Epigenetic Perturbations by Arg882-Mutated DNMT3A Potentiate Aberrant Stem Cell Gene-Expression Program and Acute Leukemia Development

DNA methyltransferase 3A (DNMT3A) is frequently mutated in hematological cancers; however, the underlying oncogenic mechanism remains elusive. Here, we report that DNMT3A mutational hotspot at Arg882 (DNMT3AR882H) cooperates with NRAS mutation to transform hematopoietic stem/progenitor cells and induce acute leukemia development. Mechanistically, DNMT3AR882H directly binds to and potentiates transactivation of stemness genes critical for leukemogenicity including Meis1, Mn1 and Hoxa gene cluster. DNMT3AR882H induces focal epigenetic alterations, including CpG hypomethylation and concurrent gain of active histone modifications, at cis-regulatory elements such as enhancers to facilitate gene transcription. CRISPR/Cas9-mediated ablation of a putative Meis1 enhancer carrying DNMT3AR882H-induced DNA hypomethylation impairs Meis1 expression. Importantly, DNMT3AR882H-induced gene expression programs can be repressed through Dot1l inhibition, providing an attractive therapeutic strategy for DNMT3A-mutated leukemias

Entropy spectrum of a Kerr anti-de Sitter black hole

The entropy spectrum of a spherically symmetric black hole was derived without the quasinormal modes in the work of Majhi and Vagenas. Extending this work to rotating black holes, we quantize the entropy and the horizon area of a Kerr anti-de Sitter black hole by two methods. The spectra of entropy and area are obtained via the Bohr-Sommerfeld quantization rule and the adiabatic invariance in the first way. By addressing the wave function of emitted (absorbed) particles, the entropy and the area are quantized in the second one. Both results show that the entropy and the area spectra are equally spaced.Comment: Accepted for publication in The European Physical Journal C, Volume 72, Issue

Spectroscopy of the Einstein-Maxwell-Dilaton-Axion black hole

The entropy spectrum of a spherically symmetric black hole was derived via the Bohr-Sommerfeld quantization rule in Majhi and Vagenas's work. Extending this work to charged and rotating black holes, we quantize the horizon area and the entropy of an Einstein-Maxwell-Dilaton-Axion (EMDA) black hole via the Bohr-Sommerfeld quantization rule and the adiabatic invariance. The result shows the area spectrum and the entropy spectrum are respectively equally spaced and independent on the parameters of the black hole.Comment: 9 page

An H3K36 Methylation-Engaging Tudor Motif of Polycomb-like Proteins Mediates PRC2 Complex Targeting

Polycomb repressive complex 2 (PRC2) regulates pluripotency, differentiation and tumorigenesis through catalysis of histone H3 lysine 27 trimethylation (H3K27me3) on chromatin. However, the mechanisms that underlie PRC2 recruitment and spreading on chromatin remain unclear. Here we report that histone H3 lysine 36 trimethylation (H3K36me3)-binding activity is harbored in the Tudor motifs of PRC2-associated polycomblike (PCL) proteins PHF1/PCL1 and PHF19/PCL3. Ectopically expressed PHF1 induced Tudor-dependent stabilization of PRC2 complexes on bulk chromatin and mediated spreading of PRC2 and H3K27me3 into H3K36me3-containing chromatin regions. In murine pluripotent stem cells, we identified coexistence of H3K36me3, H3K27me3, and PHF19/PCL3 at a subset of ‘poised’ developmental genes, and demonstrated that PHF19/PCL3 Tudor function is required for optimal H3K27me3 and repression of these loci. Collectively, our data suggest that PCL recognition of H3K36me3 promotes intrusion of PRC2 complexes into active chromatin regions to promote gene silencing and modulate the chromatin landscape during development

Factors influencing householder self-evacuation in two Australian bushfires

The thesis investigated householder self-evacuation decision-making during bushfires in the Perth and Adelaide Hills in 2014 and 2015. It explored the factors that influenced householders’ decisions to evacuate, identified factors that predict self-evacuation and established the characteristics of self-evacuators. The Protective Action Decision Model (PADM) provided a conceptual framework for the research. Its theoretical and analytical usefulness in an Australian context, was assessed. A mixed methods research strategy was used involving quantitative telephone surveys of 457 bushfire-affected participants and face-to-face interviews of 109 participants in 59 households. The study concluded that environmental and social cues and warnings and householders’ perceptions of the threat, of hazard adjustments and of other stakeholders, influenced self-evacuation decision-making. Protective action perceptions, particularly the effectiveness of evacuating or not evacuating in protecting personal safety or property, were most important in predicting self-evacuation. Receipt of official warnings and the perception of likely impact of the bushfire on property were also important predictors. Undertaking long-run hazard adjustments, although not predictive of self-evacuation, was pivotal in shaping perceptions of the effectiveness of evacuating and remaining in protecting personal safety and property and indirectly influenced evacuation decisions. Seven archetypes that characterised householders’ self-evacuation attitudes and behaviour were identified. These included Threat, and Responsibility Deniers, Dependent, and Considered Evacuators, Community Guided and Experienced Independents all who took different decisional ‘rules of thumb’ and routes toward evacuating or remaining . The PADM needs to be split into two separate models to incorporate the influence of long-run hazard adjustments on protective action decision-making in an Australian bushfire. The findings suggest that future research on those who wait and see during a bushfire should take account of their decisional rules of thumb and that design and targeting of Australian bushfire safety policy should better account for self-evacuator characteristics

Pangolin genomes and the evolution of mammalian scales and immunity

Pangolins, unique mammals with scales over most of their body, no teeth, poor vision, and an acute olfactory system, comprise the only placental order (Pholidota) without a whole-genome map. To investigate pangolin biology and evolution, we developed genome assemblies of the Malayan (Manis javanica) and Chinese (M. pentadactyla) pangolins. Strikingly, we found that interferon epsilon (IFNE), exclusively expressed in epithelial cells and important in skin and mucosal immunity, is pseudogenized in all African and Asian pangolin species that we examined, perhaps impacting resistance to infection. We propose that scale development was an innovation that provided protection against injuries or stress and reduced pangolin vulnerability to infection. Further evidence of specialized adaptations was evident from positively selected genes involving immunity-related pathways, inflammation, energy storage and metabolism, muscular and nervous systems, and scale/hair development. Olfactory receptor gene families are significantly expanded in pangolins, reflecting their well-developed olfaction system. This study provides insights into mammalian adaptation and functional diversification, new research tools and questions, and perhaps a new natural IFNE-deficient animal model for studying mammalian immunity.University of Malaya and Ministry of Education, Malaysia [UM.C/HIR/MOHE/08]; UMRG grant from the University of Malaya and Ministry of Education, Malaysia [RG541-13HTM]; Russian Ministry of Science [11.G34.31.0068]; NIH-NHGRI grant [5U54HG00307907]SCI(E)[email protected]

Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer

In search of redox mechanisms in breast cancer, we uncovered a striking role for glutathione peroxidase 2 (GPx2) in oncogenic signaling and patient survival. GPx2 loss stimulates malignant progression due to reactive oxygen species/hypoxia inducible factor-α (HIF1α)/VEGFA (vascular endothelial growth factor A) signaling, causing poor perfusion and hypoxia, which were reversed by GPx2 reexpression or HIF1α inhibition. Ingenuity Pathway Analysis revealed a link between GPx2 loss, tumor angiogenesis, metabolic modulation, and HIF1α signaling. Single-cell RNA analysis and bioenergetic profiling revealed that GPx2 loss stimulated the Warburg effect in most tumor cell subpopulations, except for one cluster, which was capable of oxidative phosphorylation and glycolysis, as confirmed by coexpression of phosphorylated-AMPK and GLUT1. These findings underscore a unique role for redox signaling by GPx2 dysregulation in breast cancer, underlying tumor heterogeneity, leading to metabolic plasticity and malignant progression