Molecular Determinants of <i>NOTCH4</i> Transcription in Vascular Endothelium

Wu, Jing; Iwata, Fumiko; Grass, Jeffrey A.; Osborne, Cameron S.; Elnitski, Laura; Fraser, Peter; Onodera, Osamu; Yamamoto, Masayuki; Bresnick, Emery H.

doi:10.1128/mcb.25.4.1458-1474.2005

Cited by 64 publications

(67 citation statements)

References 124 publications

(101 reference statements)

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“…Previous studies into the transcriptional regulation of the Notch receptors have not extended to the identification or analysis of gene enhancers (cis-regulatory elements) (Corada et al, 2013;Lizama et al, 2015;Wu et al, 2005). We therefore conducted a detailed in silico analysis of the NOTCH1 locus with the aim of identifying novel, arterial-specific enhancers.…”

Section: Identification Of An Arterial-specific Notch1 Intronic Enhancermentioning

confidence: 99%

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

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Arterial specification and differentiation are influenced by a number of regulatory pathways. While it is known that the Vegfa-Notch cascade plays a central role in this biological process, the transcriptional hierarchy controlling arterial specification has not been fully delineated. To elucidate the direct transcriptional regulators of Notch receptor expression in arterial endothelial cells, we used histone signatures, DNaseI hypersensitivity and ChIP-seq data to identify enhancers for the human NOTCH1 and zebrafish notch1b genes. These enhancers were able to direct arterial endothelial cell-restricted expression in transgenic models. Genetic disruption of SOXF binding sites clearly established a requirement for members of the SOXF group of transcription factors (SOX7,-17 and-18) to drive these enhancers activity in vivo. Further, endogenous deletion of the notch1b enhancer led to a significant augmentation of arterio-venous defects in notch-pathway deficient zebrafish. Loss of SoxF function revealed that these factors are necessary for the activity of NOTCH1 and notch1b enhancers, and for correct endogenous Notch1 gene transcription. These findings therefore position SOXF transcription factors directly upstream of Notch receptor expression during the acquisition of arterial identity in vertebrates.

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Section: Identification Of An Arterial-specific Notch1 Intronic Enhancermentioning

confidence: 99%

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

et al. 2017

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“…33 Interestingly, the genetic region encoding for the vascular remodelling factor Notch 4 is characterized by an endothelial cell-specific histone H3 K4 methylation pattern. 42 Thus, other homeodomain or nonhomeodomain transcription factors beyond those investigated could mediate MLL-dependent endothelial sprout formation, possibly in a complex regulatory network that might well involve more than one single downstream target of MLL.…”

Section: Discussionmentioning

confidence: 95%

The histone methyltransferase MLL is an upstream regulator of endothelial-cell sprout formation

Diehl

Rössig

Zeiher

et al. 2006

Blood

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Posttranslational histone modification by acetylation or methylation regulates gene expression. Here, we investigated the role of the histone lysine methyltransferase MLL for angiogenic functions in human umbilical vein endothelial cells. Suppression of MLL expression by siRNA or incubation with the pharmacologic methyltransferase inhibitor 5-deoxy-5-(methylthio)adenosine significantly decreased endothelial-cell migration and capillary sprout formation, indicating that methyltransferase activity is required for proangiogenic endothelialcell functions. Because the expression of homeodomain transcription factors (Hox) is regulated by MLL, we elucidated the role of Hox gene expression. MLL silencing was associated with reduced mRNA and protein expression of HoxA9 and HoxD3, whereas HoxB3, HoxB4, HoxB5, and HoxB9 were not altered. Overexpression of HoxA9 or HoxD3 partially compensated for impaired migration in MLL siRNA-transfected endothelial cells, suggesting that HoxA9 and HoxD3 both contribute to MLL-dependent migration. As a potential underlying mechanism, MLL siRNA down-regulated mRNA and protein levels of the HoxA9-dependent axon guidance factor EphB4. In contrast, MLL knockdown effects on capillary sprouting were not rescued by HoxA9 or HoxD3 overexpression, indicating that MLL affects additional targets required for 3-dimensional sprout formation. IntroductionMLL (mixed lineage leukemia, ALL-1, HRX) is a chromatin regulator homolog to the Drosophila trithorax gene. 1-3 MLL was originally discovered by its involvement in human acute leukemia through chromosomal translocation and fusion to a variety of genes. 4 MLL fusion proteins were shown to cause myeloid progenitor immortalization by inducing a characteristic expression profile of homeobox (Hox) transcription factors. 5,6 Physiologically, the SET domain of MLL catalyzes the methylation of lysine 4 of histone H3, thereby regulating gene expression. 7,8 In particular, native MLL is essential for the epigenetic control of gene expression of a set of homeobox proteins HoxA7, HoxA9, and HoxA10 during ex vivo differentiation of embryonic stem cells 9 and for physiologic hematopoiesis. 10-12 MLL Ϫ/Ϫ mice die around dpc 10.5 with aberrant rostrocaudal segmentation, 13 or, in a different model targeting exons 12 to 14, at dpc 11.5 to 14.5 with edematous bodies and petechiae. 12 Beyond segmental identity and hematopoiesis, MLL is crucial for the maintenance of helper T-lymphocyte function. 14 As yet, however, a function of MLL in postnatal angiogenesis has not been explored.Hox transcription factors play important roles during embryonic development of the cardiovascular system. [15][16][17] Certain members of the Hox family also regulate postnatal angiogenesis and endothelialcell adhesion and migration. HoxD3 promotes endothelial invasion and migration 18 and converts resting endothelium to an angiogenic phenotype by inducing proangiogenic genes including the integrin subunits ␣5 and ␤3. 19 HoxB3 is required for capillary morphogenesis of preformed vascular sprout...

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“…Notch-4 expression in normal tissues is more restricted than Notch-1 expression. Published data suggest that it is limited to the vascular endothelium [36,37], epidermis [38], and ovarian blood vessels during folliculogenesis [39].…”

Section: What Pharmacological Tools Do We Have At Our Disposal?mentioning

confidence: 99%

Rational targeting of Notch signaling in breast cancer

Miele¹

2008

Expert Review of Anticancer Therapy

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Molecular Determinants of NOTCH4 Transcription in Vascular Endothelium

Cited by 64 publications

References 124 publications

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

SoxF factors induce Notch1 expression via direct transcriptional regulation during early arterial development

The histone methyltransferase MLL is an upstream regulator of endothelial-cell sprout formation

Rational targeting of Notch signaling in breast cancer

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