Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis

Kanki, Yasuharu; Matsushima, Masashi; Miyamura, Yuri; Kikuchi, Kenta; Higashijima, Yoshiki; Nakaki, Ryo; Suehiro, Jun-ichi; Sasaki, Y.; Kubota, Yoshiaki; Koseki, Haruhiko; Morioka, Hiroshi; Kodama, Tatsuhiko; Nakao, Mitsuyoshi; Kurotaki, Daisuke; Aburatani, Hiroyuki; Minami, Takashi

doi:10.1016/j.celrep.2022.110332

Cited by 12 publications

(13 citation statements)

References 50 publications

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“…VEGF mediates immediate (within 1 h) gene responses on a genome-wide scale. 26 NFAT and the downstream early growth response factor transactivate early angiogenic or inflammatory responses in ECs. 27 In contrast, FOXO1 mainly regulates expression of late response proteins in VEGF-treated ECs.…”

Section: Resultsmentioning

confidence: 99%

FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

Miyamura,

Kamei,

Matsuo

et al. 2024

iScience

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Section: Resultsmentioning

confidence: 99%

FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

Miyamura,

Kamei,

Matsuo

et al. 2024

iScience

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“…It is unclear why Apold1 does not affect developmental angiogenesis while strongly restricting angiogenesis in several pathological settings. We showed that Apold1 expression is activated by VEGF, which is known to activate an immediate early gene response [62], as well as by hypoxia. A previous RNAseq screen already identified Apold1 to be part of a HIF-dependent angiogenic response downstream of YAP/TAZ in bone ECs [53].…”

Section: Discussionmentioning

confidence: 93%

The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions

Fan

Ardicoglu

Batavia

et al. 2022

Preprint

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The molecular mechanisms of angiogenesis have been intensely studied, but many genes that control endothelial behavior and fate still need to be described. Here, we characterize the role of Apold1 (Apolipoprotein L domain containing 1) in angiogenesis in vivo and in vitro. Single-cell analyses reveal that - across tissues - the expression of Apold1 is restricted to the vasculature, and that Apold1 expression in endothelial cells (ECs) is highly sensitive to environmental factors. Using Apold1-/- mice, we find that Apold1 is dispensable for development and does not affect postnatal retinal angiogenesis nor alters the vascular network in adult brain and muscle. However, when exposed to ischemic conditions following photothrombotic stroke as well as femoral artery ligation, Apold1-/- mice display dramatic impairments in recovery and revascularization. We also find that human tumor endothelial cells express strikingly higher levels of Apold1, and that Apold1 deletion in mice stunts the growth of subcutaneous B16 melanoma tumors, which have smaller and poorly perfused vessels. Mechanistically, Apold1 is activated in ECs upon growth factor stimulation as well as in hypoxia, and Apold1 intrinsically controls EC proliferation but not migration. Our data demonstrate that Apold1 is a key regulator of angiogenesis in pathological settings, whereas it does not affect developmental angiogenesis, thus making it a promising candidate for clinical investigation.

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“…Transient induction of immediate- early genes by vascular endothelial cell growth factor in human umbilical vein endothelial cells occurs through the activation of their bivalent (H3K4me3 and H3K27me3 positive [(90)]) promoters whilst H3K27me3 is maintained and EZH2 accumulates at the promoter. cPRC1 then deposits H2AK119ub1, coinciding with the reduction in gene expression (91). The sense-strand promoter shares several functional features with immediate-early genes, including bivalent promoter histone marks (26; 28; 29), independence from de novo protein synthesis for reactivation (27) and responsiveness to p38-MAPK signaling (27).…”

Section: Discussionmentioning

confidence: 99%

“…The sense-strand promoter shares several functional features with immediate-early genes, including bivalent promoter histone marks (26; 28; 29), independence from de novo protein synthesis for reactivation (27) and responsiveness to p38-MAPK signaling (27). Whilst it is tempting to draw parallels between these systems, the immediate-early gene response studied by (91) is far more short- lived ( < 4 hrs. ), with transcript levels falling by 60 minutes post-stimulation.…”

Section: Discussionmentioning

confidence: 99%

The transcriptome of HTLV-1-infected primary cells following reactivation reveals changes to host gene expression central to the proviral life cycle

Aristodemou

Rueda

Taylor

et al. 2023

Preprint

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Infections by Human T cell Leukaemia Virus type 1 (HTLV-1) persist for the lifetime of the host by integrating into the genome of CD4+ T cells. Proviral gene expression is core to proviral survival and the maintenance of the proviral load, through the pro-proliferative changes it induces in infected cells. Despite their role in HTLV-1 infection and a persistent cytotoxic T lymphocyte response raised against them, proviral transcripts from the sense-strand are rarely detected in fresh cells extracted from the peripheral blood, and have recently been found to be expressed intermittently by a small subset of cells at a given time. Ex vivo culture of infected cells prompts synchronised proviral expression in infected cells from peripheral blood, allowing the study of factors involved in reactivation in primary cells. Here, we used bulk RNA-seq to examine the host transcriptome over six days in vitro, following proviral reactivation in primary peripheral CD4+ T cells isolated from subjects with non-malignant HTLV-1 infection. Infected cells displayed a conserved response to reactivation, characterised by discrete stages of gene expression, cell division and subsequently horizontal transmission of the virus. We observed widespread changes in Polycomb gene expression following reactivation, including an increase in PRC2 transcript levels and diverse changes in the expression of PRC1 components. We hypothesize that these transcriptional changes constitute a negative feedback loop that maintains proviral latency by re-deposition of H2AK119ub1 following the end of proviral expression. Using RNAi, we found that certain deubiquitinases, BAP1, USP14 and OTUD5 each promote proviral transcription. These data demonstrate the detailed trajectory of HTLV-1 proviral reactivation in primary HTLV-1-carrier lymphocytes and the impact on the host cell.

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Bivalent-histone-marked immediate-early gene regulation is vital for VEGF-responsive angiogenesis

Cited by 12 publications

References 50 publications

FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

FOXO1 stimulates tip cell-enriched gene expression in endothelial cells

The vascular gene Apold1 is dispensable for normal development but controls angiogenesis under pathological conditions

The transcriptome of HTLV-1-infected primary cells following reactivation reveals changes to host gene expression central to the proviral life cycle

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