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Toward a Broader View of Ube3a in a Mouse Model of Angelman Syndrome: Expression in Brain, Spinal Cord, Sciatic Nerve and Glial Cells.
Grier MD, Carson RP, Lagrange AH
(2015) PLoS One 10: e0124649
MeSH Terms: Alleles, Angelman Syndrome, Animals, Astrocytes, Brain, Cell Extracts, Cells, Cultured, Disease Models, Animal, Female, Gene Silencing, Genomic Imprinting, Humans, Male, Mice, Mice, Inbred C57BL, Neuroglia, Oligodendroglia, Sciatic Nerve, Spinal Cord, Time Factors, Ubiquitin-Protein Ligases
Show Abstract · Added March 14, 2018
Angelman Syndrome (AS) is a devastating neurodevelopmental disorder characterized by developmental delay, speech impairment, movement disorder, sleep disorders and refractory epilepsy. AS is caused by loss of the Ube3a protein encoded for by the imprinted Ube3a gene. Ube3a is expressed nearly exclusively from the maternal chromosome in mature neurons. While imprinting in neurons of the brain has been well described, the imprinting and expression of Ube3a in other neural tissues remains relatively unexplored. Moreover, given the overwhelming deficits in brain function in AS patients, the possibility of disrupted Ube3a expression in the infratentorial nervous system and its consequent disability have been largely ignored. We evaluated the imprinting status of Ube3a in the spinal cord and sciatic nerve and show that it is also imprinted in these neural tissues. Furthermore, a growing body of clinical and radiological evidence has suggested that myelin dysfunction may contribute to morbidity in many neurodevelopmental syndromes. However, findings regarding Ube3a expression in non-neuronal cells of the brain have varied. Utilizing enriched primary cultures of oligodendrocytes and astrocytes, we show that Ube3a is expressed, but not imprinted in these cell types. Unlike many other neurodevelopmental disorders, AS symptoms do not become apparent until roughly 6 to 12 months of age. To determine the temporal expression pattern and silencing, we analyzed Ube3a expression in AS mice at several time points. We confirm relaxed imprinting of Ube3a in neurons of the postnatal developing cortex, but not in structures in which neurogenesis and migration are more complete. This furthers the hypothesis that the apparently normal window of development in AS patients is supported by an incompletely silenced paternal allele in developing neurons, resulting in a relative preservation of Ube3a expression during this crucial epoch of early development.
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21 MeSH Terms
Ube3a imprinting impairs circadian robustness in Angelman syndrome models.
Shi SQ, Bichell TJ, Ihrie RA, Johnson CH
(2015) Curr Biol 25: 537-45
MeSH Terms: ARNTL Transcription Factors, Analysis of Variance, Angelman Syndrome, Animals, Body Weight, Chronotherapy, Circadian Rhythm, Gene Deletion, Genomic Imprinting, Humans, Liver, Mice, Neurons, Sleep Wake Disorders, Ubiquitin-Protein Ligases
Show Abstract · Added February 12, 2015
BACKGROUND - The paternal allele of Ube3a is silenced by imprinting in neurons, and Angelman syndrome (AS) is a disorder arising from a deletion or mutation of the maternal Ube3a allele, which thereby eliminates Ube3a neuronal expression. Sleep disorders such as short sleep duration and increased sleep onset latency are very common in AS.
RESULTS - We found a unique link between neuronal imprinting of Ube3a and circadian rhythms in two mouse models of AS, including enfeebled circadian activity behavior and slowed molecular rhythms in ex vivo brain tissues. As a consequence of compromised circadian behavior, metabolic homeostasis is also disrupted in AS mice. Unsilencing the paternal Ube3a allele restores functional circadian periodicity in neurons deficient in maternal Ube3a but does not affect periodicity in peripheral tissues that are not imprinted for uniparental Ube3a expression. The ubiquitin ligase encoded by Ube3a interacts with the central clock components BMAL1 and BMAL2. Moreover, inactivation of Ube3a expression elevates BMAL1 levels in brain regions that control circadian behavior of AS-model mice, indicating an important role for Ube3a in modulating BMAL1 turnover.
CONCLUSIONS - Ube3a expression constitutes a direct mechanistic connection between symptoms of a human neurological disorder and the central circadian clock mechanism. The lengthened circadian period leads to delayed phase, which could explain the short sleep duration and increased sleep onset latency of AS subjects. Moreover, we report the pharmacological rescue of an AS phenotype, in this case, altered circadian period. These findings reveal potential treatments for sleep disorders in AS patients.
Copyright © 2015 Elsevier Ltd. All rights reserved.
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15 MeSH Terms
Genomic landscape of human allele-specific DNA methylation.
Fang F, Hodges E, Molaro A, Dean M, Hannon GJ, Smith AD
(2012) Proc Natl Acad Sci U S A 109: 7332-7
MeSH Terms: Algorithms, Alleles, Chromosomes, Human, X, Cluster Analysis, CpG Islands, DNA Methylation, Embryonic Stem Cells, Female, Genome, Human, Genomic Imprinting, Humans, Induced Pluripotent Stem Cells, Male, Models, Genetic
Show Abstract · Added February 15, 2016
DNA methylation mediates imprinted gene expression by passing an epigenomic state across generations and differentially marking specific regulatory regions on maternal and paternal alleles. Imprinting has been tied to the evolution of the placenta in mammals and defects of imprinting have been associated with human diseases. Although recent advances in genome sequencing have revolutionized the study of DNA methylation, existing methylome data remain largely untapped in the study of imprinting. We present a statistical model to describe allele-specific methylation (ASM) in data from high-throughput short-read bisulfite sequencing. Simulation results indicate technical specifications of existing methylome data, such as read length and coverage, are sufficient for full-genome ASM profiling based on our model. We used our model to analyze methylomes for a diverse set of human cell types, including cultured and uncultured differentiated cells, embryonic stem cells and induced pluripotent stem cells. Regions of ASM identified most consistently across methylomes are tightly connected with known imprinted genes and precisely delineate the boundaries of several known imprinting control regions. Predicted regions of ASM common to multiple cell types frequently mark noncoding RNA promoters and represent promising starting points for targeted validation. More generally, our model provides the analytical complement to cutting-edge experimental technologies for surveying ASM in specific cell types and across species.
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14 MeSH Terms
Parent-of-origin effects of the serotonin transporter gene associated with autism.
Kistner-Griffin E, Brune CW, Davis LK, Sutcliffe JS, Cox NJ, Cook EH
(2011) Am J Med Genet B Neuropsychiatr Genet 156: 139-44
MeSH Terms: Adolescent, Adult, Alleles, Child, Child Development Disorders, Pervasive, Child, Preschool, Female, Genomic Imprinting, Genotype, Humans, Mothers, Phenotype, Polymorphism, Genetic, Serotonin Plasma Membrane Transport Proteins, Young Adult
Show Abstract · Added February 20, 2014
A promoter-linked insertion/deletion polymorphism of the serotonin transporter gene (SLC6A4) has been implicated in autism spectrum disorders (ASDs) in numerous family based association studies. However, the results of these investigations have been inconsistent in that both the long and short alleles have been shown to be over-transmitted to affected offspring. In order to further elucidate the relationship between the 5-HTTLPR variant and autism risk, we undertook a thorough study of parent-of-origin effects, maternal genotype effects, and offspring genotype effects in a sample of affected offspring from the Autism Genetic Resource Exchange (AGRE). Both the overall autism phenotype and measures of autism behaviors from the Autism Diagnostic Interview-Revised [Lord et al. (1994); J Autism Dev Disord 24(5): 659–685] were considered. We found evidence of over-transmission (risk allele short, P = 0.012), maternal effects (risk allele long, P = 0.035), and parent-of-origin effects (risk allele short from mother, P = 0.018) of the 5-HTTLPR variant in the AGRE sample. Population- and gender-specific effects were also explored as associations may be heterogeneous across populations and sexes. Parent-of-origin effects of the variant were associated with maternally inherited copies of the short allele that resulted in more impaired overall level of language (P = 0.04). Our study was conducted to further investigate the 5-HTTLPR risk variants by identifying allelic associations that may be population-specific, phenotype-specific, or conferred by maternal or parent-of-origin effects. In light of conflicting observations from previous studies, these are just a few of the possible explanations that deserve attention.
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15 MeSH Terms
Loss of imprinting and marked gene elevation are 2 forms of aberrant IGF2 expression in colorectal cancer.
Cheng YW, Idrees K, Shattock R, Khan SA, Zeng Z, Brennan CW, Paty P, Barany F
(2010) Int J Cancer 127: 568-77
MeSH Terms: Colorectal Neoplasms, DNA Methylation, Genomic Imprinting, Humans, Insulin-Like Growth Factor II, Polymorphism, Genetic, Promoter Regions, Genetic
Show Abstract · Added March 28, 2014
Loss of imprinting (LOI) of insulin-like growth factor 2 (IGF2) is a common event in many cancers and typically activates the maternally silenced allele. The resulting biallelic IGF2 expression correlates strongly with the hypomethylation of a differentially methylated region (DMR) near its promoter. It has also been shown that IGF2 undergoes overexpression in human malignancies; nevertheless, this phenomenon and its link to aberrant DMR methylation have not been reported in colorectal cancer (CRC). The aim of this study was to determine the relationship between IGF2 LOI, overexpression and DMR hypomethylation in CRC. By analyzing IGF2 and H19 methylation in 97 primary CRC and 64 matched normal colorectal tissues, we have shown a significant correlation between IGF2 LOI and DMR hypomethylation of IGF2 and H19. Additionally, when analyzing Affymetrix expression data of 167 primary CRC tumors and 32 normal tissues, 15% of tumors showed marked IGF2 elevation. We further investigated if substantially elevated IGF2 levels were linked to IGF2 or H19 hypomethylation, but found no significant correlation. However, we demonstrated that noticeable IGF2 overexpression, rather than LOI, negatively correlated with CRC microsatellite instability. These observations indicate that IGF2 expression, particularly when transcribed at significantly high levels, is a result of mechanisms unrelated to LOI. Our results suggest that IGF2 participates in CRC tumorigenesis through 2 different forms of aberrant gene expression.
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7 MeSH Terms
Association of parental hypertension with concentrations of select biomarkers in nonhypertensive offspring.
Lieb W, Pencina MJ, Wang TJ, Larson MG, Lanier KJ, Benjamin EJ, Levy D, Tofler GH, Meigs JB, Newton-Cheh C, Vasan RS
(2008) Hypertension 52: 381-6
MeSH Terms: Adult, Adult Children, Aged, Albumins, Biomarkers, Blood Pressure, C-Reactive Protein, Case-Control Studies, Creatinine, Female, Genetic Predisposition to Disease, Genomic Imprinting, Humans, Hypertension, Incidence, Male, Middle Aged, Reference Values, Renin, Risk Assessment
Show Abstract · Added April 15, 2014
Children of parents with hypertension are at increased risk of developing high blood pressure. We hypothesize that circulating concentrations of putative biomarkers (that may play a role in development of high blood pressure) are higher in nonhypertensive offspring of parents with hypertension. We compared concentrations of 4 different biomarkers (urinary albumin:creatinine ratio, circulating C-reactive protein, aldosterone:renin ratio, and plasminogen activator inhibitor-1) in nonhypertensive Framingham offspring study participants with none (n=233), 1 (n=474), or both (n=322) parents with hypertension. Parental hypertension was defined as onset before age 60 years, based on longitudinal observations of the original Framingham cohort. Serum C-reactive protein concentrations were higher in nonhypertensive offspring with 1 (median: 1.7; Q1 to Q3: 0.8 to 3.6 mg/L) or both parents with hypertension (median: 1.8; Q1 to Q3: 0.7 to 3.6 mg/L) compared with offspring without parental hypertension (median: 1.4; Q1 to Q3: 0.7 to 3.2 mg/L). In multivariable analyses, parental hypertension was associated with higher serum C-reactive protein concentration in offspring (15% increase per parent with hypertension; P=0.004). Prospectively, the relation of parental hypertension to longitudinal changes in blood pressure in the nonhypertensive offspring was attenuated on adjustment for C-reactive protein (P=0.04 for attenuation). The levels of the other biomarkers evaluated did not significantly differ in offspring according to parental hypertension status. In conclusion, serum C-reactive protein concentrations are higher in nonhypertensive offspring of parents with hypertension. These data suggest that inflammation may partly mediate the familial influences on hypertension risk.
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20 MeSH Terms
Transmission disequilibrium testing of the chromosome 15q11-q13 region in autism.
Kim SJ, Brune CW, Kistner EO, Christian SL, Courchesne EH, Cox NJ, Cook EH
(2008) Am J Med Genet B Neuropsychiatr Genet 147B: 1116-25
MeSH Terms: Autistic Disorder, Child, Child, Preschool, Chromosomes, Human, Pair 15, Female, Gene Regulatory Networks, Genetic Predisposition to Disease, Genomic Imprinting, Genotype, Humans, Linkage Disequilibrium, Male, Phenotype, Polymorphism, Single Nucleotide, Receptors, GABA-A, Serotonin Plasma Membrane Transport Proteins
Show Abstract · Added February 22, 2016
Evidence implicates the serotonin transporter gene (SLC6A4) and the 15q11-q13 genes as candidates for autism as well as restricted repetitive behavior (RRB). We conducted dense transmission disequilibrium mapping of the 15q11-q13 region with 93 single nucleotide polymorphisms (SNPs) in 86 strictly defined autism trios and tested association between SNPs and autism using the transmission disequilibrium test (TDT). As exploratory analyses, parent-of-origin effects were examined using likelihood-ratio tests (LRTs) and genotype-phenotype associations for specific RRB using the Family-Based Association Test (FBAT). Additionally, gene-gene interactions between nominally associated 15q11-q13 variants and 5-HTTLPR, the common length polymorphism of SLC6A4, were examined using conditional logistic regression (CLR). TDT revealed nominally significant transmission disequilibrium between autism and five SNPs, three of which are located within close proximity of the GABA(A) receptor subunit gene clusters. Three SNPs in the SNRPN/UBE3A region had marginal imprinting effects. FBAT for genotype-phenotype relations revealed nominally significant association between two SNPs and one ADI-R subdomain item. However, both TDT and FBAT were not statistically significant after correcting for multiple comparisons. Gene-gene interaction analyses by CLR revealed additive genetic effect models, without interaction terms, fit the data best. Lack of robust association between the 15q11-q13 SNPs and RRB phenotypes may be due to a small sample size and absence of more specific RRB measurement. Further investigation of the 15q11-q13 region with denser genotyping in a larger sample set may be necessary to determine whether this region confers risk to autism, indicated by association, or to specific autism phenotypes.
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16 MeSH Terms
A viable mouse model of factor X deficiency provides evidence for maternal transfer of factor X.
Tai SJ, Herzog RW, Margaritis P, Arruda VR, Chu K, Golden JA, Labosky PA, High KA
(2008) J Thromb Haemost 6: 339-45
MeSH Terms: Amino Acid Substitution, Animals, Cardiomyopathies, Exons, Factor X, Factor X Deficiency, Female, Fetal Death, Fibrosis, Gene Targeting, Genes, Lethal, Genetic Complementation Test, Genomic Imprinting, Genotype, Hemosiderosis, Humans, Male, Mice, Mice, Knockout, Mice, Transgenic, Models, Animal, Myocardium
Show Abstract · Added July 20, 2010
BACKGROUND - Activated factor X (FXa) is a vitamin K-dependent serine protease that plays a pivotal role in blood coagulation by converting prothrombin to thrombin. There are no reports of humans with complete deficiency of FX, and knockout of murine F10 is embryonic or perinatal lethal.
OBJECTIVE - We sought to generate a viable mouse model of FX deficiency.
METHODS - We used a socket-targeting construct to generate F10-knockout mice by eliminating F10 exon 8 (knockout allele termed F10(tm1Ccmt), abbreviated as '-'; wild-type '+'), and a plug-targeting construct to generate mice expressing a FX variant with normal antigen levels but low levels of FX activity [4-9% normal in humans carrying the defect, Pro343-->Ser, termed FX Friuli (mutant allele termed F10(tm2Ccmt), abbreviated as F)].
RESULTS - F10 knockout mice exhibited embryonic or perinatal lethality. In contrast, homozygous Friuli mice [F10 (F/F)] had FX activity levels of approximately 5.5% (sufficient to rescue both embryonic and perinatal lethality), but developed age-dependent iron deposition and cardiac fibrosis. Interestingly, F10 (-/F) mice with FX activity levels of 1-3% also showed complete rescue of lethality. Further study of this model provides evidence supporting a role of maternal FX transfer in the embryonic survival.
CONCLUSIONS - We demonstrate that, while complete absence of FX is incompatible with murine survival, minimal FX activity as low as 1-3% is sufficient to rescue the lethal phenotype. This viable low-FX mouse model will facilitate the development of FX-directed therapies as well as investigation of the FX role in embryonic development.
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22 MeSH Terms
Genomic imprinting of Dopa decarboxylase in heart and reciprocal allelic expression with neighboring Grb10.
Menheniott TR, Woodfine K, Schulz R, Wood AJ, Monk D, Giraud AS, Baldwin HS, Moore GE, Oakey RJ
(2008) Mol Cell Biol 28: 386-96
MeSH Terms: ATPases Associated with Diverse Cellular Activities, Adenosine Triphosphatases, Alleles, Animals, Base Sequence, DNA (Cytosine-5-)-Methyltransferases, DNA Methylation, Dopa Decarboxylase, Exons, GRB10 Adaptor Protein, Genomic Imprinting, Humans, Mice, Mice, Transgenic, Microtubule-Associated Proteins, Myocardium, Nuclear Proteins, Oligonucleotide Array Sequence Analysis, Organ Specificity, Proteins
Show Abstract · Added April 7, 2010
By combining a tissue-specific microarray screen with mouse uniparental duplications, we have identified a novel imprinted gene, Dopa decarboxylase (Ddc), on chromosome 11. Ddc_exon1a is a 2-kb transcript variant that initiates from an alternative first exon in intron 1 of the canonical Ddc transcript and is paternally expressed in trabecular cardiomyocytes of the embryonic and neonatal heart. Ddc displays tight conserved linkage with the maternally expressed and methylated Grb10 gene, suggesting that these reciprocally imprinted genes may be coordinately regulated. In Dnmt3L mutant embryos that lack maternal germ line methylation imprints, we show that Ddc is overexpressed and Grb10 is silenced. Their imprinting is therefore dependent on maternal germ line methylation, but the mechanism at Ddc does not appear to involve differential methylation of the Ddc_exon1a promoter region and may instead be provided by the oocyte mark at Grb10. Our analysis of Ddc redefines the imprinted Grb10 domain on mouse proximal chromosome 11 and identifies Ddc_exon1a as the first example of a heart-specific imprinted gene.
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20 MeSH Terms
Individual mice can be distinguished by the period of their islet calcium oscillations: is there an intrinsic islet period that is imprinted in vivo?
Nunemaker CS, Zhang M, Wasserman DH, McGuinness OP, Powers AC, Bertram R, Sherman A, Satin LS
(2005) Diabetes 54: 3517-22
MeSH Terms: Animals, Calcium, Genetic Variation, Genomic Imprinting, Housing, Animal, Individuality, Insulin, Islets of Langerhans, Mice, Oscillometry, Social Behavior, Social Isolation
Show Abstract · Added July 21, 2014
Pulsatile insulin secretion in vivo is believed to be derived, in part, from the intrinsic glucose-dependent intracellular calcium concentration ([Ca2+]i) pulsatility of individual islets. In isolation, islets display fast, slow, or mixtures of fast and slow [Ca2+]i oscillations. We show that the period of islet [Ca2+]i oscillations is unique to each mouse, with the islets from an individual mouse demonstrating similar rhythms to one another. Based on their rhythmic period, mice were broadly classified as being either fast (0.65 +/- 0.1 min; n = 6 mice) or slow (4.7 +/- 0.2 min; n = 15 mice). To ensure this phenomenon was not an artifact of islet-to-islet communication, we confirmed that islets cultured in isolation (period: 2.9 +/- 0.1 min) were not statistically different from islets cultured together from the same mouse (3.1 +/- 0.1 min, P > 0.52, n = 5 mice). We also compared pulsatile insulin patterns measured in vivo with islet [Ca2+]i patterns measured in vitro from six mice. Mice with faster insulin pulse periods corresponded to faster islet [Ca2+]i patterns, whereas slower insulin patterns corresponded to slower [Ca2+]i patterns, suggesting that the insulin rhythm of each mouse is preserved to some degree by its islets in vitro. We propose that individual mice have characteristic oscillatory [Ca2+]i patterns, which are imprinted in vivo through an unknown mechanism.
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12 MeSH Terms