scholarly journals Angelman syndrome imprinting center encodes a transcriptional promoter

2014 ◽  
Vol 112 (22) ◽  
pp. 6871-6875 ◽  
Author(s):  
Michael W. Lewis ◽  
Jason O. Brant ◽  
Joseph M. Kramer ◽  
James I. Moss ◽  
Thomas P. Yang ◽  
...  
Keyword(s):  
Dna Sequences ◽  
Angelman Syndrome ◽  
Paternal Allele ◽  
Specific Gene ◽  
Prader Willi Syndrome ◽  
Maternal Allele ◽  
Expression Of Genes ◽  
Imprinting Center ◽  
Maternal Contribution ◽  
Parent Of Origin

Clusters of imprinted genes are often controlled by an imprinting center that is necessary for allele-specific gene expression and to reprogram parent-of-origin information between generations. An imprinted domain at 15q11–q13 is responsible for both Angelman syndrome (AS) and Prader–Willi syndrome (PWS), two clinically distinct neurodevelopmental disorders. Angelman syndrome arises from the lack of maternal contribution from the locus, whereas Prader–Willi syndrome results from the absence of paternally expressed genes. In some rare cases of PWS and AS, small deletions may lead to incorrect parent-of-origin allele identity. DNA sequences common to these deletions define a bipartite imprinting center for the AS–PWS locus. The PWS–smallest region of deletion overlap (SRO) element of the imprinting center activates expression of genes from the paternal allele. The AS–SRO element generates maternal allele identity by epigenetically inactivating the PWS–SRO in oocytes so that paternal genes are silenced on the future maternal allele. Here we have investigated functional activities of the AS–SRO, the element necessary for maternal allele identity. We find that, in humans, the AS–SRO is an oocyte-specific promoter that generates transcripts that transit the PWS–SRO. Similar upstream promoters were detected in bovine oocytes. This result is consistent with a model in which imprinting centers become DNA methylated and acquire maternal allele identity in oocytes in response to transiting transcription.

scholarly journals 106 GENOMIC IMPRINTING OF IGF2R IN TISSUES OF BOVINE FETUSES GENERATED BY ARTIFICIAL INSEMINATION OR IN VITRO FERTILIZATION

2005 ◽  
Vol 17 (2) ◽  
pp. 204 ◽  
Author(s):  
S. Hiendleder ◽  
D. Bebbere ◽  
S. Bauersachs ◽  
M. Stojkovic ◽  
H. Wenigerkind ◽  
...  
Keyword(s):  
In Vitro Fertilization ◽  
Artificial Insemination ◽  
Expression Patterns ◽  
Allelic Expression ◽  
Paternal Allele ◽  
Specific Gene ◽  
Vitro Fertilization ◽  
Bovine Fetuses ◽  
Parent Of Origin

The insulin-like growth factor 2 receptor gene (IGF2R) is involved in fetal growth regulation. A study in sheep associated fetal overgrowth after in vitro embryo culture with abnormal DNA methylation and expression of IGF2R (Young et al. 2001 Nat. Genet. 27, 153–154). This suggested that abnormal IGF2R imprinting is a major cause of fetal overgrowth. To test this hypothesis in bovine fetuses, we developed a microsatellite marker for IGF2R from cDNA sequence data and screened 45 Day-80 fetuses generated in vivo, by artificial insemination (AI), or in vitro, by in vitro fertilization (IVF) procedures, for parent-of-origin-specific gene expression. A total of 17 fetuses were heterozygous, but available parental DNA samples showed that only 12 (8 AI, 4 IVF) allowed unambiguous discrimination of parental alleles. Parent-of-origin-specific allelic expression patterns indicated that bovine IGF2R was expressed predominantly from the maternal allele and thus imprinted in fetal heart, kidney, liver, lung, muscle, and cotyledon tissue. However, the relative amount of expression from the paternal allele was tissue-specific and ranged from 6.4 ± 0.8% in skeletal muscle up to 27.4 ± 0.9% in cotyledon (SPSS or 11.5, ANOVA, P < 0.001). Tissues that originated from the same germ layer showed similar allelic expression ratios whereas significantly different expression ratios (P < 0.05) were observed between tissues originating from different germ layers. Contrary to expectations from sheep data, there was no evidence for gross abnormalities in IGF2R imprinting in tissues from overgrown (n = 2) or normal sized (n = 2) IVF fetuses. However, relative paternal expression levels in several tissues showed significant relationships (P < 0.05–0.001) with growth parameters and pointed to subtle changes in paternal IGF2R expression in overgrown IVF fetuses. We thank W. Scholz and M. Weppert for excellent technical assistance.

scholarly journals DNA demethylase ROS1 negatively regulates the imprinting of DOGL4 and seed dormancy in Arabidopsis thaliana

2018 ◽  
Vol 115 (42) ◽  
pp. E9962-E9970 ◽  
Author(s):  
Haifeng Zhu ◽  
Wenxiang Xie ◽  
Dachao Xu ◽  
Daisuke Miki ◽  
Kai Tang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Seed Dormancy ◽  
Genomic Imprinting ◽  
Dna Demethylation ◽  
Paternal Allele ◽  
Maternal Allele ◽  
Imprinted Gene ◽  
Differential Gene ◽  
Parent Of Origin ◽  
Dna Demethylase

Genomic imprinting is a form of epigenetic regulation resulting in differential gene expression that reflects the parent of origin. In plants, imprinted gene expression predominantly occurs in the seed endosperm. Maternal-specific DNA demethylation by the DNA demethylase DME frequently underlies genomic imprinting in endosperm. Whether other more ubiquitously expressed DNA demethylases regulate imprinting is unknown. Here, we found that the DNA demethylase ROS1 regulates the imprinting of DOGL4. DOGL4 is expressed from the maternal allele in endosperm and displays preferential methylation and suppression of the paternal allele. We found that ROS1 negatively regulates imprinting by demethylating the paternal allele, preventing its hypermethylation and complete silencing. Furthermore, we found that DOGL4 negatively affects seed dormancy and response to the phytohormone abscisic acid and that ROS1 controls these processes by regulating DOGL4. Our results reveal roles for ROS1 in mitigating imprinted gene expression and regulating seed dormancy.

scholarly journals Quantitative Analysis of SRNPN Gene Methylation by Pyrosequencing as a Diagnostic Test for Prader–Willi Syndrome and Angelman Syndrome

2006 ◽  
Vol 52 (6) ◽  
pp. 1005-1013 ◽  
Author(s):  
Helen E White ◽  
Victoria J Durston ◽  
John F Harvey ◽  
Nicholas CP Cross
Keyword(s):  
Diagnostic Test ◽  
Angelman Syndrome ◽  
Uniparental Disomy ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Maternal Uniparental Disomy ◽  
Cpg Sites ◽  
Specific Pcr ◽  
Small Nuclear Ribonucleoprotein ◽  
Maternal Contribution

Abstract Background: Angelman syndrome (AS) and Prader–Willi syndrome (PWS) are 2 distinct neurodevelopmental disorders caused primarily by deficiency of specific parental contributions at an imprinted domain within the chromosomal region 15q11.2-13. In most cases, lack of paternal contribution leads to PWS either by paternal deletion (∼70%) or maternal uniparental disomy (UPD; ∼30%). Most cases of AS result from the lack of a maternal contribution from this same region by maternal deletion (∼70%) or by paternal UPD (∼5%). Analysis of allelic methylation differences at the small nuclear ribonucleoprotein polypeptide N (SNRPN) locus can differentiate the maternally and paternally inherited chromosome 15 and can be used as a diagnostic test for AS and PWS. Methods: Sodium bisulfite–treated genomic DNA was PCR-amplified for the SNRPN gene. We used pyrosequencing to individually quantify the resulting artificial C/T sequence variation at CpG sites. Anonymized DNA samples from PWS patients (n = 40), AS patients (n = 31), and controls (n = 81) were analyzed in a blinded fashion with 2 PCR and 3 pyrosequencing reactions. We compared results from the pyrosequencing assays with those obtained with a commonly used methylation-specific PCR (MS-PCR) diagnostic protocol. Results: The pyrosequencing assays had a sensitivity and specificity of 100% and provided quantification of methylation at 12 CpG sites within the SNRPN locus. The resulting diagnoses were 100% concordant with those obtained from the MS-PCR protocol. Conclusions: Pyrosequencing is a rapid and robust method for quantitative methylation analysis of the SNRPN locus and can be used as a diagnostic test for PWS and AS.

scholarly journals BIOLOGICAL SCIENCES: Genetics

2018 ◽  
Author(s):  
Jack S. Hsiao ◽  
Noelle D. Germain ◽  
Andrea Wilderman ◽  
Christopher Stoddard ◽  
Luke A. Wojenski ◽  
...  
Keyword(s):  
Boundary Element ◽  
Angelman Syndrome ◽  
Antisense Transcript ◽  
Neurodevelopmental Disorder ◽  
Boundary Function ◽  
Paternal Allele ◽  
Loss Of Function ◽  
Maternal Allele ◽  
Specific Expression ◽  
Human Neurons

ABSTRACTAngelman syndrome (AS) is a severe neurodevelopmental disorder caused by the loss of function from the maternal allele of UBE3A, a gene encoding an E3 ubiquitin ligase. UBE3A is only expressed from the maternally-inherited allele in mature human neurons due to tissue-specific genomic imprinting. Imprinted expression of UBE3A is restricted to neurons by expression of UBE3A antisense transcript (UBE3A-ATS) from the paternally-inherited allele, which silences the paternal allele of UBE3A in cis. However, the mechanism restricting UBE3A-ATS expression and UBE3A imprinting to neurons is not understood. We used CRISPR/Cas9-mediated genome editing to functionally define a bipartite boundary element critical for neuron-specific expression of UBE3A-ATS in humans. Removal of this element led to upregulation of UBE3A-ATS without repressing paternal UBE3A. However, increasing expression of UBE3A-ATS in the absence of the boundary element resulted in full repression of paternal UBE3A, demonstrating that UBE3A imprinting requires both the loss of function from the boundary element as well as upregulation of UBE3A-ATS. These results suggest that manipulation of the competition between UBE3A-ATS and UBE3A may provide a potential therapeutic approach for AS.SIGNIFICANCE STATEMENTAngelman syndrome is a neurodevelopmental disorder caused by loss of function from the maternal allele of UBE3A, an imprinted gene. The paternal allele of UBE3A is silenced by a long, non-coding antisense transcript in mature neurons. We have identified a boundary element that stops the transcription of the antisense transcript in human pluripotent stem cells, and thus restricts UBE3A imprinted expression to neurons. We further determined that UBE3A imprinting requires both the loss of the boundary function and sufficient expression of the antisense transcript to silence paternal UBE3A. These findings provide essential details about the mechanisms of UBE3A imprinting that may suggest additional therapeutic approaches for Angelman syndrome.

The IPW Gene is Imprinted and is not Expressed in the Prader-Willi Syndrome

1996 ◽  
Vol 45 (1-2) ◽  
pp. 191-197 ◽  
Author(s):  
R. Wevrick ◽  
J.A. Kerns ◽  
U. Francke
Keyword(s):  
Genetic Defect ◽  
Original Description ◽  
Regulatory Elements ◽  
Proximal Region ◽  
Paternal Allele ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Clinical Criteria ◽  
Expression Of Genes ◽  
Definition Of

Since the original description of the Prader-Willi syndrome (PWS) in 1956 [1], and the recognition of the involvement of the proximal region of chromosome 15 in this disorder [2], understanding of the molecular basis of the genetic defect in PWS has progressed rapidly. A set of clinical criteria has been defined [3], although the diagnosis on clinical grounds alone remains difficult in the first year of life. Research has focussed both on improving the diagnostic molecular and cytogenetic tests for PWS and on identifying and defining the functions of genes whose expression is altered in this neurobehavioral disorder. Furthermore, this region is known to be subject to genomic imprinting effects, so that expression of genes involved in PWS is expected to be exclusively from the paternal allele.A critical step in the definition of the region containing such genes was the identification of a subset of unusual patients affected with either PWS or the Angelman syndrome, which also involves a gene or genes in the proximal region of chromosome 15. These unique patients, who have chromosome 15 translocations or deletions, helped to narrow the critical region to an interval containing less than 500 kb of DNA [4-6] (Fig. 1). As will be discussed, below, regulatory elements exist in this 500 kb region which alter the expression of genes located outside this interval [7, 8].

Molecular Analysis of an Extra inv dup(15)(q13) Chromosome in Two Patients with Angelman Syndrome

1996 ◽  
Vol 45 (1-2) ◽  
pp. 217-220 ◽  
Author(s):  
T. Buchholz ◽  
S. Schuffenhauer ◽  
K. Evans ◽  
L. Robson ◽  
B. Appleton ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Angelman Syndrome ◽  
Uniparental Disomy ◽  
Molecular Data ◽  
Monoallelic Expression ◽  
Chromosome 15 ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Maternal Allele ◽  
Molecular Defects

Angelman syndrome (AS) is caused by the loss of function of yet unidentified gene(s) which map within 15q 11-13 and show monoallelic expression from the maternal allele. Lack of the maternal allele(s), due to either a deletion on the maternal chromosome 15 (about 70% of AS patients) or a paternal uniparental disomy (UPD)15 (<5%), are the most common molecular defects in AS. Prader-Willi syndrome (PWS) also maps to proximal 15q, but is caused by the loss of function of paternally expressed gen(s) [1]. Here we describe clinical, cytogenetic and molecular data for two non-related patients with AS who carry a nonmosaic extra cromosome inv dup(15).

scholarly journals Prader-Willi syndrome: reflections on seminal studies and future therapies

Open Biology ◽  
2020 ◽  
Vol 10 (9) ◽  
pp. 200195
Author(s):  
Michael S. Chung ◽  
Maéva Langouët ◽  
Stormy J. Chamberlain ◽  
Gordon G. Carmichael
Keyword(s):  
Genomic Imprinting ◽  
Angelman Syndrome ◽  
Cpg Island ◽  
Uniparental Disomy ◽  
Large Deletion ◽  
Paternal Allele ◽  
Prader Willi Syndrome ◽  
Loss Of Function ◽  
Maternal Uniparental Disomy ◽  
Parental Allele

Prader-Willi syndrome (PWS) is caused by the loss of function of the paternally inherited 15q11-q13 locus. This region is governed by genomic imprinting, a phenomenon in which genes are expressed exclusively from one parental allele. The genomic imprinting of the 15q11-q13 locus is established in the germline and is largely controlled by a bipartite imprinting centre. One part, termed the Prader-Willi syndrome imprinting center (PWS-IC), comprises a CpG island that is unmethylated on the paternal allele and methylated on the maternal allele. The second part, termed the Angelman syndrome imprinting centre, is required to silence the PWS_IC in the maternal germline. The loss of the paternal contribution of the imprinted 15q11-q13 locus most frequently occurs owing to a large deletion of the entire imprinted region but can also occur through maternal uniparental disomy or an imprinting defect. While PWS is considered a contiguous gene syndrome based on large-deletion and uniparental disomy patients, the lack of expression of only non-coding RNA transcripts from the SNURF-SNRPN/SNHG14 may be the primary cause of PWS. Patients with small atypical deletions of the paternal SNORD116 cluster alone appear to have most of the PWS related clinical phenotypes. The loss of the maternal contribution of the 15q11-q13 locus causes a separate and distinct condition called Angelman syndrome. Importantly, while much has been learned about the regulation and expression of genes and transcripts deriving from the 15q11-q13 locus, there remains much to be learned about how these genes and transcripts contribute at the molecular level to the clinical traits and developmental aspects of PWS that have been observed.

scholarly journals Parent-of-origin genetic background affects the transcriptional levels of circadian and neuronal plasticity genes following sleep loss

2014 ◽  
Vol 369 (1637) ◽  
pp. 20120471 ◽  
Author(s):  
Federico Tinarelli ◽  
Celina Garcia-Garcia ◽  
Francesco Nicassio ◽  
Valter Tucci
Keyword(s):  
Gene Expression ◽  
Sleep Deprivation ◽  
Neuronal Plasticity ◽  
Genetic Background ◽  
Rebound Effect ◽  
Sleep Loss ◽  
Mouse Strains ◽  
Specific Gene ◽  
Expression Of Genes ◽  
Parent Of Origin

Sleep homoeostasis refers to a process in which the propensity to sleep increases as wakefulness progresses and decreases as sleep progresses. Sleep is tightly organized around the circadian clock and is regulated by genetic and epigenetic mechanisms. The homoeostatic response of sleep, which is classically triggered by sleep deprivation, is generally measured as a rebound effect of electrophysiological measures, for example delta sleep. However, more recently, gene expression changes following sleep loss have been investigated as biomarkers of sleep homoeostasis. The genetic background of an individual may affect this sleep-dependent gene expression phenotype. In this study, we investigated whether parental genetic background differentially modulates the expression of genes following sleep loss. We tested the progeny of reciprocal crosses of AKR/J and DBA/2J mouse strains and we show a parent-of-origin effect on the expression of circadian, sleep and neuronal plasticity genes following sleep deprivation. Thus, we further explored, by in silico , specific functions or upstream mechanisms of regulation and we observed that several upstream mechanisms involving signalling pathways (i.e. DICER1, PKA), growth factors (CSF3 and BDNF) and transcriptional regulators (EGR2 and ELK4) may be differentially modulated by parental effects. This is the first report showing that a behavioural manipulation (e.g. sleep deprivation) in adult animals triggers specific gene expression responses according to parent-of-origin genomic mechanisms. Our study suggests that the same mechanism may be extended to other behavioural domains and that the investigation of gene expression following experimental manipulations should take seriously into account parent-of-origin effects.

scholarly journals Transmission of a Novel Imprinting Center Deletion Associated With Prader–Willi Syndrome Through Three Generations of a Chinese Family: Case Presentation, Differential Diagnosis, and a Lesson Worth Thinking About

2021 ◽  
Vol 12 ◽  
Author(s):  
Kaihui Zhang ◽  
Shu Liu ◽  
Wenjun Gu ◽  
Yuqiang Lv ◽  
Haihua Yu ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Clinical Features ◽  
Preimplantation Embryos ◽  
Paternal Allele ◽  
Chinese Family ◽  
Prader Willi Syndrome ◽  
Genetic Syndrome ◽  
Small Nuclear Ribonucleoprotein ◽  
Imprinting Center ◽  
Hands And Feet

Prader–Willi syndrome (PWS) is a complex genetic syndrome caused by the loss of function of genes in 15q11-q13 that are subject to regulation by genomic imprinting and expressed from the paternal allele only. The main clinical features of PWS patients are hypotonia during the neonatal and infantile stages, accompanied by delayed neuropsychomotor development, hyperphagia, obesity, hypogonadism, short stature, small hands and feet, mental disabilities, and behavioral problems. However, PWS has a clinical overlap with other disorders, especially those with other gene variations or chromosomal imbalances but sharing part of the similar clinical manifestations with PWS, which are sometimes referred to as Prader–Willi syndrome-like (PWS-like) disorders. Furthermore, it is worth mentioning that significant obesity as a consequence of hyperphagia in PWS usually develops between the ages of 1 and 6 years, which makes early diagnosis difficult. Thus, PWS is often not clinically recognized in infants and, on the other hand, may be wrongly suspected in obese and intellectually disabled patients. Therefore, an accurate investigation is necessary to differentiate classical PWS from PWS-like phenotypes, which is imperative for further treatment. For PWS, it is usually sporadic, and very rare family history and affected siblings have been described. Here, we report the clinical and molecular findings in a three-generation family with a novel 550-kb microdeletion affecting the chromosome 15 imprinting center (IC). Overall, the present study finds that the symptoms of our patient are somewhat different from those of typical PWS cases diagnosed and given treatment in our hospital. The familial occurrence and clinical features were challenging to our diagnostic strategy. The microdeletion included a region within the complex small nuclear ribonucleoprotein polypeptide protein N (SNRPN) gene locus encompassing the PWS IC and was identified by using a variety of techniques. Haplotype studies suggest that the IC microdeletion was vertically transmitted from an unaffected paternal grandmother to an unaffected father and then caused PWS in two sibling grandchildren when the IC microdeletion was inherited paternally. Based on the results of our study, preimplantation genetic diagnosis (PGD) was applied successfully to exclude imprinting deficiency in preimplantation embryos before transfer into the mother’s uterus. Our study may be especially instructive regarding accurate diagnosis, differential diagnosis, genetic counseling, and PGD for familial PWS patients.

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