me3 modification or the removal of the H3K27 modification by lysine demethylases 6A and 6B (KDM6A and KDM6B). This study used a bioinformatics approach to identify novel genes regulated by EZH2 during MSC osteogenic differentiation. In this study, we identified the EZH2 targets, ZBTB16, MX1, and FHL1, which were expressed at low levels in MSC. EZH2 and H3K27me3 were found to be present along the transcription start site of their respective promoters. During osteogenesis, these genes become actively expressed coinciding with the disappearance of EZH2 and H3K27me3 on the transcription start site of these genes and the enrichment of the active H3K4me3 modification. Overexpression of EZH2 downregulated the transcript levels of ZBTB16, MX1, and FHL1 during osteogenesis. Small interfering RNA targeting of MX1 and FHL1 was associated with a downregulation of the key osteogenic transcription factor, RUNX2, and its downstream targets osteopontin and osteocalcin. These findings highlight that EZH2 not only acts through the direct regulation of signaling modules and lineage-specific transcription factors but also targets many novel genes important for mediating MSC osteogenic differentiation.

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Section: Discussionmentioning

confidence: 99%

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Hemming

Cakouros

Vandyke

et al. 2016

Stem Cells and Development

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“…A crucial role for PLZF has been suggested in normal development Ivins and Zelent, 1998) as well as during leukemogenesis (He et al, 1998;Hawe et al, 1996). Gene targeting studies have recently shown a role of PLZF in the control of murine embryogenesis and in the regulation of HOX gene expression (Barna et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein

et al. 2002

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We investigated the expression of the PLZF gene in purified human hematopoietic progenitors induced to unilineage erythroid, granulocytic or megakaryocytic differentiation and maturation in serum-free culture. PLZF is expressed in quiescent progenitors: the expression level progressively rises through megakaryocytic development, whereas it gradually declines in erythroid and granulopoietic culture. To investigate the role of PLZF in megakaryopoiesis, we transduced the PLZF gene into the erythro-megakaryocytic TF1 cell line. PLZF overexpression upmodulates the megakaryocytic specific markers (CD42a, CD42b, CD61, PF4) and induces the thrombopoietin receptor (TpoR). The proximal promoter of the TpoR gene is activated in PLZF-expressing TF1 cells: in this promoter region, a PLZF DNA-binding site was identified by deletion constructs studies. Interestingly, PLZF and GATA1 proteins coimmunoprecipitate in PLZF-expressing TF1 cells: enforced expression of both PLZF and GATA1 in TF1 cells results in increased upregulation of megakaryocytic markers, as compared to exogenous PLZF or GATA1 alone, suggesting a functional role for the PLZF/GATA1 complex. Our data indicate that PLZF plays a significant stimulatory role in megakaryocytic development, seemingly mediated in part by induction of TpoR expression at transcriptional level. This stimulatory effect is potentiated by physical interaction of PLZF and GATA1, which are possibly assembled in a multiprotein transcriptional complex.

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“…Moreover, the presence of RARα-PLZF increases the proliferation and resistance to RA treatment in double transgenic mice (12). At the molecular level, RARα-PLZF binds to DNA via the PLZF binding site and derepresses PLZF target genes such as cyclin A, Hoxb2a and c-Myc (13)(14)(15), thereby causing increased proliferation. In addition, RA resistance has been associated with an up-regulation of cellular retinoic acid binding protein 1 (CRABPI) (16), although additional mechanisms could also contribute to this resistance.…”

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confidence: 99%

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Girard

Tremblay

Humbert

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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In acute promyelocytic leukemia, granulocytic differentiation is arrested at the promyelocyte stage. The variant t(11;17) translocation produces two fusion proteins, promyelocytic leukemia zinc finger-retinoic acid receptor α (PLZF-RARα) and RARα-PLZF, both of which participate in leukemia development. Here we provide evidence that the activity of CCAAT/enhancer binding protein α (C/EBPα), a master regulator of granulocytic differentiation, is severely impaired in leukemic promyelocytes with the t(11;17) translocation compared with those associated with the t(15;17) translocation. We show that RARα-PLZF inhibits myeloid cell differentiation through interactions with C/EBPα tethered to DNA, using ChIP and DNA capture assays. Furthermore, RARα-PLZF recruits HDAC1 and causes histone H3 deacetylation at C/EBPα target loci, thereby decreasing the expression of C/EBPα target genes. In line with these results, HDAC inhibitors restore in part C/EBPα target gene expression. These findings provide molecular evidence for a mechanism through which RARα-PLZF acts as a modifier oncogene that subverts differentiation in the granulocytic lineage by associating with C/EBPα and inhibiting its activity.APL | granulocyte differentiation | transcription inhibition | histone modification | protein interaction

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Regulation of Hoxb2 by APL-associated PLZF protein

Cited by 39 publications

References 67 publications

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

Identification of Novel EZH2 Targets Regulating Osteogenic Differentiation in Mesenchymal Stem Cells

PLZF induces megakaryocytic development, activates Tpo receptor expression and interacts with GATA1 protein

RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

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