119 research outputs found
Mechanisms of rDNA silencing and the Nucleolar Remodelling Complex (NoRC)
Protein synthesis in living cells requires functional ribosomes which are composed of ribosomal proteins and ribosomal RNA (rRNA) molecules. rRNA is transcribed from tandemly repeated ribosomal DNA (rDNA) which is organised into a nuclear compartment termed the nucleolus in S-phase cells. It is essential that rDNA transcription is properly regulated in order to meet the cell's requirements for ribosomes and hence protein synthesis without wasting metabolic energy. In the last twenty years many proteins involved in regulating this process have been identified, suggesting that most organisms contain multiple protein complexes that regulate rDNA packaging and transcription. Importantly, it has become clear that errors in the function of these proteins can permit aberrant cellular growth, including in several classes of cancer. In this review, I discuss the history of how protein complexes such as the Nucleolar Remodelling Complex (NoRC) were discovered, using examples from humans and from model research organisms from different biological groups. I will discuss recent discoveries of the critical roles of rDNA-binding complexes in nucleolar assembly, the widespread occurrence of regulatory non-coding RNAs which interact with these complexes, and the pathways which regulate rDNA transcription in response to cellular energy status. Finally, I will review the growing evidence that misregulation of rDNA transcription not only allows the growth of cancerous cells, but can trigger oncogenesis itself
Paternally expressed imprinted genes under positive Darwinian selection in Arabidopsis thaliana
Genomic imprinting is an epigenetic phenomenon where autosomal genes display uniparental expression depending on whether they are maternally or paternally inherited. Genomic imprinting can arise from parental conflicts over resource allocation to the offspring, which could drive imprinted loci to evolve by positive selection. We investigate whether positive selection is associated with genomic imprinting in the inbreeding species Arabidopsis thaliana. Our analysis of 140 genes regulated by genomic imprinting in the A. thaliana seed endosperm demonstrates they are evolving more rapidly than expected. To investigate whether positive selection drives this evolutionary acceleration, we identified orthologs of each imprinted gene across 34 plant species and elucidated their evolutionary trajectories. Increased positive selection was sought by comparing its incidence among imprinted genes with non-imprinted controls. Strikingly, we find a statistically significant enrichment of imprinted paternally expressed genes (iPEGs) evolving under positive selection, 50.6% of the total, but no such enrichment for positive selection among imprinted maternally expressed genes (iMEGs). This suggests that maternally- and paternally-expressed imprinted genes are subject to different selective pressures. Almost all positively selected amino acids were fixed across 80 sequenced A. thaliana accessions, suggestive of selective sweeps in the A. thaliana lineage. The imprinted genes under positive selection are involved in processes important for seed development including auxin biosynthesis and epigenetic regulation. Our findings support a genomic imprinting model for plants where positive selection can affect paternally-expressed genes due to continued conflict with maternal sporophyte tissues, even when parental conflict is reduced in predominantly inbreeding species
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Barriers and facilitators to adherence to group exercise in institutionalized older people living with dementia: a systematic review
Objectives
Research suggests targeted exercise is important for people living with dementia, especially those living in residential care. The aim of this review was to collect and synthesize evidence on the known barriers and facilitators to adherence to group exercise of institutionalized older people living with dementia.
Methods
We searched all available electronic databases. Additionally, we searched trial registries (clinicaltrial.gov, and WHO ICTRP) for ongoing studies. We searched for and included papers from January 1990 until September 2017 in any language. We included randomized, non-randomized trials. Studies were not eligible if participants were either healthy older people or people suffering from dementia but not living in an institution. Studies were also excluded if they were not focused on barriers and facilitators to adherence to group exercise.
Results
Using narrative analysis, we identified the following themes for barriers: bio-medical reasons and mental wellbeing and physical ability, relationships dynamics, and socioeconomic reasons. The facilitators were grouped under the following thematic frames: bio-medical benefits and benefits related to physical ability, feelings and emotions and confidence improvements, therapist and group relationships dynamics and activity related reasons.
Conclusions
We conclude that institutionalized older people living with dementia, even those who are physically frail, incontinent and/or have mild dementia can demonstrate certain level of exercise adherence, and therefore can respond positively to exercise programs. Tailored, individually-adjusted and supported physical activity, led by a knowledgeable, engaging and well communicating therapist/facilitator improves the adherence to group exercise interventions of institutionalized older people living with dementia
Penetrance of colorectal cancer among MLH1/MSH2 carriers participating in the colorectal cancer familial registry in Ontario
<p>Abstract</p> <p>Background</p> <p>Several DNA mismatch repair (MMR) genes, responsible for the majority of Lynch Syndrome cancers, have been identified, predominantly <it>MLH1 </it>and <it>MSH2</it>, but the risk associated with these mutations is still not well established. The aim of this study is to provide population-based estimates of the risks of colorectal cancer (CRC) by gender and mutation type from the Ontario population.</p> <p>Methods</p> <p>We analyzed 32 families segregating MMR mutations selected from the Ontario Familial Colorectal Cancer Registry and including 199 first-degree and 421 second-degree relatives. The cumulative risks were estimated using a modified segregation-based approach, which allows correction for the ascertainment of the Lynch Syndrome families and permits account to be taken for missing genotype information.</p> <p>Results</p> <p>The risks of developing CRC by age 70 were 60% and 47% among men and women carriers of any MMR mutation, respectively. Among <it>MLH1 </it>mutation carriers, males had significantly higher risks than females at all ages (67% vs. 35% by age 70, p-value = 0.02), while the risks were similar in <it>MSH2 </it>carriers (about 54%). The relative risk associated with <it>MLH1 </it>was almost constant with age (hazard ratio (HR) varied between 5.5-5.1 over age 30–70), while the HR for <it>MSH2 </it>decreased with age (from 13.1 at age 30 to 5.4 at age 70).</p> <p>Conclusion</p> <p>This study provides a unique population-based study of CRC risks among <it>MSH2</it>/<it>MLH1 </it>mutation carriers in a Canadian population and can help to better define and understand the patterns of risks among members of Lynch Syndrome families.</p
Mutations in Wnt2 Alter Presynaptic Motor Neuron Morphology and Presynaptic Protein Localization at the Drosophila Neuromuscular Junction
Wnt proteins are secreted proteins involved in a number of developmental processes including neural development and synaptogenesis. We sought to determine the role of the Drosophila Wnt7b ortholog, Wnt2, using the neuromuscular junction (NMJ). Mutations in wnt2 produce an increase in the number of presynaptic branches and a reduction in immunolabeling of the active zone proteins, Bruchpilot and synaptobrevin, at the NMJ. There was no change, however, in immunolabeling for the presynaptic proteins cysteine-string protein (CSP) and synaptotagmin, nor the postsynaptic proteins GluRIIA and DLG at the NMJ. Consistent with the presynaptic defects, wnt2 mutants exhibit approximately a 50% reduction in evoked excitatory junctional currents. Rescue, RNAi, and tissue-specific qRT-PCR experiments indicate that Wnt2 is expressed by the postsynaptic cell where it may serve as a retrograde signal that regulates presynaptic morphology and the localization of presynaptic proteins
Initial Genomics of the Human Nucleolus
We report for the first time the genomics of a nuclear compartment of the eukaryotic cell. 454 sequencing and microarray analysis revealed the pattern of nucleolus-associated chromatin domains (NADs) in the linear human genome and identified different gene families and certain satellite repeats as the major building blocks of NADs, which constitute about 4% of the genome. Bioinformatic evaluation showed that NAD–localized genes take part in specific biological processes, like the response to other organisms, odor perception, and tissue development. 3D FISH and immunofluorescence experiments illustrated the spatial distribution of NAD–specific chromatin within interphase nuclei and its alteration upon transcriptional changes. Altogether, our findings describe the nature of DNA sequences associated with the human nucleolus and provide insights into the function of the nucleolus in genome organization and establishment of nuclear architecture
A Cell Cycle Role for the Epigenetic Factor CTCF-L/BORIS
CTCF is a ubiquitous epigenetic regulator that has been proposed as a master keeper of chromatin organisation. CTCF-like,
or BORIS, is thought to antagonise CTCF and has been found in normal testis, ovary and a large variety of tumour cells. The
cellular function of BORIS remains intriguing although it might be involved in developmental reprogramming of gene
expression patterns. We here unravel the expression of CTCF and BORIS proteins throughout human epidermis. While CTCF
is widely distributed within the nucleus, BORIS is confined to the nucleolus and other euchromatin domains. Nascent RNA
experiments in primary keratinocytes revealed that endogenous BORIS is present in active transcription sites. Interestingly,
BORIS also localises to interphase centrosomes suggesting a role in the cell cycle. Blocking the cell cycle at S phase or
mitosis, or causing DNA damage, produced a striking accumulation of BORIS. Consistently, ectopic expression of wild type
or GFP- BORIS provoked a higher rate of S phase cells as well as genomic instability by mitosis failure. Furthermore, downregulation
of endogenous BORIS by specific shRNAs inhibited both RNA transcription and cell cycle progression. The results
altogether suggest a role for BORIS in coordinating S phase events with mitosis
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