The bHLH TAL-1/SCL regulates endothelial cell migration and morphogenesis

Lazrak, Monia; Deleuze, Virginie; Noël, Danièle; Haouzi, D.; Chalhoub, Elias; Dohet, Christiane; Robbins, Ian; Mathieu, D

doi:10.1242/jcs.00969

Cited by 40 publications

(43 citation statements)

References 52 publications

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“…5D). Consistent with the G9a mutant labyrinth phenotype, positive regulators of endothelial cell migration and proliferation, including TAL BHLH transcription factor 1 (Tal1) (Lazrak et al, 2004), mouse double minute 2 homolog (Mdm2) (Secchiero et al, 2007) and glutathione peroxidase 1 (Gpx1) (Galasso et al, 2006), were decreased in the G9a mutant labyrinth. Thus, G9a controls the transcriptional switch from the development phase to the maturation phase.…”

Section: G9a Controls the Balance Of Endothelial And Trophoblast Prolmentioning

confidence: 80%

Ehmt2/G9a controls placental vascular maturation by activating the Notch pathway

et al. 2017

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Defective fetoplacental vascular maturation causes intrauterine growth restriction (IUGR). A transcriptional switch initiates placental maturation where blood vessels elongate. However, cellular mechanisms and regulatory pathways involved are unknown. We show that the histone methyltransferase Ehmt2, also known as G9a, activates the Notch pathway to promote placental vascular maturation. Placental vasculature from embryos with G9a-deficient endothelial progenitor cells failed to expand due to decreased endothelial cell proliferation and increased trophoblast proliferation. Moreover, G9a deficiency altered the transcriptional switch initiating placental maturation and caused downregulation of Notch pathway effectors including Rbpj. Importantly, Notch pathway activation in G9a-deficient endothelial progenitors extended embryonic life and rescued placental vascular expansion. Thus, G9a activates the Notch pathway to balance endothelial cell and trophoblast proliferation and coordinates the transcriptional switch controlling placental vascular maturation. Accordingly, G9A and RBPJ were downregulated in human placentae from IUGR-affected pregnancies, suggesting that G9a is an important regulator in placental diseases caused by defective vascular maturation.

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Section: G9a Controls the Balance Of Endothelial And Trophoblast Prolmentioning

confidence: 80%

Ehmt2/G9a controls placental vascular maturation by activating the Notch pathway

et al. 2017

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“…With our assay system, following attachment to the Matrigel, ECs start to gradually form networks with each other, resulting in capillary-like structures (data not shown). The expression of TAL-1/SCL, another HLH factor involved in angiogenesis, was reported to be up-regulated during the formation of these capillary-like structures (29). Thus, we initially evaluated the expression levels of Id1 in HUVECs on Matrigel.…”

Section: Id1 Localization Is Predominantly Cytoplasmic In Vascularmentioning

confidence: 99%

Protein Kinase A-regulated Nucleocytoplasmic Shuttling of Id1 during Angiogenesis

Nishiyama

Takaji

Uchijima

et al. 2007

Journal of Biological Chemistry

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Id1, an inhibitory partner of basic-helix-loop-helix transcriptional factors, has recently been recognized as a potent contributor to angiogenesis. However, the molecular mechanism underlying its role in angiogenesis remains essentially unknown. Herein we demonstrate the subcellular localization of Id1 to be altered depending on the cellular context of vascular endothelial cells. Id1 was localized in the nuclei of human umbilical vein endothelial cells (HUVECs) cultured on uncoated plates, whereas it was translocated to the cytoplasm in HUVECs on Matrigel along with the formation of capillary-like structures. Treatment with the nuclear export inhibitor leptomycin B and mutagenesis analysis using green fluorescent protein-fused Id1 revealed CRM1/exportin-dependent nuclear export of Id1 in HUVECs on Matrigel. This nuclear export of Id1 was inhibited by protein kinase A (PKA) activation by dibutyryl cyclic AMP and forskolin but was promoted by PKA inactivation by H-89 and MDL-12,330A. Mutagenesis analysis of Id1 showed the phosphorylation of Ser-5 to possibly mediate the effect of PKA. These results suggest the function of Id1 as a transcriptional factor to be controlled by nucleocytoplasmic shuttling during angiogenesis and that PKA might be involved in this process. This may serve as a novel mechanism regulating angiogenesis and as a possible target for therapeutic vascular regeneration.

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“…The RNAi sequence against TAL1 (nt 879-897) was described in Lazrak et al 25 Both sequences were cloned into the BglII/HindIII sites of the pSuperior (Oligoengine, Seattle, WA) retroviral vector.…”

Section: Rnai Constructsmentioning

confidence: 99%

Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia

Palomero

Odom

O’Neil

et al. 2006

Blood

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Aberrant expression of 1 or more transcription factor oncogenes is a critical component of the molecular pathogenesis of human T-cell acute lymphoblastic leukemia (T-ALL); however, oncogenic transcriptional programs downstream of T-ALL oncogenes are mostly unknown. TAL1/SCL is a basic helix-loop-helix (bHLH) transcription factor oncogene aberrantly expressed in 60% of human TALLs. We used chromatin immunoprecipitation (ChIP) on chip to identify 71 direct transcriptional targets of TAL1/SCL. Promoters occupied by TAL1 were also frequently bound by the class I bHLH proteins E2A and HEB, suggesting that TAL1/ E2A as well as TAL1/HEB heterodimers play a role in transformation of T-cell precursors. Using RNA interference, we demonstrated that TAL1 is required for the maintenance of the leukemic phenotype in Jurkat cells and showed that TAL1 binding can be associated with either repression or activation of genes whose promoters occupied by TAL1, E2A, and HEB. In addition, oligonucleotide microarray analysis of RNA from 47 primary T-ALL samples showed specific expression signatures involving TAL1 targets in TAL1-expressing compared with -nonexpressing human T-ALLs. Our results indicate that TAL1 may act as a bifunctional transcriptional regulator (activator and repressor) at the top of a complex regulatory network that disrupts normal T-cell homeostasis and contributes to leukemogenesis. IntroductionTAL1/SCL (hereafter referred to as TAL1) is a basic helix-loophelix (bHLH) transcription factor that is required for normal hematopoiesis, 1,2 and whose aberrant expression leads to T-cell acute lymphoblastic leukemia (T-ALL). TAL1 is expressed by the leukemic cells of 60% of patients with T-ALL 3,4 as a result of chromosomal translocations or intrachromosomal rearrangements leading to its monoallelic expression, as well as by unknown mechanisms leading to biallelic up-regulation in double-positive thymocytes. 5,6 According to the prevailing model of TAL1-induced leukemogenesis, TAL1 acts as a transcriptional repressor through heterodimerization with E2A and HEB, leading to a block of the transcriptional activity of these class-I bHLH factors. [7][8][9][10][11][12] However, transcriptional activation of the RALDH2 gene by TAL1 has also been described suggesting a more complex effect on gene regulation. 13 Despite the importance of transcriptional programs downstream of TAL1, the collection of genes directly regulated by TAL1 is mostly unknown. Although TAL1 targets have been reported in the context of early hematopoietic development (KIT), 14 red-cell differentiation (GPA and P4.2), 15,16 T-cell development (pTA is a likely target of TAL1), [17][18][19] or leukemia (RALDH2), 13 none of them has elucidated the regulatory roles that TAL1 plays in the pathogenesis of T-ALL. The identification of a more comprehensive set of genes regulated by TAL1 will lead to improved understanding of the transcriptional role of TAL1 and its regulation circuits that control cell proliferation, differentiation, and apoptosis during T-cell deve...

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The bHLH TAL-1/SCL regulates endothelial cell migration and morphogenesis

Cited by 40 publications

References 52 publications

Ehmt2/G9a controls placental vascular maturation by activating the Notch pathway

Ehmt2/G9a controls placental vascular maturation by activating the Notch pathway

Protein Kinase A-regulated Nucleocytoplasmic Shuttling of Id1 during Angiogenesis

Transcriptional regulatory networks downstream of TAL1/SCL in T-cell acute lymphoblastic leukemia

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