Sabine Hagemann

Aging is associated with highly defined epigenetic changes in the human epidermis

BackgroundAltered DNA methylation patterns represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Several studies have described global and complex age-related methylation changes, but their structural and functional significance has remained largely unclear.ResultsWe have used transcriptome sequencing to characterize age-related gene expression changes in the human epidermis. The results revealed a significant set of 75 differentially expressed genes with a strong functional relationship to skin homeostasis. We then used whole-genome bisulfite sequencing to identify age-related methylation changes at single-base resolution. Data analysis revealed no global aberrations, but rather highly localized methylation changes, particularly in promoter and enhancer regions that were associated with altered transcriptional activity.ConclusionsOur results suggest that the core developmental program of human skin is stably maintained through the aging process and that aging is associated with a limited destabilization of the epigenome at gene regulatory elements.

Epigenetic regulation of depot-specific gene expression in adipose tissue.

In humans, adipose tissue is distributed in subcutaneous abdominal and subcutaneous gluteal depots that comprise a variety of functional differences. Whereas energy storage in gluteal adipose tissue has been shown to mediate a protective effect, an increase of abdominal adipose tissue is associated with metabolic disorders. However, the molecular basis of depot-specific characteristics is not completely understood yet. Using array-based analyses of transcription profiles, we identified a specific set of genes that was differentially expressed between subcutaneous abdominal and gluteal adipose tissue. To investigate the role of epigenetic regulation in depot-specific gene expression, we additionally analyzed genome-wide DNA methylation patterns in abdominal and gluteal depots. By combining both data sets, we identified a highly significant set of depot-specifically expressed genes that appear to be epigenetically regulated. Interestingly, the majority of these genes form part of the homeobox gene family. Moreover, genes involved in fatty acid metabolism were also differentially expressed. Therefore we suppose that changes in gene expression profiles might account for depot-specific differences in lipid composition. Indeed, triglycerides and fatty acids of abdominal adipose tissue were more saturated compared to triglycerides and fatty acids in gluteal adipose tissue. Taken together, our results uncover clear differences between abdominal and gluteal adipose tissue on the gene expression and DNA methylation level as well as in fatty acid composition. Therefore, a detailed molecular characterization of adipose tissue depots will be essential to develop new treatment strategies for metabolic syndrome associated complications.

Reduced DNA methylation patterning and transcriptional connectivity define human skin aging

Epigenetic changes represent an attractive mechanism for understanding the phenotypic changes associated with human aging. Age‐related changes in DNA methylation at the genome scale have been termed ‘epigenetic drift’, but the defining features of this phenomenon remain to be established. Human epidermis represents an excellent model for understanding age‐related epigenetic changes because of its substantial cell‐type homogeneity and its well‐known age‐related phenotype. We have now generated and analyzed the currently largest set of human epidermis methylomes (N = 108) using array‐based profiling of 450 000 methylation marks in various age groups. Data analysis confirmed that age‐related methylation differences are locally restricted and characterized by relatively small effect sizes. Nevertheless, methylation data could be used to predict the chronological age of sample donors with high accuracy. We also identified discontinuous methylation changes as a novel feature of the aging methylome. Finally, our analysis uncovered an age‐related erosion of DNA methylation patterns that is characterized by a reduced dynamic range and increased heterogeneity of global methylation patterns. These changes in methylation variability were accompanied by a reduced connectivity of transcriptional networks. Our findings thus define the loss of epigenetic regulatory fidelity as a key feature of the aging epigenome.

DNA methylation regulates lineage-specifying genes in primary lymphatic and blood endothelial cells

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 blood endothelial cells (BEC) and lymphatic endothelial cells (LEC) have been reported. Since phenotypic plasticity and cellular differentiation processes frequently involve epigenetic mechanisms, we hypothesized that 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 LEC and BEC, we identified a highly significant set of genes, which were differentially methylated and expressed. Pathway analyses of the differentially methylated and upregulated genes in LEC 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.

Implications of epigenetic mechanisms for vascular development and disease

to the blind-ending lymphatic vasculature, the blood vasculature represents a closed circulating system and facilitates the exchange of gases (i.e., O 2 and CO 2 ) and nutrients [1]. Although both BECs and LECs display distinct features and functions, they share a close molecular and developmental relationship. In the early embryo, progenitor cells, the so-called angioblasts, differentiate from the mesodermal compartment and establish a primitive vascular network [2,3]. After determination of arteries and veins, venous endothelial cells further transdifferentiate into LECs forming primary lymph sacs [1]. This process is carefully regulated and requires a defined expression of lineage-specifying genes (i.e., PROX1) [4]. After terminal endothelial differentiation both LECs and BECs are characterized by distinct gene-expression profiles regulating cell type-specific functions [5]. There is growing evidence to suggest that epigenetic mechanisms (i.e., DNA methylation at CpG dinucleotides and histone modifications) are involved in regulating vascular endothelial gene-expression changes during development and in maintaining cell-type-specific expression patterns in adulthood. For example, histone deacetylase activity has been implicated in the regulation of embryonic endothelial differentiation [6], and histone acetylation controls the expression of NOTCH4 [7], a key signaling molecule involved in vascular development and remodeling. Furthermore, shear stress, which is a particularly distinctive stimulus for vessels and vessel-associated diseases, can alter chromatin structure and change the gene-expression profile in cultured human endothelial cells [8]. In addition, histone modifications such as H3K4 methylation are involved in vessel sprouting and endothelial cell migration [9]. However, the role of Nearly all cells of the human body have an identical genetic background. Nevertheless, cellular specialization into distinct functional entities is a hallmark of biological complexity in multi cellular organisms. But how can a single stem cell give rise to a variety of functionally different cell types? During past decades it has become clear that epigenetic mechanisms play a crucial role in regulating cell type-specific gene expression and thereby contribute to the determination of cellular fate. Furthermore, alterations of epigenetic signatures cause a variety of diseases. The fact that epigenetic marks are reversible makes them an attractive target for therapeutic interventions, aiming at reconstituting a healthy phenotype by reversing aberrant methylation marks. The present editorial summarizes the latest findings on epigenetic regulation and disease-associated dysregulation of blood and lymphatic vessel formation, focusing primarily on the characterization of blood endothelial cells (BECs) and lymphatic endothelial cells (LECs). Although both cell types share a close developmental relationship, they show specific functional differences. Thus, BECs and LECs represent an interesting model system to investigate the involvement of epigenetic mechanisms in regulating these cell-type-specific functions. We will further discuss whether treatment approaches targeting aberrant methylation marks may represent a rewarding strategy to recover epigenetically induced functional disorders of the vascular systems. The human vasculature is characterized by two types of tubular networks; the blood and the lymphatic systems, which comprise different but interdependent functions. The lymphatic system regulates tissue fluid homeostasis, immune surveillance, and absorption of fluids and macromolecules from the interstitium [1]. In contrast