1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development

Wang, Ting; Wang, Zheng; Fabritus, Lauriane de; Tao, Jinglian; Saied, Essa M.; Lee, Ho‐Joon; Ramazanov, Bulat; Jackson, Benjamin C.; Burkhardt, Daniel; Parker, Mikhail; Gleinich, Anne; Wang, Zhirui; Seo, Dong Eun; Zhou, Ting; Xu, Shihao; Alecu, Irina; Azadi, Parastoo; Hornemann, Thorsten; Krishnaswamy, Smita; Pavert, Serge A. van de; Kaech, Susan M.; Ivanovа, Natalia; Santori, Fabio R.

doi:10.1016/j.devcel.2021.10.018

Cited by 8 publications

(3 citation statements)

References 110 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Melanocytes that serve as precursor for nevi cells for uveal melanoma initiation originates from neural crest cells 65,66 . NR2F1 a nuclear receptor with only recently identified putative ligands (e.g., sphingolipids) 67 , is a critical regulator of this lineage program and serve a pivotal role in cortical pattering during eye morphogenesis 44,68,69 . Our data identified that among neural crest lineage genes, OMM1.3-QR + dormant UM DCCs upregulate NR2F1 expression, previously linked to dormancy in breast, head and neck squamous, and prostate cancer DCC models 58,70 .…”

Section: Discussionmentioning

confidence: 99%

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Kadamb,

Anton,

Purwin

et al. 2024

Preprint

View full text Add to dashboard Cite

The mechanisms driving late relapse in uveal melanoma (UM) patients remains a medical mystery and major challenge. Clinically it is inferred that UM disseminated cancer cells (DCCs) persist asymptomatic for years-to-decades mainly in the liver before they manifest as symptomatic metastasis. Here we reveal using Gαq/11mut/BAPwt human uveal melanoma models and human UM metastatic samples, that the neural crest lineage commitment nuclear receptor NR2F1 is a key regulator of spontaneous UM DCC dormancy in the liver. Using a quiescence reporter, RNA-seq and multiplex imaging we revealed that rare dormant UM DCCs upregulate NR2F1 expression and genes related to neural crest programs while repressing gene related to cell cycle progression. Gain and loss of function assays showed that NR2F1 silences YAP1/TEAD1 transcription downstream of Gαq/11 signaling and that NR2F1 expression can also be repressed by YAP1. YAP1 expression is repressed by NR2F1 binding to its promoter and changing the histone H3 tail activation marks to repress YAP1 transcription. In vivo CRISPR KO of NR2F1 led dormant UM DCCs to awaken and initiate relentless liver metastatic growth. Cut&Run and bulk RNA sequencing further confirmed that NR2F1 epigenetically stimulates neuron axon guidance and neural lineage programs, and it globally represses gene expression linked to G-protein signaling to drive dormancy. Pharmacological inhibition of Gαq/11mut signaling resulted in NR2F1 upregulation and robust UM growth arrest, which was also achieved using a novel NR2F1 agonist. Our work sheds light on the molecular underpinnings of UM dormancy revealing that transcriptional programs driven by NR2F1 epigenetically short-circuit Gαq/11 signaling to its downstream target YAP1.

show abstract

Section: Discussionmentioning

confidence: 99%

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Kadamb,

Anton,

Purwin

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Serine palmitoyltransferase long chain base subunit 2 (Sptlc2), the rate-limiting enzyme of sphingolipid biosynthesis, increases Coup-TFII transcriptional activity. EC-specific deletion of Sptlc2 in mice induces fetal nuchal edema with dilated dermal lymphatic vessels ( Wang et al, 2021 ). Polycystin is a cell surface receptor involved in cell-cell and cell-matrix interactions and is encoded by PKD1 and PKD2 , the genes responsible for autosomal dominant polycystic kidney disease ( Delmas, 2004 ).…”

Section: Defective Lymphatic Vascular Developmentmentioning

confidence: 99%

Fetal nuchal edema and developmental anomalies caused by gene mutations in mice

Sugiyama

Hirashima²

2022

Front. Cell Dev. Biol.

View full text Add to dashboard Cite

Fetal nuchal edema, a subcutaneous accumulation of extracellular fluid in the fetal neck, is detected as increased nuchal translucency (NT) by ultrasonography in the first trimester of pregnancy. It has been demonstrated that increased NT is associated with chromosomal anomalies and genetic syndromes accompanied with fetal malformations such as defective lymphatic vascular development, cardiac anomalies, anemia, and a wide range of other fetal anomalies. However, in many clinical cases of increased NT, causative genes, pathogenesis and prognosis have not been elucidated in humans. On the other hand, a large number of gene mutations have been reported to induce fetal nuchal edema in mouse models. Here, we review the relationship between the gene mutants causing fetal nuchal edema with defective lymphatic vascular development, cardiac anomalies, anemia and blood vascular endothelial barrier anomalies in mice. Moreover, we discuss how studies using gene mutant mouse models will be useful in developing diagnostic method and predicting prognosis.

show abstract

“…NR2F1 is now listed among the 10 top genes causally linked to rare hereditary optic neuropathies 21 . In addition, NR2F1 has recently been linked to Hirschsprung disease 22 and Waardenburg syndrome type IV 23 , as well as to the development of lymphoid and cardiac cells 24 , but its precise role in these disorders remains to be investigated.…”

Section: Introductionmentioning

confidence: 99%

Unravelling the conundrum of nucleolar NR2F1 localization: A comparative analysis of NR2F1 antibody-based approachesin vitroandin vivo

Bertacchi,

Theiß,

Ahmed

et al. 2024

Preprint

View full text Add to dashboard Cite

As a transcription factor,NR2F1regulates spatiotemporal gene expression during development and in adulthood. AberrantNR2F1causes a rare neurodevelopmental disorder known as Bosch-Boonstra- Schaaf Optic Atrophy Syndrome. In addition, alteredNR2F1expression is frequently observed in various cancers and is considered a prognostic marker or potential therapeutic target. In this context, NR2F1 has been shown to localize not only in the nucleus but also in the nucleoli, suggesting a novel non-canonical role in this compartment. Hence, we studied this phenomenon employing variousin vitroandin vivomodels in different antibody-dependent approaches. Examination of seven commonly used anti-NR2F1 antibodies in different human cancer and stem cells as well as in wild type and null mice revealed that the nucleolar localization of NR2F1 is artificial and does not play a functional role. Our subsequent comparative analysis demonstrated for the first time which anti-NR2F1 antibody best fits which approach. As our data allow for correct data interpretation, making them publicly available may have far-reaching implications for NR2F1 research in health and disease. More generally, the study also underlines the need to optimize any antibody-mediated technique.

show abstract

1-deoxysphingolipids bind to COUP-TF to modulate lymphatic and cardiac cell development

Cited by 8 publications

References 110 publications

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Lineage commitment pathways epigenetically oppose oncogenic Gαq/11-YAP signaling in dormant disseminated uveal melanoma

Fetal nuchal edema and developmental anomalies caused by gene mutations in mice

Unravelling the conundrum of nucleolar NR2F1 localization: A comparative analysis of NR2F1 antibody-based approachesin vitroandin vivo

Contact Info

Product

Resources

About