Epigenetic aberrations and cancer

The correlation between epigenetic aberrations and disease underscores the importance of epigenetic mechanisms. Here, we review recent findings regarding chromatin modifications and their relevance to cancer

Histone deacetylase 2-mediated deacetylation of the Ribonuclease 1 promoter in inflamed human endothelial cells

Endothelial cells (ECs) function as protective barrier to separate the blood from the surrounding tissue by conducting crucial roles in regulation and maintenance of vascular homeostasis, such as control of vessel permeability or coagulation. Therefore, dysfunction of the EC barrier due to inflammation, infection or injury can cause a variety of vascular pathologies, such as thrombosis or atherosclerosis. In this context, the circulating extracellular endonuclease Ribonuclease 1 (RNase1) was identified as a vessel- and tissue-protective enzyme and a potent regulator of vascular homeostasis. Upon acute inflammation, RNase1 functions as a natural counterpart to extracellular RNA (eRNA), a damage-associated molecular pattern, via degradation to protect the EC cell layer from excessive inflammation. However, long-term inflammation disrupts the RNase1-eRNA system. Thereby, eRNA accumulates in the extracellular space to induce massive proinflammatory cytokine release from circulating inflammatory cells, such as tumor necrosis factor alpha (TNF-α) or interleukin 1 beta (IL-1β). These cytokines negatively affect the EC layer by downregulation of RNase1 presumably through activation of histone deacetylases (HDACs). In this regard, this study investigated whether inflammation-mediated deacetylase function of HDACs suppresses RNase1 expression in human ECs through modulation of chromatin modifications. Proinflammatory stimulation with TNF-α or IL-1β of human umbilical vein endothelial cells significantly reduced RNase1 expression. Thus, identification of the RNASE1 promoter region and analysis of its chromatin state revealed the association of RNASE1 repression with deacetylation of histone 3 at lysine 27 and histone 4. The important role of HDACs in this process was further confirmed by administration of the specific class I HDAC1-3 inhibitor MS275 that successfully restored RNASE1 promoter acetylation and mRNA abundance upon TNF-α or IL-1β treatment. These results indicate an essential impact of HDAC1-3 in RNase1 regulation. Additionally, identification of specific HDACs involved in RNase1 regulation was obtained by chromatin immunoprecipitation kinetics confirming significant accumulation of HDAC2 at the RNASE1 promoter upon TNF-α stimulation. These findings were further validated by siRNA double knockdown of HDAC2 and its redundant enzyme HDAC1, which also recovered RNase1 mRNA abundance upon proinflammatory stimulation. In conclusion, our data identified HDAC2 as a crucial factor in RNase1 regulation in human ECs. HDAC2 is recruited to the RNASE1 promoter site to attenuate histone acetylation and suppress subsequent gene repression. This effect can be blocked by the specific HDAC inhibitor MS275 implicating the potential of HDAC inhibitors as novel therapeutic strategy to promote vascular integrity by preventing RNase1 downregulation in EC inflammation

A small molecule activator of p300/CBP histone acetyltransferase promotes survival and neurite growth in a cellular model of Parkinson’s disease

Parkinson’s disease (PD) is a progressive neurodegenerative disease characterised by motor and non-motor symptoms, resulting from the degeneration of nigrostriatal dopaminergic neurons and peripheral autonomic neurons. Given the limited success of neurotrophic factors in clinical trials, there is a need to identify new small molecule drugs and drug targets to develop novel therapeutic strategies to protect all neurons that degenerate in PD. Epigenetic dysregulation has been implicated in neurodegenerative disorders, while targeting histone acetylation is a promising therapeutic avenue for PD. We and others have demonstrated that histone deacetylase inhibitors have neurotrophic effects in experimental models of PD. Activators of histone acetyltransferases (HAT) provide an alternative approach for the selective activation of gene expression, however little is known about the potential of HAT activators as drug therapies for PD. To explore this potential, the present study investigated the neurotrophic effects of CTPB (N-(4-chloro-3-trifluoromethyl-phenyl)-2-ethoxy-6-pentadecyl-benzamide), which is a potent small molecule activator of the histone acetyltransferase p300/CBP, in the SH-SY5Y neuronal cell line. We report that CTPB promoted the survival and neurite growth of the SH-SY5Y cells, and also protected these cells from cell death induced by the neurotoxin 6-hydroxydopamine. This study is the first to investigate the phenotypic effects of the HAT activator CTPB, and to demonstrate that p300/CBP HAT activation has neurotrophic effects in a cellular model of PD

Measurement of (anti)deuteron and (anti)proton production in DIS at HERA

The first observation of (anti)deuterons in deep inelastic scattering at HERA has been made with the ZEUS detector at a centre-of-mass energy of 300--318 GeV using an integrated luminosity of 120 pb-1. The measurement was performed in the central rapidity region for transverse momentum per unit of mass in the range 0.3<p_T/M<0.7. The particle rates have been extracted and interpreted in terms of the coalescence model. The (anti)deuteron production yield is smaller than the (anti)proton yield by approximately three orders of magnitude, consistent with the world measurements.Comment: 26 pages, 9 figures, 5 tables, submitted to Nucl. Phys.

Inclusive jet cross sections and dijet correlations in D∗±D^{*\pm} photoproduction at HERA

Inclusive jet cross sections in photoproduction for events containing a $D^*$ meson have been measured with the ZEUS detector at HERA using an integrated luminosity of $78.6 {\rm pb}^{-1}$. The events were required to have a virtuality of the incoming photon, $Q^2$, of less than 1 GeV$^2$, and a photon-proton centre-of-mass energy in the range $130<W_{\gamma p}<280 {\rm GeV}$. The measurements are compared with next-to-leading-order (NLO) QCD calculations. Good agreement is found with the NLO calculations over most of the measured kinematic region. Requiring a second jet in the event allowed a more detailed comparison with QCD calculations. The measured dijet cross sections are also compared to Monte Carlo (MC) models which incorporate leading-order matrix elements followed by parton showers and hadronisation. The NLO QCD predictions are in general agreement with the data although differences have been isolated to regions where contributions from higher orders are expected to be significant. The MC models give a better description than the NLO predictions of the shape of the measured cross sections.Comment: 43 pages, 12 figures, charm jets ZEU

Acetate Promotes T Cell Effector Function during Glucose Restriction.

Competition for nutrients like glucose can metabolically restrict T cells and contribute to their hyporesponsiveness during cancer. Metabolic adaptation to the surrounding microenvironment is therefore key for maintaining appropriate cell function. For instance, cancer cells use acetate as a substrate alternative to glucose to fuel metabolism and growth. Here, we show that acetate rescues effector function in glucose-restricted CD8+ T cells. Mechanistically, acetate promotes histone acetylation and chromatin accessibility and enhances IFN-γ gene transcription and cytokine production in an acetyl-CoA synthetase (ACSS)-dependent manner. Ex vivo acetate treatment increases IFN-γ production by exhausted T cells, whereas reducing ACSS expression in T cells impairs IFN-γ production by tumor-infiltrating lymphocytes and tumor clearance. Thus, hyporesponsive T cells can be epigenetically remodeled and reactivated by acetate, suggesting that pathways regulating the use of substrates alternative to glucose could be therapeutically targeted to promote T cell function during cancer

Histone deacetylase 2-mediated deacetylation of the Ribonuclease 1 promoter in inflamed human endothelial cells

Endothelial cells (ECs) function as protective barrier to separate the blood from the surrounding tissue by conducting crucial roles in regulation and maintenance of vascular homeostasis, such as control of vessel permeability or coagulation. Therefore, dysfunction of the EC barrier due to inflammation, infection or injury can cause a variety of vascular pathologies, such as thrombosis or atherosclerosis. In this context, the circulating extracellular endonuclease Ribonuclease 1 (RNase1) was identified as a vessel- and tissue-protective enzyme and a potent regulator of vascular homeostasis. Upon acute inflammation, RNase1 functions as a natural counterpart to extracellular RNA (eRNA), a damage-associated molecular pattern, via degradation to protect the EC cell layer from excessive inflammation. However, long-term inflammation disrupts the RNase1-eRNA system. Thereby, eRNA accumulates in the extracellular space to induce massive proinflammatory cytokine release from circulating inflammatory cells, such as tumor necrosis factor alpha (TNF-α) or interleukin 1 beta (IL-1β). These cytokines negatively affect the EC layer by downregulation of RNase1 presumably through activation of histone deacetylases (HDACs). In this regard, this study investigated whether inflammation-mediated deacetylase function of HDACs suppresses RNase1 expression in human ECs through modulation of chromatin modifications. Proinflammatory stimulation with TNF-α or IL-1β of human umbilical vein endothelial cells significantly reduced RNase1 expression. Thus, identification of the RNASE1 promoter region and analysis of its chromatin state revealed the association of RNASE1 repression with deacetylation of histone 3 at lysine 27 and histone 4. The important role of HDACs in this process was further confirmed by administration of the specific class I HDAC1-3 inhibitor MS275 that successfully restored RNASE1 promoter acetylation and mRNA abundance upon TNF-α or IL-1β treatment. These results indicate an essential impact of HDAC1-3 in RNase1 regulation. Additionally, identification of specific HDACs involved in RNase1 regulation was obtained by chromatin immunoprecipitation kinetics confirming significant accumulation of HDAC2 at the RNASE1 promoter upon TNF-α stimulation. These findings were further validated by siRNA double knockdown of HDAC2 and its redundant enzyme HDAC1, which also recovered RNase1 mRNA abundance upon proinflammatory stimulation. In conclusion, our data identified HDAC2 as a crucial factor in RNase1 regulation in human ECs. HDAC2 is recruited to the RNASE1 promoter site to attenuate histone acetylation and suppress subsequent gene repression. This effect can be blocked by the specific HDAC inhibitor MS275 implicating the potential of HDAC inhibitors as novel therapeutic strategy to promote vascular integrity by preventing RNase1 downregulation in EC inflammation