Regulated Histone H3 Proteolysis During Mouse Embryonic Stem Cell Differentiation

The association of genomic DNA with histone proteins in the three-dimensional structure known as chromatin is the central framework for “epigenetics,†which is defined as inherited phenotypes governed by differences that cannot be explained by changes in DNA sequence. In recent years, studies have shown that regulated changes in the chemical and physical properties of chromatin often lead to dynamic changes in many cellular processes, including development and differentiation, by affecting the accessibility of the genomic information stored in the DNA. The cell uses many different mechanisms to regulate chromatin in order to establish, maintain, and propagate patterns of gene expression that are necessary for proper development and differentiation. Many of these mechanisms involve the histone component of chromatin, both through chemical and structural changes of the histone proteins themselves and via complex interactions with other non-histone chromatin proteins. Here, in my thesis work, I describe how a few of these chromatin regulatory mechanisms are used during mammalian differentiation, specifically focusing on those involving histone H3. First, in Chapter 2, I describe how certain non-histone chromatin proteins that are key to development specifically interact with modified histones using biochemical, biophysical and structural approaches. Next, in Chapter 3, I describe how chromatin undergoes specific, dramatic changes as cells lose their capacity for self-renewal and proceed toward a specific lineage using a mouse embryonic stem cell model of differentiation and early embryonic development. These changes involve both the post-translational modification of histone H3 and the incorporation of different H3 variant proteins into the chromatin fiber. Finally, I describe the observation that differentiating mouse embryonic stem cells proteolytically cleave histone H3 and identify a protease that accomplishes this cleavage

Uncertainty in mass-balance trends derived from altimetry: a case study along the EGIG line, central Greenland

This is the author accepted manuscript. The final version is available from The International Glaciological Society via http://dx.doi.org/10.3189/2015JoG14J123AbstractRepeated measurements of density profiles and surface elevation along a 515 km traverse of the Greenland ice sheet are used to determine elevation change rates and the error in determining mass-balance trends from these rates which arises from short-term fluctuations in mass input, compaction and surface density. Mean values of this error, averaged over 100 km sections of the traverse, decrease with time from the start of observations in 2004, with a half-time of ∼4 years. After 7 years the mean error is less than the ice equivalent mass imbalance.This project is a contribution to the calibration and validation of the European Space Agency (ESA) CryoSat satellite altimeter and is supported by ESA and by the UK Natural Environment Research Council (NERC) Consortium grant NER/O/S/2003/00620. We are grateful to the NERC Geo- physical Equipment Facility and the University of Edinburgh for the loan of Leica GPS systems. Logistic support for the traverses was provided by CH2M HILL Polar Services, G. Somers, J. Pailthorpe, H. Chamberlain, M. Hignell and J. Sweeny gave invaluable assistance in the field and T. Benham provided Figure 1. Finally, we thank R. Arthern for useful discussions and our Scientific Editor, H. Fricker, and two anonymous reviewers for helpful comments

Set1 Targets Genes with Essential Identity and Tumor-Suppressing Functions in Planarian Stem Cells

Tumor suppressor genes (TSGs) are essential for normal cellular function in multicellular organisms, but many TSGs and tumor-suppressing mechanisms remain unknown. Planarian flatworms exhibit particularly robust tumor suppression, yet the specific mechanisms underlying this trait remain unclear. Here, we analyze histone H3 lysine 4 trimethylation (H3K4me3) signal across the planarian genome to determine if the broad H3K4me3 chromatin signature that marks essential cell identity genes and TSGs in mammalian cells is conserved in this valuable model of in vivo stem cell function. We find that this signature is indeed conserved on the planarian genome and that the lysine methyltransferase Set1 is largely responsible for creating it at both cell identity and putative TSG loci. In addition, we show that depletion of set1 in planarians induces stem cell phenotypes that suggest loss of TSG function, including hyperproliferation and an abnormal DNA damage response (DDR). Importantly, this work establishes that Set1 targets specific gene loci in planarian stem cells and marks them with a conserved chromatin signature. Moreover, our data strongly suggest that Set1 activity at these genes has important functional consequences both during normal homeostasis and in response to genotoxic stress

The Genetics of Axonal Transport and Axonal Transport Disorders

Neurons are specialized cells with a complex architecture that includes elaborate dendritic branches and a long, narrow axon that extends from the cell body to the synaptic terminal. The organized transport of essential biological materials throughout the neuron is required to support its growth, function, and viability. In this review, we focus on insights that have emerged from the genetic analysis of long-distance axonal transport between the cell body and the synaptic terminal. We also discuss recent genetic evidence that supports the hypothesis that disruptions in axonal transport may cause or dramatically contribute to neurodegenerative diseases

Autonomous motivation mediates the relation between goals for physical activity and physical activity behavior in adolescents

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Evolutionary origin and genomic organisation of runt-domain containing genes in arthropods

<p>Abstract</p> <p>Background</p> <p>Gene clusters, such as the <it>Hox </it>gene cluster, are known to have critical roles in development. In eukaryotes gene clusters arise primarily by tandem gene duplication and divergence. Genes within a cluster are often co-regulated, providing selective pressure to maintain the genome organisation, and this co-regulation can result in temporal or spatial co-linearity of gene expression. It has been previously noted that in <it>Drosophila melanogaster</it>, three of the four runt-domain (RD) containing genes are found in a relatively tight cluster on chromosome 1, raising the possibility of a putative functional RD gene cluster in <it>D. melanogaster</it>.</p> <p>Results</p> <p>To investigate the possibility of such a gene cluster, orthologues of the <it>Drosophila melanogaste</it>r RD genes were identified in several endopterygotan insects, two exopterygotan insects and two non-insect arthropods. In all insect species four RD genes were identified and orthology was assigned to the <it>Drosophila </it>sequences by phylogenetic analyses. Although four RD genes were found in the crustacean <it>D. pulex</it>, orthology could not be assigned to the insect sequences, indicating independent gene duplications from a single ancestor following the split of the hexapod lineage from the crustacean lineage.</p> <p>In insects, two chromosomal arrangements of these genes was observed; the first a semi-dispersed cluster, such as in <it>Drosophila</it>, where <it>lozenge </it>is separated from the core cluster of three RD genes often by megabases of DNA. The second arrangement was a tight cluster of the four RD genes, such as in <it>Apis mellifera</it>.</p> <p>This genomic organisation, particularly of the three core RD genes, raises the possibility of shared regulatory elements. <it>In situ </it>hybridisation of embryonic expression of the four RD genes in <it>Drosophila melanogaster </it>and the honeybee <it>A. mellifera </it>shows no evidence for either spatial or temporal co-linearity of expression during embryogenesis.</p> <p>Conclusion</p> <p>All fully sequenced insect genomes contain four RD genes and orthology can be assigned to these genes based on similarity to the <it>D. melanogaster </it>protein sequences. Examination of the genomic organisation of these genes provides evidence for a functional RD gene cluster. RD genes from non-insect arthropods are also clustered, however the lack of orthology between these and insect RD genes suggests this cluster is likely to have resulted from a duplication event independent from that which created the insect RD gene cluster. Analysis of embryonic RD gene expression in two endopterygotan insects, <it>A. mellifera </it>and <it>D. melanogaster</it>, did not show evidence for coordinated gene expression, therefore while the functional significance of this gene cluster remains unknown its maintenance during insect evolution implies some functional significance to the cluster.</p

Effects of Housing Aid on Psychosocial Health after a Disaster

Little is known about whether the provision of aid in the aftermath of a large-scale natural disaster affects psychological well-being. We investigate the effects of housing assistance, a key element of the reconstruction program implemented after the 2004 Indian Ocean tsunami. Population-representative individual-level longitudinal data collected in Aceh, Indonesia, during the decade after the tsunami as part of the Study of the Tsunami Aftermath and Recovery (STAR) are used. Housing aid was targeted to people whose homes were destroyed and, to a lesser extent, damaged by the tsunami and to those who lived, at the time of the tsunami, in communities that sustained the greatest damage. The effects of receipt of aid on post-traumatic stress reactivity (PTSR) are examined using panel data models that take into account observed and unobserved individual-specific fixed characteristics that affect both PTSR and aid receipt, drawing comparisons in each survey wave between individuals who had been living in the same kecamatan when the tsunami hit. Those who received aid have better psychological health; the effects increase with time since aid receipt and are the greatest at two years or longer after the receipt. The effects are concentrated among those whose homes were destroyed in the tsunami

Mixed Candida albicans strain populations in colonized and infected mucosal tissues

Multilocus sequence typing of six Candida albicans colonies from primary isolation plates revealed instances of colony-to-colony microvariation and carriage of two strain types in single oropharyngeal and vaginal samples. Higher rates of colony variation in commensal samples suggest selection of types from mixed populations either in the shift to pathogenicity or the response to antifungal treatment