Genome-wide mapping of H3K79me2 in EPZ5676-treated lymphatic endothelial cells [ChIP-Seq]
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE104809 | GEO | 2018/10/10
REPOSITORIES: GEO
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Project description:Proper functioning of the lymphatic system is required for normal immune response, fluid balance and lipid reabsorption. Multiple regulatory mechanisms are employed to ensure correct formation of lymphatic vessels; however, whether epigenetic regulation is involved in this process remains largely unknown. We report that epigenetic priming by the Disruptor of telomeric silencing 1-like (DOT1L) in endothelial cell (EC) is indispensable for generation and function of lymphatic endothelial cells (LECs). Mechanistically, loss function of DOT1L leads to reduction of H3K79 di-methylation and expression of the genes important for LEC development and function. Thus, our study establishes DOT1L-mediated transcriptional regulation in ECs plays an important role in differentiation and function of LECs.
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Project description:To observe the global changes in the lymphatic endothelial cells upon exposure to filarial antigens or parasites, LECs were stimulated for 24, 48, and 72hrs and the expression profiles were carried out. Human filarial parasites Brugia malayi and Wuchereria bancrofti habitat the lymphatics and cause lymphatic dilatation and lymphedema. In order to evaluate the effect of various stage specific effects on the lymphatic endothelial cells (LEC) and understand how they modulate the lymphatic dysfunction, LECs were stimulated in antigens derived from the Brugia malayi. These are preliminary time course data towards understanding how the filarial antigens induce lymphangiogenesis.
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Project description:Epigenetic mechanisms are mandatory for endothelial cells (ECs) during cardiovascular development. Dot1l-mediated gene transcription in mice is essential for development and function of lymphatic ECs (LECs). The role of Dot1l in development and function of blood ECs (BECs) is unclear. RNA-seq datasets from Dot1l-depleted or -overexpressing BECs and LECs were used to comprehensively analyze regulatory networks of gene transcription and pathways. Dot1l depletion in BECs changed the expression of genes involving cell-to-cell adhesion and immunity-related biological processes. Dot1l overexpression changed the expression of genes involved in different types of cell-to-cell adhesion and angiogenesis-related biological processes. Genes involved in specific tissue development-related biological pathways were altered in Dot1l-depleted BECs and LECs. Vascular endothelial growth factor production-related genes were specifically regulated in BECs by Dot1l. Dot1l overexpression uniquely altered ion transportation-related genes in BECs and immune response regulation-related genes in LECs. Importantly, Dot1l overexpression in BECs led to expression of many genes related to the angiogenesis and mitogen-activated protein kinase signaling pathways. The expression of these genes was unchanged in Dot1l-overexpressing LECs. The findings demonstrate the unique transcriptomic program of ECs and the differential functions of Dot1l in the regulation of gene transcription in BECs and LECs.
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Project description:<p>Breast cancer metastasis occurs via blood and lymphatic vessels. Breast cancer cells 'educate' lymphatic endothelial cells (LECs) to support tumor vascularization and growth. However, despite known metabolic alterations in breast cancer, it remains unclear how lymphatic endothelial cell metabolism is altered in the tumor microenvironment and its effect in lymphangiogenic signaling in LECs. We analyzed metabolites inside LECs in co-culture with MCF-7, MDA-MB-231, and SK-BR-3 breast cancer cell lines using 1H nuclear magnetic resonance (NMR) metabolomics, Seahorse, and the spatial distribution of metabolic co-enzymes using optical redox ratio imaging to describe breast cancer-LEC metabolic crosstalk. LECs co-cultured with breast cancer cells exhibited cell-line dependent altered metabolic profiles, including significant changes in lactate concentration in breast cancer co-culture. Cell metabolic phenotype analysis using Seahorse showed LECs in co-culture exhibited reduced mitochondrial respiration, increased reliance on glycolysis and reduced metabolic flexibility. Optical redox ratio measurements revealed reduced NAD(P)H levels in LECs potentially due to increased NAD(P)H utilization to maintain redox homeostasis. 13C-labeled glucose experiments did not reveal lactate shuttling into LECs from breast cancer cells, yet showed other 13C signals in LECs suggesting internalized metabolites and metabolic exchange between the two cell types. We also determined that breast cancer co-culture stimulated lymphangiogenic signaling in LECs, yet activation was not stimulated by lactate alone. Increased lymphangiogenic signaling suggests paracrine signaling between LECs and breast cancer cells which could have a pro-metastatic role.</p>
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Project description:Tissue lymphatic vessels network plays critical roles in immune surveillance and tissue homeostasis in response to pathogen invasion, but how lymphatic system per se is remolded during infection is less understood. Here, we observed that influenza infection induces a significant increase of lymphatic vessel numbers in the lung, accompanied with extensive proliferation of lymphatic endothelial cells (LECs). Single-cell RNA sequencing illustrated the heterogeneity of LECs, identifying a novel PD-L1+ subpopulation that is present during viral infection but not at steady state. Specific deletion of Pd-l1 in LECs elevated the expansion of lymphatic vessel numbers during viral infection. Together these findings elucidate a dramatic expansion of lung lymphatic network in response to viral infection, and reveal a PD-L1+ LEC subpopulation that potentially modulates lymphatic vessel remolding.
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