Mapping Dynamic Histone Acetylation Patterns to Gene Expression in Nanog-depleted Murine Embryonic Stem Cells

Embryonic stem cells (ESC) have the potential to self-renew indefinitely and to differentiate into any of the three germ layers. The molecular mechanisms for self-renewal, maintenance of pluripotency and lineage specification are poorly understood, but recent results point to a key role for epigenetic mechanisms. In this study, we focus on quantifying the impact of histone 3 acetylation (H3K9,14ac) on gene expression in murine embryonic stem cells. We analyze genome-wide histone acetylation patterns and gene expression profiles measured over the first five days of cell differentiation triggered by silencing Nanog, a key transcription factor in ESC regulation. We explore the temporal and spatial dynamics of histone acetylation data and its correlation with gene expression using supervised and unsupervised statistical models. On a genome-wide scale, changes in acetylation are significantly correlated to changes in mRNA expression and, surprisingly, this coherence increases over time. We quantify the predictive power of histone acetylation for gene expression changes in a balanced cross-validation procedure. In an in-depth study we focus on genes central to the regulatory network of Mouse ESC, including those identified in a recent genome-wide RNAi screen and in the PluriNet, a computationally derived stem cell signature. We find that compared to the rest of the genome, ESC-specific genes show significantly more acetylation signal and a much stronger decrease in acetylation over time, which is often not reflected in an concordant expression change. These results shed light on the complexity of the relationship between histone acetylation and gene expression and are a step forward to dissect the multilayer regulatory mechanisms that determine stem cell fate.Comment: accepted at PLoS Computational Biolog

Ocean acidification through the lens of ecological theory

Ocean acidification, chemical changes to the carbonate system of seawater, is emerging as a key environmental challenge accompanying global warming and other human-induced perturbations. Considerable research seeks to define the scope and character of potential outcomes from this phenomenon, but a crucial impediment persists. Ecological theory, despite its power and utility, has been only peripherally applied to the problem. Here we sketch in broad strokes several areas where fundamental principles of ecology have the capacity to generate insight into ocean acidification's consequences. We focus on conceptual models that, when considered in the context of acidification, yield explicit predictions regarding a spectrum of population- and community-level effects, from narrowing of species ranges and shifts in patterns of demographic connectivity, to modified consumer–resource relationships, to ascendance of weedy taxa and loss of species diversity. Although our coverage represents only a small fraction of the breadth of possible insights achievable from the application of theory, our hope is that this initial foray will spur expanded efforts to blend experiments with theoretical approaches. The result promises to be a deeper and more nuanced understanding of ocean acidification and the ecological changes it portends

Estrogen-dependent dynamic profile of eNOS-DNA associations in prostate cancer

In previous work we have documented the nuclear translocation of endothelial NOS (eNOS) and its participation in combinatorial complexes with Estrogen Receptor Beta (ERβ) and Hypoxia Inducible Factors (HIFs) that determine localized chromatin remodeling in response to estrogen (E2) and hypoxia stimuli, resulting in transcriptional regulation of genes associated with adverse prognosis in prostate cancer (PCa). To explore the role of nuclear eNOS in the acquisition of aggressive phenotype in PCa, we performed ChIP-Sequencing on chromatin-associated eNOS from cells from a primary tumor with poor outcome and from metastatic LNCaP cells. We found that: 1. the eNOS-bound regions (peaks) are widely distributed across the genome encompassing multiple transcription factors binding sites, including Estrogen Response Elements. 2. E2 increased the number of peaks, indicating hormone-dependent eNOS re-localization. 3. Peak distribution was similar with/without E2 with ≈ 55% of them in extragenic DNA regions and an intriguing involvement of the 5′ domain of several miRs deregulated in PCa. Numerous potentially novel eNOS-targeted genes have been identified suggesting that eNOS participates in the regulation of large gene sets. The parallel finding of downregulation of a cluster of miRs, including miR-34a, in PCa cells associated with poor outcome led us to unveil a molecular link between eNOS and SIRT1, an epigenetic regulator of aging and tumorigenicity, negatively regulated by miR-34a and in turn activating eNOS. E2 potentiates miR-34a downregulation thus enhancing SIRT1 expression, depicting a novel eNOS/SIRT1 interplay fine-tuned by E2-activated ER signaling, and suggesting that eNOS may play an important role in aggressive PCa

Assessment of Heat-Related Health Impacts in Brisbane, Australia: Comparison of Different Heatwave Definitions

Background: There is no global definition of a heatwave because local acclimatisation and adaptation influence the impact of extreme heat. Even at a local level there can be multiple heatwave definitions, based on varying temperature levels or time periods. We investigated the relationship between heatwaves and health outcomes using ten different heatwave definitions in Brisbane, Australia. ---------- Methodology/Principal Findings: We used daily data on climate, air pollution, and emergency hospital admissions in Brisbane between January 1996 and December 2005; and mortality between January 1996 and November 2004. Case-crossover analyses were used to assess the relationship between each of the ten heatwave definitions and health outcomes. During heatwaves there was a statistically significant increase in emergency hospital admissions for all ten definitions, with odds ratios ranging from 1.03 to 1.18. A statistically significant increase in the odds ratios of mortality was also found for eight definitions. The size of the heat-related impact varied between definitions.---------- Conclusions/Significance Even a small change in the heatwave definition had an appreciable effect on the estimated health impact. It is important to identify an appropriate definition of heatwave locally and to understand its health effects in order to develop appropriate public health intervention strategies to prevent and mitigate the impact of heatwaves

PARP16 is a tail-anchored endoplasmic reticulum protein required for the PERK- and IRE1α-mediated unfolded protein response

Poly(ADP-ribose) polymerases (PARPs; also known as ADP-ribosyl transferase D proteins) modify acceptor proteins with ADP-ribose modifications of varying length (reviewed in refs 1, 2, 3). PARPs regulate key stress response pathways, including DNA damage repair and the cytoplasmic stress response. Here, we show that PARPs also regulate the unfolded protein response (UPR) of the endoplasmic reticulum (ER). Human PARP16 (also known as ARTD15) is a tail-anchored ER transmembrane protein required for activation of the functionally related ER stress sensors PERK and IRE1α during the UPR. The third identified ER stress sensor, ATF6, is not regulated by PARP16. As is the case for other PARPs that function during stress, the enzymatic activity of PARP16 is upregulated during ER stress when it ADP-ribosylates itself, PERK and IRE1α. ADP-ribosylation by PARP16 is sufficient for activating PERK and IRE1α in the absence of ER stress, and is required for PERK and IRE1α activation during the UPR. Modification of PERK and IRE1α by PARP16 increases their kinase activities and the endonuclease activity of IRE1α. Interestingly, the carboxy-terminal luminal tail of PARP16 is required for PARP16 function during ER stress, suggesting that it transduces stress signals to the cytoplasmic PARP catalytic domain.National Cancer Institute (U.S.) (Cancer Center Support Core Grant P30-CA14051)National Institutes of Health (U.S.) (Grant 5R01 GM087465-02)Kathy and Curt Marble Cancer Research FundJeptha H. and Emily V. Wade FundVirginia and D.K. Ludwig Fund for Cancer Researc

Prospective Study Examining Clinical Outcomes Associated with a Negative Pressure Wound Therapy System and Barker’s Vacuum Packing Technique

Background The open abdomen has become a common procedure in the management of complex abdominal problems and has improved patient survival. The method of temporary abdominal closure (TAC) may play a role in patient outcome. Methods A prospective, observational, open-label study was performed to evaluate two TAC techniques in surgical and trauma patients requiring open abdomen management: Barker’s vacuum-packing technique (BVPT) and the ABTheraTM open abdomen negative pressure therapy system (NPWT). Study endpoints were days to and rate of 30-day primary fascial closure (PFC) and 30-day all-cause mortality. Results Altogether, 280 patients were enrolled from 20 study sites. Among them, 168 patients underwent at least 48 hours of consistent TAC therapy (111 NPWT, 57 BVPT). The two study groups were well matched demographically. Median days to PFC were 9 days for NPWT versus 12 days for BVPT (p = 0.12). The 30-day PFC rate was 69 % for NPWT and 51 % for BVPT (p = 0.03). The 30-day all-cause mortality was 14 % for NPWT and 30 % for BVPT (p = 0.01). Multivariate logistic regression analysis identified that patients treated with NPWT were significantly more likely to survive than the BVPT patients [odds ratio 3.17 (95 % confidence interval 1.22–8.26); p = 0.02] after controlling for age, severity of illness, and cumulative fluid administration. Conclusions Active NPWT is associated with significantly higher 30-day PFC rates and lower 30-day all-cause mortality among patients who require an open abdomen for at least 48 h during treatment for critical illness

Discovery and characterization of chromatin states for systematic annotation of the human genome

A plethora of epigenetic modifications have been described in the human genome and shown to play diverse roles in gene regulation, cellular differentiation and the onset of disease. Although individual modifications have been linked to the activity levels of various genetic functional elements, their combinatorial patterns are still unresolved and their potential for systematic de novo genome annotation remains untapped. Here, we use a multivariate Hidden Markov Model to reveal 'chromatin states' in human T cells, based on recurrent and spatially coherent combinations of chromatin marks. We define 51 distinct chromatin states, including promoter-associated, transcription-associated, active intergenic, large-scale repressed and repeat-associated states. Each chromatin state shows specific enrichments in functional annotations, sequence motifs and specific experimentally observed characteristics, suggesting distinct biological roles. This approach provides a complementary functional annotation of the human genome that reveals the genome-wide locations of diverse classes of epigenetic function.National Science Foundation (U.S.). (Award 0905968)National Human Genome Research Institute (U.S.) (Award U54-HG004570)National Human Genome Research Institute (U.S.) (Award RC1-HG005334

Validating the German Version of the Quality of Relationship Inventory: Confirming the Three-Factor Structure and Report of Psychometric Properties

Research on psychosocial influences such as relationship characteristics has received increased attention in the clinical as well as social-psychological field. Several studies demonstrated that the quality of relationships, in particular with respect to the perceived support within intimate relationships, profoundly affects individuals' mental and physical health. There is, however, a limited choice of valid and internationally known assessments of relationship quality in Germany. We report the validation of the German version of the Quality of Relationships Inventory (QRI). First, we evaluated its factor structure in a representative German sample of 1.494 participants by means of confirmatory factor analysis. Our findings support the previously proposed three-factor structure. Second, importance and satisfaction with different relationship domains (family/children and relationship/sexuality) were linked with the QRI scales, demonstrating high construct validity. Finally, we report sex and age differences regarding the perceived relationship support, conflict and depth in our German sample. In conclusion, the QRI is a reliable and valid measurement to assess social support in romantic relationships in the German population

Exploring the Mode of Action of Bioactive Compounds by Microfluidic Transcriptional Profiling in Mycobacteria

10.1371/journal.pone.0069191PLoS ONE87-POLN