Project description:During embryonic development, the lymphatic system emerges by transdifferentiation from the cardinal vein. Although lymphatic and blood vasculature share a close molecular and developmental relationship, they display distinct features and functions. However, even after terminal differentiation, transitions between the two endothelial cell types have been reported. Since changes in phenotypic plasticity and cellular differentiation processes frequently involve epigenetic mechanisms, we wondered whether DNA methylation might play a role in regulating cell type-specific expression in endothelial cells. By analyzing global gene expression and methylation patterns of primary human dermal lymphatic and blood endothelial cells, we identified a highly significant set of genes, which were differentially methylated and expressed. Pathway analyses of the differentially methylated and upregulated genes in lymphatic endothelial cells revealed involvement in developmental and transdifferentiation processes. We further identified a set of novel genes, which might be implicated in regulating BEC-LEC plasticity and could serve as therapeutic targets and/or biomarkers in vascular diseases associated with alterations in the endothelial phenotype.
Project description:This SuperSeries is composed of the following subset Series: GSE32709: DNA methylation regulates lineage-specifying genes in the human vascular system [expression array]. GSE34486: DNA methylation regulates lineage-specifying genes in the human vascular system [methylation array]. Refer to individual Series
Project description:During embryonic development, the lymphatic system emerges by transdifferentiation from the cardinal vein. Although lymphatic and blood vasculature share a close molecular and developmental relationship, they display distinct features and functions. However, even after terminal differentiation, transitions between the two endothelial cell types have been reported. Since changes in phenotypic plasticity and cellular differentiation processes frequently involve epigenetic mechanisms, we wondered whether DNA methylation might play a role in regulating cell type-specific expression in endothelial cells. By analyzing global gene expression and methylation patterns of primary human dermal lymphatic and blood endothelial cells, we identified a highly significant set of genes, which were differentially methylated and expressed. Pathway analyses of the differentially methylated and upregulated genes in lymphatic endothelial cells revealed involvement in developmental and transdifferentiation processes. We further identified a set of novel genes, which might be implicated in regulating BEC-LEC plasticity and could serve as therapeutic targets and/or biomarkers in vascular diseases associated with alterations in the endothelial phenotype. Bisulphite converted DNA from the 16 samples were hybridised to the Illumina Infinium 450k Human Methylation Beadchip v1.1
Project description:During embryonic development, the lymphatic system emerges by transdifferentiation from the cardinal vein. Although lymphatic and blood vasculature share a close molecular and developmental relationship, they display distinct features and functions. However, even after terminal differentiation, transitions between the two endothelial cell types have been reported. Since changes in phenotypic plasticity and cellular differentiation processes frequently involve epigenetic mechanisms, we wondered whether DNA methylation might play a role in regulating cell type-specific expression in endothelial cells. By analyzing global gene expression and methylation patterns of primary human dermal lymphatic and blood endothelial cells, we identified a highly significant set of genes, which were differentially methylated and expressed. Pathway analyses of the differentially methylated and upregulated genes in lymphatic endothelial cells revealed involvement in developmental and transdifferentiation processes. We further identified a set of novel genes, which might be implicated in regulating BEC-LEC plasticity and could serve as therapeutic targets and/or biomarkers in vascular diseases associated with alterations in the endothelial phenotype. Expression profile of 10 lymphatic endothelial cells was compared to that of 6 blood endothelial cells, no replicates, no control samples.
Project description:During embryonic development, the lymphatic system emerges by transdifferentiation from the cardinal vein. Although lymphatic and blood vasculature share a close molecular and developmental relationship, they display distinct features and functions. However, even after terminal differentiation, transitions between the two endothelial cell types have been reported. Since changes in phenotypic plasticity and cellular differentiation processes frequently involve epigenetic mechanisms, we wondered whether DNA methylation might play a role in regulating cell type-specific expression in endothelial cells. By analyzing global gene expression and methylation patterns of primary human dermal lymphatic and blood endothelial cells, we identified a highly significant set of genes, which were differentially methylated and expressed. Pathway analyses of the differentially methylated and upregulated genes in lymphatic endothelial cells revealed involvement in developmental and transdifferentiation processes. We further identified a set of novel genes, which might be implicated in regulating BEC-LEC plasticity and could serve as therapeutic targets and/or biomarkers in vascular diseases associated with alterations in the endothelial phenotype.
Project description:DNA methylation regulates eukaryotic gene expression and is extensively reprogrammed during animal development. However, whether developmental methylation reprogramming during the sporophytic life cycle of flowering plants regulates genes is presently unknown. Here we report a distinctive gene-targeted RNA-directed DNA methylation (RdDM) activity in the Arabidopsis thaliana male sexual lineage that regulates gene expression in meiocytes. Loss of sexual-lineage-specific RdDM causes mis-splicing of the MPS1 gene (also known as PRD2), thereby disrupting meiosis. Our results establish a regulatory paradigm in which de novo methylation creates a cell-lineage-specific epigenetic signature that controls gene expression and contributes to cellular function in flowering plants.
Project description:We report a distinctive gene-targeted RNA-directed DNA methylation (RdDM) activity in the Arabidopsis thaliana male sexual lineage that regulates gene expression in meiocytes. Loss of sexual-lineage-specific RdDM causes mis-splicing of the MPS1 gene (also known as PRD2), thereby disrupting meiosis. Our results establish a regulatory paradigm in which de novo methylation creates a cell-lineage-specific epigenetic signature that controls gene expression and contributes to cellular function in flowering plants.
Project description:T-lineage committed precursor thymocytes are screened by a fate-determination process mediated via T cell receptor (TCR) signals for differentiation into distinct lineages. However, it remains unclear whether any antecedent event is required to couple TCR signals with the transcriptional program governing lineage decisions. Here we show that Bcl11b, known as a T-lineage commitment factor, is essential for proper expression of ThPOK and Runx3, central regulators for the CD4-helper/CD8-cytotoxic lineage choice. Loss of Bcl11b results in random expression of these factors and, thereby, lineage scrambling that is disconnected from TCR restriction by MHC. Initial Thpok repression by Bcl11b prior to the pre-selection stage is independent of a known silencer for Thpok, and requires the last zinc-finger motif in Bcl11b protein, which by contrast is dispensable for T-lineage commitment. Collectively, our findings shed new light on the function of Bcl11b in priming lineage-specifying genes to integrate TCR signals into subsequent transcriptional regulatory mechanisms.CD4 and CD8 T cells develop in the thymus with their transcription programs controlled by ThPOK and Runx3, respectively. Here the authors show that a pre-commitment event modulated by the transcription factor, Bcl11b, is required for the proper expression of ThPOK and Runx3 and correct CD4/CD8 lineage commitment.
Project description:During development, transcription factors select distinct gene programs, providing the necessary regulatory complexity for temporal and tissue-specific gene expression. How related factors retain specificity, especially when they recognize the same DNA motifs, is not understood. We address this paradox using basic helix-loop-helix (bHLH) transcription factors ASCL1, ASCL2, and MYOD1, crucial mediators of lineage specification. In vivo, these factors recognize the same DNA motifs, yet bind largely different genomic sites and regulate distinct transcriptional programs. This suggests that their ability to identify regulatory targets is defined either by the cellular environment of the partially defined lineages in which they are endogenously expressed, or by intrinsic properties of the factors themselves. To distinguish between these mechanisms, we directly compared the chromatin binding properties of this subset of bHLH factors when ectopically expressed in embryonic stem cells, presenting them with a common chromatin landscape and cellular components. We find that these factors retain distinct binding sites; thus, specificity of binding is an intrinsic property not requiring a restricted landscape or lineage-specific cofactors. Although the ASCL factors and MYOD1 have some distinct DNA motif preference, it is not sufficient to explain the extent of the differential binding. All three factors can bind inaccessible chromatin and induce changes in chromatin accessibility and H3K27ac. A reiterated pattern of DNA binding motifs is uniquely enriched in inaccessible chromatin at sites bound by these bHLH factors. These combined properties define a subclass of lineage-specific bHLH factors and provide context for their central roles in development and disease.
Project description:Endothelial cells line the inside of all blood vessels forming a single layer of quiescent, non-proliferating cells. While the mechanisms of sprouting angiogenesis, network formation and vascular remodelling are molecularly unravelled in increasing detail, the molecular mechanisms of vascular maturation are still poorly understood. We performed whole-genome bisulfite sequencing on endothelial cells isolated from infant and adult mice to establish the epigenetic landscape of vascular maturation.