Non-CG DNA methylation is a biomarker for assessing endodermal differentiation capacity in pluripotent stem cells.

Non-CG methylation is an unexplored epigenetic hallmark of pluripotent stem cells. Here we report that a reduction in non-CG methylation is associated with impaired differentiation capacity into endodermal lineages. Genome-wide analysis of 2,670 non-CG sites in a discovery cohort of 25 phenotyped human induced pluripotent stem cell (hiPSC) lines revealed unidirectional loss (Δβ=13%, P<7.

The Epigenetics of Normal Pregnancy.

Epigenetic modifications to chromatin are essential for the specification and maintenance of cell fate, enabling the same genome to programme a variety of cellular outcomes. Epigenetic modulation of gene expression is also a critical mechanism by which cells stabilize their responses to environmental stimuli, including both nutritional cues and hormonal signalling. Unsurprisingly, epigenetics is proving to be vitally important in fetal development, and this review addresses our current understanding of the roles of epigenetic regulation in the prenatal phase.

DNA demethylases: a new epigenetic frontier in drug discovery.

DNA methylation is one of the most extensively studied, and one of the most stable, of all epigenetic modifications. Two drugs that target DNA methyltransferase enzymes are licensed for clinical use in oncology but relatively little attention has focused on the enzymatic pathways by which DNA methylation can be reversed. Recent breakthroughs have identified at least two classes of enzymes that can achieve functional reversal.

Epigenetic therapies for non-oncology indications.

Chronic and degenerative disorders are a major, and growing, human health burden, and current treatments are in many cases inadequate or very expensive. Epigenetic therapies are attractive options for treating such disorders because they manipulate the processes that maintain cells in an abnormal transcriptional state. The challenges lie in identifying the most appropriate diseases and the enzymes that should be targeted.

Epigenetic opportunities and challenges in cancer.

Epigenetic covalent modifications of DNA and chromatin proteins strongly affect gene expression and cellular activity, and epigenetic misregulation occurs in several diseases, especially cancer. First-generation drugs targeting the relatively promiscuous DNA methylation and histone acetylation modifiers have had successes in the treatment of haematological cancers. Second-generation drug programmes are in the discovery phase, targeting epigenetic enzymes with more tightly defined modes of action.

Genomics screen in transformed stem cells reveals RNASEH2A, PPAP2C, and ADARB1 as putative anticancer drug targets.

Since the sequencing of the human genome, recent efforts in cancer drug target discovery have focused more on the identification of novel functions of known genes and the development of more appropriate tumor models. In the present study, we investigated in vitro transformed human adult mesenchymal stem cells (MSC) to identify novel candidate cancer drug targets by analyzing the transcriptional profile of known enzymes compared with non-transformed MSC. The identified enzymes were compared with published cancer gene expression data sets.

Determination of the class and isoform selectivity of small-molecule histone deacetylase inhibitors.

The human HDAC (histone deacetylase) family, a well-validated anticancer target, plays a key role in the control of gene expression through regulation of transcription. While HDACs can be subdivided into three main classes, the class I, class II and class III HDACs (sirtuins), it is presently unclear whether inhibiting multiple HDACs using pan-HDAC inhibitors, or targeting specific isoforms that show aberrant levels in tumours, will prove more effective as an anticancer strategy in the clinic. To address the above issues, we have tested a number of clinically relevant HDACis (HDAC inhibitors) against a panel of rhHDAC (recombinant human HDAC) isoforms.

Histone deacetylase inhibitors: gathering pace.

Reversible histone acetylation is one of the key mechanisms involved in the epigenetic control of gene expression. A variety of recent studies has revealed a role for acetylation in a much broader repertoire of physiological processes, including proliferation control and protein folding, and has highlighted how a variety of non-histone regulatory proteins are influenced by acetylation. Inhibition of histone deacetylase (HDAC) prompts tumour cells to enter apoptosis and, as a consequence, several HDAC inhibitors have entered clinical trials.

Flow-dependent increase of ICAM-1 on saphenous vein endothelium is sensitive to apamin.

The potassium channel blocker tetraethylammonium blocks the flow-induced increase in endothelial ICAM-1. We have investigated the subtype of potassium channel that modulates flow-induced increased expression of ICAM-1 on saphenous vein endothelium. Cultured human saphenous vein endothelial cells (HSVECs) or intact saphenous veins were perfused at fixed low and high flows in a laminar shear chamber or flow rig, respectively, in the presence or absence of potassium channel blockers.

Generation and characterisation of human saphenous vein endothelial cell lines.

Primary human endothelial cells have a finite life span in vitro. After 3-4 passages, they tend to de-differentiate and eventually reach senescence. This limits their use in studies of endothelial cell function.