48 results found
Schon KR, Horvath R, Wei W, et al., 2021, Use of whole genome sequencing to determine genetic basis of suspected mitochondrial disorders: cohort study, BMJ-BRITISH MEDICAL JOURNAL, Vol: 375, ISSN: 0959-535X
Ng RC-L, Jian M, Ma OK-F, et al., 2020, Chronic oral administration of adipoRon reverses cognitive impairments and ameliorates neuropathology in an Alzheimer's disease mouse model, Molecular Psychiatry, ISSN: 1359-4184
Circulating adiponectin (APN) levels decrease with age and obesity. On the other hand, a reduction in APN levels is associated with neurodegeneration and neuroinflammation. We previously showed that aged adiponectin knockout (APN−/−) mice developed Alzheimer’s like pathologies, cerebral insulin resistance, and cognitive impairments. More recently, we also demonstrated that APN deficiency increased Aβ-induced microglia activation and neuroinflammatory responses in 5xFAD mice. There is compelling evidence that deregulated insulin activities or cerebral insulin resistance contributes to neuroinflammation and Alzheimer’s disease (AD) pathogenesis. Here, we demonstrated that APN levels were reduced in the brain of AD patients and 5xFAD mice. We crossbred 5xFAD mice with APN−/− mice to generate APN-deficient 5xFAD (5xFAD;APN−/−). APN deficiency in 5xFAD mice accelerated amyloid loading, increased cerebral amyloid angiopathy, and reduced insulin-signaling activities. Pharmacokinetics study demonstrated adipoRon (APN receptor agonist) was a blood–brain barrier penetrant. AdipoRon improved neuronal insulin-signaling activities and insulin sensitivity in vitro and in vivo. Chronic adipoRon treatment improved spatial memory functions and significantly rescued neuronal and synaptic loss in 5xFAD and 5xFAD;APN−/− mice. AdipoRon lowered plaque and Aβ levels in AD mice. AdipoRon also exerted anti-inflammatory effects by reducing microglial and astrocytes activation as well as suppressing cerebral cytokines levels. The microglial phagocytic activity toward Aβ was restored after adipoRon treatment. Our results indicated that adipoRon exerts multiple beneficial effects providing important therapeutic implications. We propose chronic adipoRon administration as a potential treatment for AD.
Reetz K, Hilgers R-D, Isfort S, et al., 2019, Protocol of a randomized, double-blind, placebo-controlled, parallel-group, multicentre study of the efficacy and safety of nicotinamide in patients with Friedreich ataxia (NICOFA), Neurological Research and Practice, Vol: 1, ISSN: 2524-3489
Introduction: Currently, no treatment that delays with the progression of Friedreich ataxia is available. In the majority of patients Friedreich ataxia is caused by homozygous pathological expansion of GAA repeats in the first intron of the FXN gene. Nicotinamide acts as a histone deacetylase inhibitor. Dose escalation studies have shown, that short term treatment with dosages of up to 4 g/day increase the expression of FXN mRNA and frataxin protein up to the levels of asymptomatic heterozygous gene carriers. The long-term effects and the effects on clinical endpoints, activities of daily living and quality of life are unknown. Methods: The aim of the NICOFA study is to investigate the efficacy and safety of nicotinamide for the treatment of Friedreich ataxia over 24 months. An open-label dose adjustment wash-in period with nicotinamide (phase A: weeks 1-4) to the individually highest tolerated dose of 2-4 g nicotinamide/day will be followed by a 2 (nicotinamide group): 1 (placebo group) randomization (phase B: weeks 5-104). In the nicotinamide group, patients will continue with their individually highest tolerated dose between 2 and 4 g/d per os once daily and the placebo group patients will be receiving matching placebo. Safety assessments will consist of monitoring and recording of all adverse events and serious adverse events, regular monitoring of haematology, blood chemistry and urine values, regular measurement of vital signs and the performance of physical examinations including cardiological signs. The primary outcome is the change in the Scale for the Assessment and Rating of Ataxia (SARA) over time as compared with placebo in patients with Friedreich ataxia based on the linear mixed effect model (LMEM) model. Secondary endpoints are measures of quality of life, functional motor and cognitive measures, clinician's and patient's global impression-change scales as well as the up-regulation of the frataxin protein level, safety and
Natisvili T, Yandim C, Silva R, et al., 2016, Transcriptional activation of pericentromeric satellite repeats and disruption of centromeric clustering upon proteasome inhibition, PLOS One, Vol: 11, ISSN: 1932-6203
Heterochromatinisation of pericentromeres, which in mice consist of arrays of major satellite repeats, are important for centromere formation and maintenance of genome stability. The dysregulation of this process has been linked to genomic stress and various cancers. Here we show in mice that the proteasome binds to major satellite repeats and proteasome inhibition by MG132 results in their transcriptional de-repression; this de-repression is independent of cell-cycle perturbation. The transcriptional activation of major satellite repeats upon proteasome inhibition is accompanied by delocalisation of heterochromatin protein 1 alpha (HP1α) from chromocentres, without detectable change in the levels of histone H3K9me3, H3K4me3, H3K36me3 and H3 acetylation on the major satellite repeats. Moreover, inhibition of the proteasome was found to increase the number of chromocentres per cell, reflecting destabilisation of the chromocentre structures. Our findings suggest that the proteasome plays a role in maintaining heterochromatin integrity of pericentromeres.
Tam KT, Chan PK, Zhang W, et al., 2016, Identification of a novel distal regulatory element of the human Neuroglobin gene by the chromosome conformation capture approach, Nucleic Acids Research, Vol: 45, Pages: 115-126, ISSN: 1362-4962
Neuroglobin (NGB) is predominantly expressed in the brain and retina. Studies suggest that NGB exerts protective effects to neuronal cells and is implicated in reducing the severity of stroke and Alzheimer's disease. However, little is known about the mechanisms which regulate the cell type-specific expression of the gene. In this study, we hypothesized that distal regulatory elements (DREs) are involved in optimal expression of the NGB gene. By chromosome conformation capture we identified two novel DREs located -70 kb upstream and +100 kb downstream from the NGB gene. ENCODE database showed the presence of DNaseI hypersensitive and transcription factors binding sites in these regions. Further analyses using luciferase reporters and chromatin immunoprecipitation suggested that the -70 kb region upstream of the NGB gene contained a neuronal-specific enhancer and GATA transcription factor binding sites. Knockdown of GATA-2 caused NGB expression to drop dramatically, indicating GATA-2 as an essential transcription factor for the activation of NGB expression. The crucial role of the DRE in NGB expression activation was further confirmed by the drop in NGB level after CRISPR-mediated deletion of the DRE. Taken together, we show that the NGB gene is regulated by a cell type-specific loop formed between its promoter and the novel DRE.
Festenstein RJ, Nageshwaran S, 2015, Epigenetics and triplet-repeat neurological diseases, Frontiers in Neurology, Vol: 6, ISSN: 1664-2295
The term “junk DNA” has been reconsidered following the delineation of the functional significance of repetitive DNA regions. Typically associated with centromeres and telomeres, DNA repeats are found in nearly all organisms throughout their genomes. Repetitive regions are frequently heterochromatinized resulting in silencing of intrinsic and nearby genes. However, this is not a uniform rule, with several genes known to require such an environment to permit transcription. Repetitive regions frequently exist as dinucleotide, trinucleotide, and tetranucleotide repeats. The association between repetitive regions and disease was emphasized following the discovery of abnormal trinucleotide repeats underlying spinal and bulbar muscular atrophy (Kennedy’s disease) and fragile X syndrome of mental retardation (FRAXA) in 1991. In this review, we provide a brief overview of epigenetic mechanisms and then focus on several diseases caused by DNA triplet-repeat expansions, which exhibit diverse epigenetic effects. It is clear that the emerging field of epigenetics is already generating novel potential therapeutic avenues for this group of largely incurable diseases.
Hajkova P, Nashun B, Hill PWS, et al., 2015, Continuous histone replacement by Hira is essential for normal transcriptional regulation and efficient de novo DNA methylation during mouse oogenesis, Molecular Cell, Vol: 60, Pages: 611-625, ISSN: 1097-4164
The integrity of chromatin, which provides a dynamic template for all DNA-related processes in eukaryotes, is maintained through replication-dependent and -independent assembly pathways. To address the role of histone deposition in the absence of DNA replication, we deleted the H3.3 chaperone Hira in developing mouse oocytes. We show that chromatin of non-replicative developing oocytes is dynamic and that lack of continuous H3.3/H4 deposition alters chromatin structure, resulting in increased DNase I sensitivity, the accumulation of DNA damage, and a severe fertility phenotype. On the molecular level, abnormal chromatin structure leads to a dramatic decrease in the dynamic range of gene expression, the appearance of spurious transcripts, and inefficient de novo DNA methylation. Our study thus unequivocally shows the importance of continuous histone replacement and chromatin homeostasis for transcriptional regulation and normal developmental progression in a non-replicative system in vivo.
Festenstein R, 2015, OVERCOMING TRIPLET REPEAT-MEDIATED EPIGENETIC SILENCING IN HUMANS, Journal of Intellectual Disability Research, Vol: 59, Pages: 801-801, ISSN: 1365-2788
Gavriel C, Thomik A, Lourenco PR, et al., 2015, Kinematic body sensor networks and behaviourmetrics for objective efficacy measurements in neurodegenerative disease drug trials, IEEE Body Sensor Networks Conference 2015
In this study, we have deployed body sensor network (BSN) technology in clinical trials for monitoring and quantifying the behaviour of Friedreich's Ataxia (FRDA) patients on a longitudinal scale. Using our ETHO1 wireless BSN nodes, we captured motion time-series from patients' sleep and we extracted behavioural biomarkers that can objectively highlight the progression of the disease throughout time. The clinical scales that are currently used to capture the stage of the ataxic disease require patients to perform a series of lengthy tasks where clinicians can observe patients' performance and aggregate a score that represents the stage of the disease. Unfortunately, these scales have been shown to be inconsistent mainly due to the underlying subjective measures, they are highly dependent on the assessor's experience and they also have low sensitivity that fails to capture the slow disease progression in short periods of time. This entails lengthy clinical trials for monitoring the effects of any drugs on patients that has huge effects on the cost of medical healthcare. Using the data we collected from our clinical trials, we extracted behavioural biomarkers based on the distribution of patients' movement and stillness durations in bed during their sleep and also the intensity of their movements. Our biomarkers exhibit trends similar to patients' SARA scores, one of the standard clinical scales used for capturing the disease progression in FRDA patients. This establishes a proof of concept that BSN technology can objectively capture patients' behaviour and can be used to perform rapid efficacy of clinical measurements on the effects of drugs. Additionally, understanding the underlying effects of Friedreich's Ataxia on our motor control system can potentially enable detection of the disease at a very early stage.
Sylaidi ANASTASIA, Rente Lourenço P, Nageshwaran S, et al., 2015, F2move: fMRI-compatible haptic object manipulation system for closed-loop motor control studies, 7th Annual International IEEE EMBS Conference on Neural Engineering, Publisher: IEEE, Pages: 1104-1107
Functional neuroimaging plays a key role in addressing open questions in systems and motor neuroscience directly applicable to brain machine interfaces. Building on our low-cost motion capture technology (fMOVE), we developed f2MOVE, an fMRI-compatible system for 6DOF goal-directed hand and wrist movements of human subjects enabling closed-loop sensorimotor haptic experiments with simultaneous neuroimaging. f2MOVE uses a high-zoom lens high frame rate camera and a motion tracking algorithm that tracks in real-time the position of special markers attached to a hand-held object in a novel customized haptic interface. The system operates with high update rate ($120$~Hz) and sufficiently low time delays ($<20$~ms) to enable visual feedback while complex, goal-oriented movements are recorded. We present here both the accuracy of our motion tracking against a reference signal and the efficacy of the system to evoke motor control specific brain activations in healthy subjects. Our technology and approach thus support the real-time, closed-loop study of the neural foundations of complex haptic motor tasks using neuroimaging.
Gavriel C, Thomik A, Lourenco P, et al., 2015, Towards neurobehavioral biomarkers for longitudinal monitoring ofneurodegeneration with wearable body sensor networks, IEEE Neural Engineering (NER), Pages: 348-351
This study focuses on the objective quantificationof the disease progression in patients with Friedreich’s Ataxia(FRDA) through the use of kinematic body sensor networktechnology. Currently, this quantification is performed througha series of task-oriented score-based metrics, which, althoughthey provide an efficient way of quantifying the ataxic disease,they are dependent on the assessor’s experience and they alsopresent high levels of variability. We used our ETHO1 inertialmotion capturing sensors for longitudinal monitoring of FRDApatients during sleep and we collected behavioural timeseriesfrom which we extracted biomarkers that can objectivelyhighlight the subtle changes of patients’ motor control system.These biomarkers exhibit trends consistent with the clinicalassessments of the disease.
The different cellular phenotypes that compose multicellular organisms are generated by the expression of house-keeping and cell-type specific genes and repression of inappropriate ones. The pattern of gene expression that defines a cell-type is termed the ‘epigenotype’ which is established and maintained by ‘epigenetic’ mechanisms able to govern gene expression regardless of the underlying genetic code. Genomic imprinting, where genes are expressed from only one of the inherited parental alleles, represents a classical example of epigenetic gene regulation; memory of the expression state, presumably established during gametic meiosis, is thus transmitted to the zygote, maintained throughout embryonic and post-embryonic development, and re-established during gametogenesis of the newly formed organism in a sex specific manner. It follows that epigenetic ‘plasticity’ would enable pluripotent stem cells to give rise to a variety of epigenotypes. Cells can acquire an epigenotype by modulating the availability of trans-acting factors to regulatory cis-acting genetic elements that specify gene activity or inactivity. Such availability can be controlled by the manner in which DNA is packaged as chromatin inside the nucleus. Silent genes may thus be packaged in ‘condensed’ chromatin such as heterochromatin. Conversely, active genes may be packaged in ‘open’ chromatin, termed euchromatin. It is clear that previously mysterious aspects of gene regulation that can be grouped under the term ‘epigenetic’ or ‘epigenomic’ are finally yielding to molecular biology approaches and have revealed a new level of genome organization and regulation. Already, the rapid increase in our understanding of the control of gene expression patterns has revealed potentially powerful new therapeutic avenues for an ever-increasing number of human diseases, and a great variety of human cancers, many of which are curren
Libri V, Yandim C, Athanasopoulos S, et al., 2014, Epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia: an exploratory, open-label, dose-escalation study, The Lancet, Vol: 384, Pages: 504-513, ISSN: 0140-6736
BackgroundFriedreich's ataxia is a progressive degenerative disorder caused by deficiency of the frataxin protein. Expanded GAA repeats within intron 1 of the frataxin (FXN) gene lead to its heterochromatinisation and transcriptional silencing. Preclinical studies have shown that the histone deacetylase inhibitor nicotinamide (vitamin B3) can remodel the pathological heterochromatin and upregulate expression of FXN. We aimed to assess the epigenetic and neurological effects and safety of high-dose nicotinamide in patients with Friedreich's ataxia.MethodsIn this exploratory, open-label, dose-escalation study in the UK, male and female patients (aged 18 years or older) with Friedreich's ataxia were given single doses (phase 1) and repeated daily doses of 2–8 g oral nicotinamide for 5 days (phase 2) and 8 weeks (phase 3). Doses were gradually escalated during phases 1 and 2, with individual maximum tolerated doses used in phase 3. The primary outcome was the upregulation of frataxin expression. We also assessed the safety and tolerability of nicotinamide, used chromatin immunoprecipitation to investigate changes in chromatin structure at the FXN gene locus, and assessed the effect of nicotinamide treatment on clinical scales for ataxia. This study is registered with ClinicalTrials.gov, number NCT01589809.FindingsNicotinamide was generally well tolerated; the main adverse event was nausea, which in most cases was mild, dose-related, and resolved spontaneously or after dose reduction, use of antinausea drugs, or both. Phase 1 showed a dose-response relation for proportional change in frataxin protein concentration from baseline to 8 h post-dose, which increased with increasing dose (p=0·0004). Bayesian analysis predicted that 3·8 g would result in a 1·5-times increase and 7·5 g in a doubling of frataxin protein concentration. Phases 2 and 3 showed that daily dosing at 3·5–6 g resulted in a sustained and significant (p<0&m
Yandim C, Natisvili T, Festenstein R, 2013, Gene regulation and epigenetics in Friedreich's ataxia, JOURNAL OF NEUROCHEMISTRY, Vol: 126, Pages: 21-42, ISSN: 0022-3042
Chan PK, Torres R, Yandim C, et al., 2013, Heterochromatinization induced by GAA-repeat hyperexpansion in Friedreichs ataxia can be reduced upon HDAC inhibition by vitamin B3, HUMAN MOLECULAR GENETICS, Vol: 22, Pages: 2662-2675, ISSN: 0964-6906
Goula A-V, Stys A, Chan JPK, et al., 2012, Transcription Elongation and Tissue-Specific Somatic CAG Instability, PLOS GENETICS, Vol: 8, ISSN: 1553-7404
Festenstein R, Chan JPK, 2012, Context is everything: activators can also repress, NATURE STRUCTURAL & MOLECULAR BIOLOGY, Vol: 19, Pages: 973-975, ISSN: 1545-9993
Wijchers PJ, Festenstein RJ, 2011, Epigenetic regulation of autosomal gene expression by sex chromosomes, TRENDS IN GENETICS, Vol: 27, Pages: 132-140, ISSN: 0168-9525
Guillemette B, Drogaris P, Lin H-HS, et al., 2011, H3 lysine 4 8 is acetylated at active gene promoters and is regulated by H3 lysine 4 methylation, PLoS Genetics, Vol: 7, Pages: 1-16, ISSN: 1553-7390
Methylation of histone H3 lysine 4 (H3K4me) is an evolutionarily conserved modification whose role in the regulation of gene expression has been extensively studied. In contrast, the function of H3K4 acetylation (H3K4ac) has received little attention because of a lack of tools to separate its function from that of H3K4me. Here we show that, in addition to being methylated, H3K4 is also acetylated in budding yeast. Genetic studies reveal that the histone acetyltransferases (HATs) Gcn5 and Rtt109 contribute to H3K4 acetylation in vivo. Whilst removal of H3K4ac from euchromatin mainly requires the histone deacetylase (HDAC) Hst1, Sir2 is needed for H3K4 deacetylation in heterochomatin. Using genome-wide chromatin immunoprecipitation (ChIP), we show that H3K4ac is enriched at promoters of actively transcribed genes and located just upstream of H3K4 tri-methylation (H3K4me3), a pattern that has been conserved in human cells. We find that the Set1-containing complex (COMPASS), which promotes H3K4me2 and -me3, also serves to limit the abundance of H3K4ac at gene promoters. In addition, we identify a group of genes that have high levels of H3K4ac in their promoters and are inadequately expressed in H3-K4R, but not in set1Δ mutant strains, suggesting that H3K4ac plays a positive role in transcription. Our results reveal a novel regulatory feature of promoter-proximal chromatin, involving mutually exclusive histone modifications of the same histone residue (H3K4ac and H3K4me).
Bishop MW, Chakraborty S, Matthews GAC, et al., 2010, Hyperexcitable Substantia Nigra Dopamine Neurons in PINK1- and HtrA2/Omi-Deficient Mice, JOURNAL OF NEUROPHYSIOLOGY, Vol: 104, Pages: 3009-3020, ISSN: 0022-3077
Wijchers PJ, Yandim C, Panousopoulou E, et al., 2010, Sexual Dimorphism in Mammalian Autosomal Gene Regulation Is Determined Not Only by Sry but by Sex Chromosome Complement As Well, DEVELOPMENTAL CELL, Vol: 19, Pages: 477-484, ISSN: 1534-5807
Hiragami-Hamada K, Xie SQ, Saveliev A, et al., 2009, The molecular basis for stability of heterochromatin-mediated silencing in mammals, Epigenetics & Chromatin, Vol: 2, ISSN: 1756-8935
The archetypal epigenetic phenomenon of position effect variegation (PEV) in Drosophila occurs when a gene is brought abnormally close to heterochromatin, resulting in stochastic silencing of the affected gene in a proportion of cells that would normally express it. PEV has been instrumental in unraveling epigenetic mechanisms. Using an in vivo mammalian model for PEV we have extensively investigated the molecular basis for heterochromatin-mediated gene silencing. Here we distinguish 'epigenetic effects' from other cellular differences by studying ex vivo cells that are identical, apart from the expression of the variegating gene which is silenced in a proportion of the cells. By separating cells according to transgene expression we show here that silencing appears to be associated with histone H3 lysine 9 trimethylation (H3K9me3), DNA methylation and the localization of the silenced gene to a specific nuclear compartment enriched in these modifications. In contrast, histone H3 acetylation (H3Ac) and lysine 4 di or tri methylation (H3K4me2/3) are the predominant modifications associated with expression where we see the gene in a euchromatic compartment. Interestingly, DNA methylation and inaccessibility, rather than H3K9me3, correlated most strongly with resistance to de-repression by cellular activation. These results have important implications for understanding the contribution of specific factors involved in the establishment and maintenance of gene silencing and activation in vivo.
Wijchers PJEC, Huntley D, Kazazi D, et al., 2009, VISUALISATION OF HETEROCHROMATIN-MEDIATED SILENCING: TARGETING OF HP1 AND SUV39H1 TO CHROMOSOMAL REGIONS IN VIVO IN MAMMALS, 3rd Marie Curie-Genome Architecture in Relation to Disease Meeting (MC-GARD), Publisher: IOS PRESS, Pages: 107-107, ISSN: 1570-5870
Wu K, Lane RJ, Perry RJ, et al., 2009, A NOVEL PRESENILIN 1 MUTATION IN EARLY ONSET ALZHEIMER'S DISEASE WITH SPASTIC PARAPARESIS, Spring Scientific Meeting of the Association-of-British-Neurologists, Publisher: B M J PUBLISHING GROUP, Pages: 115-115, ISSN: 0022-3050
Uribe Lewis SL, Everett C, Festenstein RJ, 2008, Epigenomics and Human Disease, Genomics and clinical medicine, Editors: Kumar, Weatherall, Publisher: Oxford University Press, USA, ISBN: 9780195188134
Epigenomics and Human Disease Santiago Uribe Lewis, Christopher Everett, ... Festenstein, 2002). Processes exist to allow changes in accessibility at both ...
Festenstein R, 2006, Breaking the silence in Friedreich's ataxia, NATURE CHEMICAL BIOLOGY, Vol: 2, Pages: 512-513, ISSN: 1552-4450
Manderson AP, Carlucci F, Lachmann PJ, et al., 2006, The in vivo expression of actin/salt-resistant hyperactive DNase I inhibits the development of anti-ssDNA and anti-histone autoantibodies in a murine model of systemic lupus erythematosus, ARTHRITIS RESEARCH & THERAPY, Vol: 8, ISSN: 1478-6354
Poot RA, Festenstein R, 2006, Epigenetic regulation: DNA confers identity but is not enough to maintain it, Genome Biology, Vol: 7, ISSN: 1474-7596
A report on the conference 'Epigenetics and the dynamic genome', 30 June-2 July 2005, Babraham, Cambridge, UK.
Hiragami K, Festenstein R, 2005, Heterochromatin protein 1: a pervasive controlling influence, CELLULAR AND MOLECULAR LIFE SCIENCES, Vol: 62, Pages: 2711-2726, ISSN: 1420-682X
Festenstein R, Aragon L, 2003, Decoding the epigenetic effects of chromatin., Genome Biology, Vol: 4, ISSN: 1474-760X
A report on the Alan Wolffe EMBO Workshop on 'Chromatin and Epigenetics', Heidelberg, Germany, 19-22 June 2003.
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