PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia

Martens, Joost H.A.; Brinkman, Arie B.; Simmer, Femke; Françoijs, Kees−Jan; Nebbioso, Angela; Ferrara, Felicetto; Altucci, Lucia; Stunnenberg, Hendrik G.

doi:10.1016/j.ccr.2009.12.042

Cited by 278 publications

(336 citation statements)

References 61 publications

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“…Genomic DNA isolated from blastula and gastrula (NieuwkoopFaber stages 9 and 12.5) embryos was purified by affinity capture (MethylCap) using the methyl-CpG-binding domain (MBD) of human MECP2 protein (Cross et al 1994;Kangaspeska et al 2008;Brinkman et al 2010;Martens et al 2010). MethylCap has been benchmarked as a robust, accurate, and effective approach to map DNA methylation (Bock et al 2010).…”

Section: Dna Methylation Profiles Of X Tropicalis Embryosmentioning

confidence: 99%

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Bogdanović

Long²,

Heeringen³

et al. 2011

Genome Res.

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DNA methylation is a tightly regulated epigenetic mark associated with transcriptional repression. Next-generation sequencing of purified methylated DNA obtained from early Xenopus tropicalis embryos demonstrates that this genome is heavily methylated during blastula and gastrula stages. Although DNA methylation is largely absent from transcriptional start sites marked with histone H3 lysine 4 trimethylation (H3K4me3), we find both promoters and gene bodies of active genes robustly methylated. In contrast, DNA methylation is absent in large H3K27me3 domains, indicating that these two repression pathways have different roles. Comparison with chromatin state maps of human ES cells reveals strong conservation of epigenetic makeup and gene regulation between the two systems. Strikingly, genes that are highly expressed in pluripotent cells and in Xenopus embryos but not in differentiated cells exhibit relatively high DNA methylation. Therefore, we tested the repressive potential of DNA methylation using transient and transgenic approaches and show that methylated promoters are robustly transcribed in blastula-and gastrula-stage embryos, but not in oocytes or late embryos. These findings have implications for reprogramming and the epigenetic regulation of pluripotency and differentiation and suggest a relatively open, pliable chromatin state in early embryos followed by reestablished methylation-dependent transcriptional repression during organogenesis and differentiation.

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Section: Dna Methylation Profiles Of X Tropicalis Embryosmentioning

confidence: 99%

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Bogdanović

Long²,

Heeringen³

et al. 2011

Genome Res.

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“…At the molecular level, PML-RAR␣ acts as a transcriptional repressor that interferes with gene expression programs normally leading to full myeloid differentiation. Recently, PML-RAR␣ was shown to be bound to the ASB2 promoter in acute promyelocytic leukemia cells in the absence of retinoic acid leading to hypoacetylation of histone H3 (19). Moreover, following retinoic acid treatment of acute promyelocytic leuke-mia cells, hyperacetylation and recruitment of RNA polymerase II to the ASB2 promoter were observed (19).…”

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confidence: 99%

Functional and Structural Insights into ASB2α, a Novel Regulator of Integrin-dependent Adhesion of Hematopoietic Cells

Lamsoul

Burande

Razinia

et al. 2011

Journal of Biological Chemistry

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By providing contacts between hematopoietic cells and the bone marrow microenvironment, integrins are implicated in cell adhesion and thereby in control of cell fate of normal and leukemia cells. The ASB2 gene, initially identified as a retinoic acid responsive gene and a target of the promyelocytic leukemia retinoic acid receptor ␣ oncoprotein in acute promyelocytic leukemia cells, encodes two isoforms, a hematopoietic-type (ASB2␣) and a muscle-type (ASB2␤) that are involved in hematopoietic and myogenic differentiation, respectively. ASB2␣ is the specificity subunit of an E3 ubiquitin ligase complex that targets filamins to proteasomal degradation. To examine the relationship of the ASB2␣ structure to E3 ubiquitin ligase function, functional assays and molecular modeling were performed. We show that ASB2␣, through filamin A degradation, enhances adhesion of hematopoietic cells to fibronectin, the main ligand of ␤1 integrins. Furthermore, we demonstrate that a short N-terminal region specific to ASB2␣, together with ankyrin repeats 1 to 10, is necessary for association of ASB2␣ with filamin A. Importantly, the ASB2␣ N-terminal region comprises a 9-residue segment with predicted structural homology to the filamin-binding motifs of migfilin and ␤ integrins. Together, these data provide new insights into the molecular mechanisms of ASB2␣ binding to filamin.

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“…Certains complexes contiennent ainsi quatre domaines de liaison à l'ADN (deux dans RXRa et deux dans RARa) permettant alors d'expliquer la coopération dans la liaison à l'ADN : les domaines non fixés sur les motifs AGGTCA peuvent contribuer à la stabilisation du complexe via des interactions à l'ADN non spécifiques des séquences ( Figure 3A). Plusieurs études ont montré que la liaison de l'hétérocomplexe PML-RARa:RXRa n'a plus de préférence de structure ou d'orientation au niveau des répétitions AGGTCA : la fixation de PML-RARa a ainsi été observée dans des cellules de LAP humaines sur des répétitions directes espacées de 1 à 20 nucléotides mais aussi sur des répéti-tions inversées ou reversées aussi bien in vitro que in vivo [9,21,22]. En modifiant les propriétés de liaison à l'ADN du complexe sur …”

Section: Rxr Et La Leucémie Aiguë Promyélocytaireunclassified

“…Cette sumoylation, ainsi que d'autres modifications post-traductionnelles (notamment des phosphorylations ou acétylations), pourraient influencer le rôle de RXRa dans la répression et/ou l'activation basale des gènes cibles de PML-RARa [17]. Enfin, le traitement par l'AR des LAP entraîne in vivo la perte de l'ancrage de PML-RARa et RXRa sur les gènes cibles ainsi que leur dégradation [21,25], en parallèle de l'activation de ces gènes. [26].…”

Section: Revuesunclassified

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RXR, un cofacteur essentiel à la transformation dans les leucémies aiguës promyélocytaires

Halftermeyer

Bras

2011

Med Sci (Paris)

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PML-RARα/RXR Alters the Epigenetic Landscape in Acute Promyelocytic Leukemia

Cited by 278 publications

References 61 publications

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Temporal uncoupling of the DNA methylome and transcriptional repression during embryogenesis

Functional and Structural Insights into ASB2α, a Novel Regulator of Integrin-dependent Adhesion of Hematopoietic Cells

RXR, un cofacteur essentiel à la transformation dans les leucémies aiguës promyélocytaires

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