Temporal changes in Hox gene expression accompany endothelial cell differentiation of embryonic stem cells

Bahrami, Sajad; Veiseh, Mandana; Dunn, Ashley A.; Boudreau, Nancy

doi:10.4161/cam.5.2.14373

Cited by 23 publications

(20 citation statements)

References 54 publications

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“…Our predictive network and KDA found 7 possible regulators of variability (GATA4, GATA6, EOMES, APOA2, LINC00261 (DEANR1), FOXQ1 and CER1) in iPSCs and 2 possible regulators ( HOXA5 and HOXC10 ) of endothelial differentiation efficiency (Bahrami et al, 2011; Rhoads et al, 2005). Surprisingly, many of the key drivers are strongly associated with early stages of mesendodermal development.…”

Section: Discussionmentioning

confidence: 94%

Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity

et al. 2017

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SUMMARY Variability in induced pluripotent stem cell (iPSC) lines remains a concern for disease modeling and regenerative medicine. We have used RNA sequencing analysis and linear mixed models to examine the sources of gene expression variability in 317 human iPSC lines from 101 individuals. We found that ~50% of genome-wide expression variability is explained by variation across individuals and identified a set of expression quantitative trait loci that contribute to this variation. These analyses coupled with allele specific expression show that iPSCs retain a donor specific gene expression pattern. Network, pathway and key driver analyses showed that Polycomb targets contribute significantly to the non-genetic variability seen within and across individuals, highlighting this chromatin regulator as a likely source of reprogramming-based variability. Our findings therefore shed light on variation between iPSC lines and illustrate the potential for our dataset and other similar large-scale analyses to identify underlying drivers relevant to iPSC applications.

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Section: Discussionmentioning

confidence: 94%

Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity

et al. 2017

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“…HOX proteins, characterized by the presence of a unique 60-amino-acid highly conserved DNA-binding homeodomain, bind to specific DNA sequences in the promoter regions to regulate target gene expression (31). Importantly, they play a regulatory role in EC function, including differentiation from embryonic stem cells (3), EC maturation and vascular development from mesoderm-derived precursor cells (23,66), proliferation, migration, and angiogenesis (9,10,12,13,39,51). Recently, the pursuit of HOXA9 in EC gene regulation has led to the recognition of important new concepts (4,8,44,53,63).…”

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confidence: 99%

HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules

Bandyopadhyay

Harris

Adams

et al. 2012

Molecular and Cellular Biology

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The induction of proinflammatory proteins in stimulated endothelial cells (EC) requires activation of multiple transcription programs. The homeobox transcription factor HOXA9 has an important regulatory role in cytokine induction of the EC-leukocyte adhesion molecules (ELAM) E-selectin and vascular cell adhesion molecule 1 (VCAM-1). However, the mechanism underlying stimulus-dependent activation of HOXA9 is completely unknown. Here, we elucidate the molecular mechanism of HOXA9 activation by tumor necrosis factor alpha (TNF-␣) and show an unexpected requirement for arginine methylation by protein arginine methyltransferase 5 (PRMT5). PRMT5 was identified as a TNF-␣-dependent binding partner of HOXA9 by mass spectrometry. Small interfering RNA (siRNA)-mediated depletion of PRMT5 abrogated stimulus-dependent HOXA9 methylation with concomitant loss in E-selectin or VCAM-1 induction. Chromatin immunoprecipitation analysis revealed that PRMT5 is recruited to the E-selectin promoter following transient HOXA9 binding to its cognate recognition sequence. PRMT5 induces symmetric dimethylation of Arg140 on HOXA9, an event essential for E-selectin induction. In summary, PRMT5 is a critical coactivator component in a newly defined, HOXA9-containing transcription complex. Moreover, stimulus-dependent methylation of HOXA9 is essential for ELAM expression during the EC inflammatory response.

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“…HOX transcriptional factors, master regulators of body patterning (40) have been reported to specify positional identities in arterial blood vessels (41,42). The HOX genes regulate endothelial cell proliferation, migration, differentiation, morphogenesis and permeability during development and vascular remodeling in adults.…”

Section: Endothelial Dna Methylation and Arterial Hemodynamicsmentioning

confidence: 99%

“…The HOX genes regulate endothelial cell proliferation, migration, differentiation, morphogenesis and permeability during development and vascular remodeling in adults. HOXA3/9, HOXB3/5 and HOXD3 regulate endothelial cell activation, whereas HOXA5 and HOXD10 sustain quiescent endothelial phenotype (41,43,44). HOXA3 and HOXD3, which promote a proliferative and migrative phenotype, are induced in early phase of endothelial differentiation; HOXA5 and HOXD10, which maintain a quiescent EC phenotype, are increased during the maturation of endothelial cells (41).…”

Section: Endothelial Dna Methylation and Arterial Hemodynamicsmentioning

confidence: 99%

“…HOXA3/9, HOXB3/5 and HOXD3 regulate endothelial cell activation, whereas HOXA5 and HOXD10 sustain quiescent endothelial phenotype (41,43,44). HOXA3 and HOXD3, which promote a proliferative and migrative phenotype, are induced in early phase of endothelial differentiation; HOXA5 and HOXD10, which maintain a quiescent EC phenotype, are increased during the maturation of endothelial cells (41). A link between DMR and HoxA5 gene expression in vivo was reported by Dunn et al (31) who studied DNA methylation patterns in endothelium harvested from apoE -/- mice carotid artery.…”

Section: Endothelial Dna Methylation and Arterial Hemodynamicsmentioning

confidence: 99%

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Emerging topic: Flow-related epigenetic regulation of endothelial phenotype through DNA methylation

Davies¹,

Manduchi²,

Stoeckert³

et al. 2014

Vascular Pharmacology

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Atherosclerosis is a multi-focal disease; it is associated with arterial curvatures, asymmetries and branches/bifurcations where non-uniform arterial geometry generates patterns of blood flow that are considerably more complex than elsewhere, and are collectively referred to as disturbed flow. Such regions are predisposed to atherosclerosis and are the sites of ‘athero-susceptible’ endothelial cells that express regionally different cell phenotypes than endothelium in nearby athero-protected locations. The regulatory hierarchy of endothelial function includes control at the epigenetic level. MicroRNAs and histone modifications are established epigenetic regulators that respond to disturbed flow. However, very recent reports have linked transcriptional regulation by DNA methylation to endothelial gene expression in disturbed flow in vivo and in vitro. We outline these in the context of site-specific atherosusceptibility mediated by local hemodynamics.

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Temporal changes in Hox gene expression accompany endothelial cell differentiation of embryonic stem cells

Cited by 23 publications

References 54 publications

Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity

Analysis of Transcriptional Variability in a Large Human iPSC Library Reveals Genetic and Non-genetic Determinants of Heterogeneity

HOXA9 Methylation by PRMT5 Is Essential for Endothelial Cell Expression of Leukocyte Adhesion Molecules

Emerging topic: Flow-related epigenetic regulation of endothelial phenotype through DNA methylation

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