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"Patrick J. Murphy"
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Genome-wide chromatin accessibility is restricted by ANP32E
Genome-wide chromatin state underlies gene expression potential and cellular function. Epigenetic features and nucleosome positioning contribute to the accessibility of DNA, but widespread regulators of chromatin state are largely unknown. Our study investigates how coordination of ANP32E and H2A.Z contributes to genome-wide chromatin state in mouse fibroblasts. We define H2A.Z as a universal chromatin accessibility factor, and demonstrate that ANP32E antagonizes H2A.Z accumulation to restrict chromatin accessibility genome-wide. In the absence of ANP32E, H2A.Z accumulates at promoters in a hierarchical manner. H2A.Z initially localizes downstream of the transcription start site, and if H2A.Z is already present downstream, additional H2A.Z accumulates upstream. This hierarchical H2A.Z accumulation coincides with improved nucleosome positioning, heightened transcription factor binding, and increased expression of neighboring genes. Thus, ANP32E dramatically influences genome-wide chromatin accessibility through subtle refinement of H2A.Z patterns, providing a means to reprogram chromatin state and to hone gene expression levels.
Chromatin state underlies cellular function, and transcription factor binding patterns along with epigenetic marks define chromatin state. Here the authors show that the histone chaperone ANP32E functions through regulation of H2A.Z to restrict genome-wide chromatin accessibility and to inhibit gene transcriptional activation.
Journal Article
Sensing Magnetic Field and Intermolecular Interactions in Diamagnetic Solution Using Residual Dipolar Couplings of Zephycandidine
An unusual residual dipolar coupling of methylene protons was recorded in NMR spectra because aromatic zephycandidine has preferential orientation at the external magnetic field. The observed splitting contains contribution from the dipole–dipole D-coupling and the anisotropic component of J-coupling. Absolute values of the anisotropy of magnetic susceptibility |Δχax| are larger for protic solvents because of the hydrogen-bonding compared to aprotic solvents for which polar and dispersion forces are more important. The energy barrier for the reorientation due to hydrogen-bonding is 1.22 kJ/mol in methanol-d4, 0.85 kJ/mol in ethanol-d6 and 0.87 kJ/mol in acetic acid-d6. In dimethyl sulfoxide-d6, 1.08 kJ/mol corresponds to the interaction of solvent lone pair electrons with π-electrons of zephycandidine. This energy barrier decreases for acetone-d6 which has smaller electric dipole moment. In acetonitrile-d3, there is no energy barrier which suggests solvent ordering around the solute due to the solvent-solvent interactions. The largest absolute values of the magnetic anisotropy are observed for aromatic benezene-d6 and tolune-d8 which have their own preferential orientation and enhance the order in the solution. The magnetic anisotropy of “isolated” zephycandidine, not hindered by intermolecular interaction could be estimated from the correlation between Δχax and cohesion energy density.
Journal Article
Medieval Studies and the Ghost Stories of M. R. James
Montague Rhodes James authored some of the most highly regarded ghost stories of all time—classics such as \"Oh, Whistle, and I'll Come to You, My Lad\" that have been adapted many times over for radio and television and have never gone out of print. But while James is best known as a fiction writer and storyteller, he was also a provost of King's College, Cambridge, and Eton College, and a legendary and influential scholar whose pioneering work in the study of biblical texts and medieval manuscripts, art, and architecture is still relevant today.
In Medieval Studies and the Ghost Stories of M. R. James, Patrick J. Murphy argues that these twin careers are inextricably linked. James's research not only informed his fiction but also reflected his anxieties about the nature of academic life and explored the delicate divide between professional, university men and erratic hobbyists or antiquaries. Murphy shows how detailed attention to the scholarly inspirations behind James's fiction provides considerable insight into a formative moment in medieval studies, as well as into James's methods as a master stylist of understated horror.
During his life, James often claimed that his stories were mere entertainments—pleasing distractions from a life largely defined by academic discipline and restraint—and readers over the years have been content to take him at his word. This intriguing volume, however, convincingly proves otherwise.
eBook
Establishment of developmental gene silencing by ordered polycomb complex recruitment in early zebrafish embryos
Vertebrate embryos achieve developmental competency during zygotic genome activation (ZGA) by establishing chromatin states that silence yet poise developmental genes for subsequent lineage-specific activation. Here, we reveal the order of chromatin states in establishing developmental gene poising in preZGA zebrafish embryos. Poising is established at promoters and enhancers that initially contain open/permissive chromatin with ‘Placeholder’ nucleosomes (bearing H2A.Z, H3K4me1, and H3K27ac), and DNA hypomethylation. Silencing is initiated by the recruitment of polycomb repressive complex 1 (PRC1), and H2Aub1 deposition by catalytic Rnf2 during preZGA and ZGA stages. During postZGA, H2Aub1 enables Aebp2-containing PRC2 recruitment and H3K27me3 deposition. Notably, preventing H2Aub1 (via Rnf2 inhibition) eliminates recruitment of Aebp2-PRC2 and H3K27me3, and elicits transcriptional upregulation of certain developmental genes during ZGA. However, upregulation is independent of H3K27me3 – establishing H2Aub1 as the critical silencing modification at ZGA. Taken together, we reveal the logic and mechanism for establishing poised/silent developmental genes in early vertebrate embryos.
Journal Article
Subtype-Independent ANP32E Reduction During Breast Cancer Progression in Accordance with Chromatin Relaxation
Background
Chromatin state provides a clear decipherable blueprint for maintenance of transcriptional patterns, exemplifying a mitotically stable form of cellular programming in dividing cells. In this regard, genomic studies of chromatin states within cancerous tissues have the potential to uncover novel aspects of tumor biology and unique mechanisms associated with disease phenotypes and outcomes. The degree to which chromatin state differences occur in accordance with breast cancer features has not been established.
Methods
We applied a series of unsupervised computational methods to identify chromatin and molecular differences associated with discrete physiologies across human breast cancer tumors.
Results
Chromatin patterns alone are capable of stratifying tumors in association with cancer subtype and disease progression. Major differences occur at DNA motifs for the transcription factor FOXA1, in hormone receptor-positive tumors, and motifs for SOX9 in Basal-like tumors. We find that one potential driver of this effect, the histone chaperone
ANP32E,
is inversely correlated with tumor progression and relaxation of chromatin at FOXA1 binding sites. Tumors with high levels of
ANP32E
exhibit an immune response and proliferative gene expression signature, whereas tumors with low
ANP32E
levels appear programmed for differentiation.
Conclusions
Our results indicate that ANP32E may function through chromatin state regulation to control breast cancer differentiation and tumor plasticity. This study sets a precedent for future computational studies of chromatin changes in carcinogenesis.
Journal Article
Metabolite profiling reveals a connection between aldehyde dehydrogenase 1A3 and GABA metabolism in breast cancer metastasis
IntroductionAldehyde dehydrogenase 1A3 (ALDH1A3) is a cancer stem cell (CSC) marker and in breast cancer it is associated with triple-negative/basal-like subtypes and aggressive disease. Studies on the mechanisms of ALDH1A3 in cancer have primarily focused on gene expression changes induced by the enzyme; however, its effects on metabolism have thus far been unstudied and may reveal novel mechanisms of pathogenesis.ObjectiveDetermine how ALDH1A3 alters the metabolite profile in breast cancer cells and assess potential impacts.MethodTriple-negative MDA-MB-231 tumors and cells with manipulated ALDH1A3 levels were assessed by HPLC–MS metabolomics and metabolite data was integrated with transcriptome data. Mice harboring MDA-MB-231 tumors with or without altered ALDH1A3 expression were treated with γ-aminobutyric acid (GABA) or placebo. Effects on tumor growth, and lungs and brain metastasis were quantified by staining of fixed thin sections and quantitative PCR. Breast cancer patient datasets from TCGA, METABRIC and GEO were used to assess the co-expression of GABA pathway genes with ALDH1A3.ResultsIntegrated metabolomic and transcriptome data identified GABA metabolism as a primary dysregulated pathway in ALDH1A3 expressing breast tumors. Both ALDH1A3 and GABA treatment enhanced metastasis. Patient dataset analyses revealed expression association between ALDH1A3 and GABA pathway genes and corresponding increased risk of metastasis.ConclusionThis study revealed a novel pathway affected by ALDH1A3, GABA metabolism. Like ALDH1A3 expression, GABA treatment promotes metastasis. Given the clinical use of GABA mimics to relieve chemotherapy-induced peripheral nerve pain, further study of the effects of GABA in breast cancer progression is warranted.
Journal Article
Single-molecule analysis of combinatorial epigenomic states in normal and tumor cells
Proper placement of epigenetic marks on DNA and histones is fundamental to normal development, and perturbations contribute to a variety of disease states. Combinations of marks act together to control gene expression; therefore, detecting their colocalization is important, but because of technical challenges, such measurements are rarely reported. Instead, measurements of epigenetic marks are typically performed one at a time in a population of cells, and their colocalization is inferred by association. Here, we describe a single-molecule analytical approach that can perform direct detection of multiple epigenetic marks simultaneously and use it to identify mechanisms coordinating placement of three gene silencing marks, trimethylated histone H3 lysine 9, lysine 27 (H3K9me3, H3K27me3), and cytosine methylation (mC), in the normal and cancer genome. We show that H3K9me3 and mC are present together on individual chromatin fragments in mouse embryonic stem cells and that half of the H3K9me3 marks require mC for their placement. In contrast, mC and H3K27me3 coincidence is rare, and in fact, mC antagonizes H3K27me3 in both embryonic stem cells and primary mouse fibroblasts, indicating this antagonism is shared among primary cells. However, upon immortalization or tumorigenic transformation of mouse fibroblasts, mC is required for complete H3K27me3 placement. Importantly, in human promyelocytic cells, H3K27me3 is also dependent on mC. Because aberrant placement of gene silencing marks at tumor suppressor genes contributes to tumor progression, the improper dependency of H3K27me3 by mC in immortalized cells is likely to be fundamental to cancer. Our platform can enable other studies involving coordination of epigenetic marks and leverage efforts to discover disease biomarkers and epigenome-modifying drugs.
Journal Article
NRF2 loss recapitulates heritable impacts of paternal cigarette smoke exposure
Paternal cigarette smoke (CS) exposure is associated with increased risk of behavioral disorders and cancer in offspring, but the mechanism has not been identified. Here we use mouse models to investigate mechanisms and impacts of paternal CS exposure. We demonstrate that CS exposure induces sperm DNAme changes that are partially corrected within 28 days of removal from CS exposure. Additionally, paternal smoking is associated with changes in prefrontal cortex DNAme and gene expression patterns in offspring. Remarkably, the epigenetic and transcriptional effects of CS exposure that we observed in wild type mice are partially recapitulated in Nrf2-/- mice and their offspring, independent of smoking status. Nrf2 is a central regulator of antioxidant gene transcription, and mice lacking Nrf2 consequently display elevated oxidative stress, suggesting that oxidative stress may underlie CS-induced heritable epigenetic changes. Importantly, paternal sperm DNAme changes do not overlap with DNAme changes measured in offspring prefrontal cortex, indicating that the observed DNAme changes in sperm are not directly inherited. Additionally, the changes in sperm DNAme associated with CS exposure were not observed in sperm of unexposed offspring, suggesting the effects are likely not maintained across multiple generations.
Journal Article