'; ?> geneimprint : Hot off the Press http://www.geneimprint.com/site/hot-off-the-press Daily listing of the most recent articles in epigenetics and imprinting, collected from the PubMed database. en-us Mon, 22 May 2017 13:34:46 PDT Mon, 22 May 2017 13:34:46 PDT jirtle@radonc.duke.edu james001@jirtle.com Disruption of NNAT, NAP1L5 and MKRN3 DNA methylation and transcription in rabbit parthenogenetic fetuses. Wang D, Liu Z, Yao H, Hao Y, Zhou L, Du J, Zhu Y, Xu Y, Wang G, Song Y, Li Z
Gene (May 2017)

Parthenogenetically activated oocytes cannot develop to term in mammals due to lack of paternal gene expression. Disruption of imprinted gene expression and DNA methylation status in parthenogenetic fetuses has been reported in mice and pigs, but not in rabbits. In this study, the genomic imprinting status of the paternally expressed genes Neuronatin (NNAT), Nucleosome assembly protein 1-like 5 (NAP1L5), and Makorin ring finger protein 3 (MKRN3) was compared between rabbit parthenogenetic (PA) and normally fertilized fetuses (Con) using quantitative real-time PCR (qRT-PCR) and bisulfite sequencing PCR (BSP). The results revealed a significantly reduced expression of NNAT, NAP1L5, and MKRN3 in rabbit PA fetuses compared with Con fetuses (p<0.05). In addition, the BSP results demonstrated hypermethylation in the differentially methylated regions (DMRs) of NNAT, NAP1L5, and MKRN3 in rabbit PA fetuses. Taken together, these results suggest that hypermethylation of DMRs is associated with decreased NNAT, NAP1L5, and MKRN3 expression, which may be responsible for developmental failure of rabbit PA fetuses.]]>
Sat, 20 May 2017 00:00:00 PDT
Unfolding the pathogenesis of scleroderma through genomics and epigenomics. Tsou PS, Sawalha AH
J Autoimmun (May 2017)

With unknown etiology, scleroderma (SSc) is a multifaceted disease characterized by immune activation, vascular complications, and excessive fibrosis in internal organs. Genetic studies, including candidate gene association studies, genome-wide association studies, and whole-exome sequencing have supported the notion that while genetic susceptibility to SSc appears to be modest, SSc patients are genetically predisposed to this disease. The strongest genetic association for SSc lies within the MHC region, with loci in HLA-DRB1, HLA-DQB1, HLA-DPB1, and HLA-DOA1 being the most replicated. The non-HLA genes associated with SSc are involved in various functions, with the most robust associations including genes for B and T cell activation and innate immunity. Other pathways include genes involved in extracellular matrix deposition, cytokines, and autophagy. Among these genes, IRF5, STAT4, and CD247 were replicated most frequently while SNPs rs35677470 in DNASE1L3, rs5029939 in TNFAIP3, and rs7574685 in STAT4 have the strongest associations with SSc. In addition to genetic predisposition, it became clear that environmental factors and epigenetic influences also contribute to the development of SSc. Epigenetics, which refers to studies that focus on heritable phenotypes resulting from changes in chromatin structure without affecting the DNA sequence, is one of the most rapidly expanding fields in biomedical research. Indeed extensive epigenetic changes have been described in SSc. Alteration in enzymes and mediators involved in DNA methylation and histone modification, as well as dysregulated non-coding RNA levels all contribute to fibrosis, immune dysregulation, and impaired angiogenesis in this disease. Genes that are affected by epigenetic dysregulation include ones involved in autoimmunity, T cell function and regulation, TGFβ pathway, Wnt pathway, extracellular matrix, and transcription factors governing fibrosis and angiogenesis. In this review, we provide a comprehensive overview of the current findings of SSc genetic susceptibility, followed by an extensive description and a systematic review of epigenetic research that has been carried out to date in SSc. We also summarize the therapeutic potential of drugs that affect epigenetic mechanisms, and outline the future prospective of genomics and epigenomics research in SSc.]]>
Sat, 20 May 2017 00:00:00 PDT
Systemic and ocular fluid compounds as potential biomarkers in age-related macular degeneration. Kersten E, Paun CC, Schellevis RL, Hoyng CB, Delcourt C, Lengyel I, Peto T, Ueffing M, Klaver CCW, Dammeier S, den Hollander AI, de Jong EK
Surv Ophthalmol (May 2017)

Biomarkers can help unravel mechanisms of disease and identify new targets for therapy. They can also be useful in clinical practice for monitoring disease progression, evaluation of treatment efficacy and risk assessment in multifactorial diseases, such as age-related macular degeneration (AMD). AMD is a highly prevalent progressive retinal disorder for which multiple genetic and environmental risk factors have been described, but the exact etiology is not yet fully understood. Many compounds have been evaluated for their association with AMD. We performed an extensive literature review of all compounds measured in serum, plasma, vitreous, aqueous humor and urine of AMD patients. Over 3600 articles were screened resulting in more than 100 different compounds analyzed in AMD studies, involved in neovascularization, immunity, lipid metabolism, extracellular matrix, oxidative stress, diet, hormones, and comorbidities (such as kidney disease). For each compound we provide a short description of its function and discuss the results of the studies in relation to its usefulness as AMD biomarker. Additionally, biomarkers identified by hypothesis-free techniques, including metabolomics, proteomics and epigenomics, are covered. In summary, compounds belonging to the oxidative stress pathway, the complement system, and lipid metabolism are the most promising biomarker candidates for AMD. We hope that this comprehensive survey of the literature on systemic and ocular fluid compounds as potential biomarkers in AMD will provide a stepping stone for future research and possible implementation in clinical practice.]]>
Fri, 19 May 2017 00:00:00 PDT
Coordinates and intervals in graph-based reference genomes. Rand KD, Grytten I, Nederbragt AJ, Storvik GO, Glad IK, Sandve GK
BMC Bioinformatics (May 2017)

It has been proposed that future reference genomes should be graph structures in order to better represent the sequence diversity present in a species. However, there is currently no standard method to represent genomic intervals, such as the positions of genes or transcription factor binding sites, on graph-based reference genomes.]]>
Fri, 19 May 2017 00:00:00 PDT
Genomic imprinting does not reduce the dosage of UBE3A in neurons. Hillman PR, Christian SGB, Doan R, Cohen ND, Konganti K, Douglas K, Wang X, Samollow PB, Dindot SV
Epigenetics Chromatin (2017)

The ubiquitin protein E3A ligase gene (UBE3A) gene is imprinted with maternal-specific expression in neurons and biallelically expressed in all other cell types. Both loss-of-function and gain-of-function mutations affecting the dosage of UBE3A are associated with several neurodevelopmental syndromes and psychological conditions, suggesting that UBE3A is dosage-sensitive in the brain. The observation that loss of imprinting increases the dosage of UBE3A in brain further suggests that inactivation of the paternal UBE3A allele evolved as a dosage-regulating mechanism. To test this hypothesis, we examined UBE3A transcript and protein levels among cells, tissues, and species with different imprinting states of UBE3A.]]>
Thu, 18 May 2017 00:00:00 PDT
Epigenomics, Pharmacoepigenomics, and Personalized Medicine in Cervical Cancer. Kabekkodu SP, Chakrabarty S, Ghosh S, Brand A, Satyamoorthy K
Public Health Genomics (May 2017)

Epigenomics encompasses the study of genome-wide changes in DNA methylation, histone modifications and noncoding RNAs leading to altered transcription, chromatin structure, and posttranscription RNA processing, respectively, resulting in an altered rate of gene expression. The role of epigenetic modifications facilitating human diseases is well established. Previous studies have identified histone and cytosine code during normal and pathological conditions with special emphasis on how these modifications regulate transcriptional events. Recent studies have also mapped these epigenetic modification and pathways leading to carcinogenesis. Discovery of drugs that target proteins/enzymes in the epigenetic pathways may provide better therapeutic opportunities, and identification of such modulators for DNA methylation, histone modifications, and expression of noncoding RNAs for several cancer types is underway. In this review, we provide a detailed description of recent developments in the field of epigenetics and its impact on personalized medicine to manage cervical cancer.]]>
Thu, 18 May 2017 00:00:00 PDT
A Generalized Linear Model for Decomposing Cis-regulatory, Parent-of-Origin, and Maternal Effects on Allele-Specific Gene Expression. Takada Y, Miyagi R, Takahashi A, Endo T, Osada N
G3 (Bethesda) (May 2017)

Joint quantification of genetic and epigenetic effects on gene expression is important for understanding the establishment of complex gene regulation systems in living organisms. In particular, genomic imprinting and maternal effects play important roles in the developmental process of mammals and flowering plants. However, the influence of these effects on gene expression are difficult to quantify because they act simultaneously with cis-regulatory mutations. Here we propose a simple method to decompose cis-regulatory (i.e., allelic genotype, AG), genomic imprinting (i.e, parent-of-origin, PO), and maternal (i.e, maternal genotype, MG) effects on allele-specific gene expression using RNA-seq data obtained from reciprocal crosses. We evaluated the efficiency of method using a simulated dataset and applied the method to whole-body Drosophila and mouse trophoblast stem cell (TSC) and liver RNA-seq data. Consistent with previous studies, we found little evidence of PO and MG effects in adult Drosophila samples. In contrast, we identified dozens and hundreds of mouse genes with significant PO and MG effects, respectively. Interestingly, a similar number of genes with significant PO effect were detect in mouse TSCs and livers, whereas more genes with significant MG effect were observed in livers. Further application of this method will clarify how these three effects influence gene expression levels in different tissues and developmental stages, and provide novel insight into the evolution of gene expression regulation.]]>
Thu, 18 May 2017 00:00:00 PDT
Association of CD8(+) T-cells with bone erosion in patients with rheumatoid arthritis. Joo YB, Park Y, Kim K, Bang SY, Bae SC, Lee HS
Int J Rheum Dis (May 2017)

Bone erosion is a major problem worsening quality of rheumatoid arthritis (RA) patients' lives. However, causal factors responsible for bone erosion in RA have remained unclear. We aimed to examine genetic variants conferring bone erosion in RA using a Korean genome-wide association study (GWAS) and to search for possible biological mechanisms underlying the development of bone erosion.]]>
Wed, 17 May 2017 00:00:00 PDT
Williams syndrome deletions and duplications: Genetic windows to understanding anxiety, sociality, autism, and schizophrenia. Crespi BJ, Procyshyn TL
Neurosci Biobehav Rev (May 2017)

We describe and evaluate an integrative hypothesis for helping to explain the major neurocognitive features of individuals with Williams syndrome region deletions and duplications. First, we demonstrate how the cognitive differences between Williams syndrome individuals, individuals with duplications of this region, and healthy individuals parallel the differences between individuals subject to effects of increased or decreased oxytocin. Second, we synthesize evidence showing that variation in expression of the gene GTF2I (General Transcription Factor II-I) underlies the primary social phenotypes of Williams syndrome and that common genetic variation in GTF2I mediates oxytocin reactivity, and its correlates, in healthy populations. Third, we describe findings relevant to the hypothesis that the GTF2I gene is subject to parent of origin effects whose behavioral expression fits with predictions from the kinship theory of genomic imprinting. Fourth, we describe how Williams syndrome can be considered, in part, as an autistic syndrome of Lorna Wing's 'active-but-odd' autism subtype, in contrast to associations of duplications with both schizophrenia and autism.]]>
Sat, 13 May 2017 00:00:00 PDT
Epimetheus - a multi-profile normalizer for epigenomic sequencing data. Saleem MM, Mendoza-Parra MA, Cholley PE, Blum M, Gronemeyer H
BMC Bioinformatics (May 2017)

Exponentially increasing numbers of NGS-based epigenomic datasets in public repositories like GEO constitute an enormous source of information that is invaluable for integrative and comparative studies of gene regulatory mechanisms. One of today's challenges for such studies is to identify functionally informative local and global patterns of chromatin states in order to describe the regulatory impact of the epigenome in normal cell physiology and in case of pathological aberrations. Critically, the most preferred Chromatin ImmunoPrecipitation-Sequencing (ChIP-Seq) is inherently prone to significant variability between assays, which poses significant challenge on comparative studies. One challenge concerns data normalization to adjust sequencing depth variation.]]>
Sat, 13 May 2017 00:00:00 PDT
The Intersection Of Aging Biology and The Pathobiology of Lung Diseases: A Joint NHLBI/NIA Workshop. Budinger GS, Kohanski RA, Gan W, Kobor MS, Amaral LA, Armanios M, Kelsey KT, Pardo A, Tuder R, Macian F, Chandel N, Vaughan D, Rojas M, Mora AL, Kovacs E, Duncan SR, Finkel T, Choi A, Eickelberg O, Chen D, Agusti A, Selman M, Balch WE, Busse P, Lin A, Morimoto R, Sznajder JI, Thannickal VJ
J Gerontol A Biol Sci Med Sci (May 2017)

Death from chronic lung disease is increasing and Chronic Obstructive Pulmonary Disease has become the third leading cause of death in the United States in the past decade. Both chronic and acute lung diseases disproportionately affect elderly individuals, making it likely that these diseases will become more frequent and severe as the worldwide population ages. Chronic lung diseases are associated with substantial morbidity, frequently resulting in exercise limiting dyspnea, immobilization and isolation. Therefore, effective strategies to prevent or treat lung disease are likely to increase healthspan as well as lifespan. This review summarizes the findings of a joint workshop sponsored by the NIA and NHLBI that brought together investigators focused on aging and lung biology. These investigators encouraged the use of genetic systems and aged animals in the study of lung disease and the development of integrative systems-based platforms that can dynamically incorporate datasets that describe the genomics, transcriptomics, epigenomics, metabolomics and proteomics of the aging lung in health and disease. Further research was recommended to integrate benchmark biological hallmarks of aging in the lung with the pathobiology of acute and chronic lung diseases with divergent pathologies for which advanced age is the most important risk factor.]]>
Fri, 12 May 2017 00:00:00 PDT
The Epigenomic Landscape in Osteoarthritis. Simon TC, Jeffries MA
Curr Rheumatol Rep (Jun 2017)

Epigenomics has emerged as a key player in our rapidly evolving understanding of osteoarthritis. Historical studies implicated epigenetic alterations, particularly DNA methylation, in OA pathogenesis; however, recent technological advances have resulted in numerous epigenome-wide studies examining in detail epigenetic modifications in OA. The purpose of this article is to introduce basic concepts in epigenetics and their recent applications to the study of osteoarthritis development and progression.]]>
Sun, 30 Apr 2017 00:00:00 PDT
Blocked transcription through KvDMR1 results in absence of methylation and gene silencing resembling Beckwith-Wiedemann syndrome. Singh VB, Sribenja S, Wilson KE, Attwood KM, Hillman JC, Pathak S, Higgins MJ
Development (May 2017)

The maternally methylated KvDMR1 ICR regulates imprinted expression of a cluster of maternally expressed genes on human chromosome 11p15.5. Disruption of imprinting leads to Beckwith-Wiedemann syndrome (BWS), an overgrowth and cancer predisposition condition. In the majority of individuals with BWS, maternal-specific methylation at KvDMR1 is absent and genes under its control are repressed. We analyzed a mouse model carrying a poly(A) truncation cassette inserted to prevent RNA transcripts from elongation through KvDMR1. Maternal inheritance of this mutation resulted in absence of DNA methylation at KvDMR1, which led to biallelic expression of Kcnq1ot1 and suppression of maternally expressed genes. This study provides further evidence that transcription is required for establishment of methylation at maternal gametic DMRs. More importantly, this mouse model recapitulates the molecular phenotypic characteristics of the most common form of BWS, including loss of methylation at KvDMR1 and biallelic repression of Cdkn1c, suggesting that deficiency of maternal transcription through KvDMR1 may be an underlying cause of some BWS cases.]]>
Fri, 21 Apr 2017 00:00:00 PDT
Multi-omics and male infertility: status, integration and future prospects. Sinha A, Singh V, Yadav S
Front Biosci (Schol Ed) (Jun 2017)

Within the cell, gene expression analysis is the key to gain information about  different cellular and physiological events. The multifaceted route of fertilization is a combination of different processes, which include production, maturation and ejaculation of the sperm, its travel through the female genital tract, followed by the ultimate fusion of the fertile sperm with the egg. Early embryogenesis and gametogenesis as well as gene expression at tissue level and global gene silencing are under different levels of stringent epigenetic checks. Moreover, transcriptome (expressed segment of the genome in form of RNA) and the proteome (expressed set of genomic proteins) contribute uniformly to the overall cellular gene expression. In both normal and pathophysiological environments, this gene expression is altered across various levels viz., genome variations, post-transcriptional modifications, protein expression and post translational modifications. Consequently, more informative conclusions can be drawn through a new 'omics' approach of system biology, which takes into account all the genomics, epigenomics, proteomics, and metabolomics findings under one roof, thus computing the alterations in all the entities (genes, proteins, metabolites) concurrently.]]>
Fri, 14 Apr 2017 00:00:00 PDT
Clinical and genetic aspects of the 15q11.2 BP1-BP2 microdeletion disorder. Butler MG
J Intellect Disabil Res (Jun 2017)

The 15q11.2 BP1-BP2 microdeletion (Burnside-Butler susceptibility locus) is an emerging condition with over 200 individuals reported in the literature. TUBGCP5, CFYIP1, NIPA1 and NIPA2 genes are located in this chromosome 15 region and when disturbed individually are known to cause neurological, cognitive or behavioural problems as well as playing a role in both Prader-Willi and Angelman syndromes. These syndromes were the first examples in humans of genomic imprinting and typically caused by a deletion but involving the distal chromosome 15q11-q13 breakpoint BP3 and proximally placed breakpoints BP1 or BP2 of different parental origin. The typical 15q11-q13 deletion involves BP1 and BP3 and the typical type II deletion at BP2 and BP3. Several studies have shown that individuals with the larger type I deletion found in both Prader-Willi and Angelman syndromes are reported with more severe neurodevelopmental symptoms compared to those individuals with the smaller type II deletion.]]>
Fri, 07 Apr 2017 00:00:00 PDT
Neurodevelopmental consequences in offspring of mothers with preeclampsia during pregnancy: underlying biological mechanism via imprinting genes. Nomura Y, John RM, Janssen AB, Davey C, Finik J, Buthmann J, Glover V, Lambertini L
Arch Gynecol Obstet (Jun 2017)

Preeclampsia is known to be a leading cause of mortality and morbidity among mothers and their infants. Approximately 3-8% of all pregnancies in the US are complicated by preeclampsia and another 5-7% by hypertensive symptoms. However, less is known about its long-term influence on infant neurobehavioral development. The current review attempts to demonstrate new evidence for imprinting gene dysregulation caused by hypertension, which may explain the link between maternal preeclampsia and neurocognitive dysregulation in offspring.]]>
Thu, 06 Apr 2017 00:00:00 PDT
Maternal mutations of FOXF1 cause alveolar capillary dysplasia despite not being imprinted. Alsina Casanova M, Monteagudo-Sánchez A, Rodiguez Guerineau L, Court F, Gazquez Serrano I, Martorell L, Rovira Zurriaga C, Moore GE, Ishida M, Castañon M, Moliner Calderon E, Monk D, Moreno Hernando J
Hum Mutat (Jun 2017)

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a rare cause of pulmonary hypertension in newborns. Maternally inherited point mutations in Forkhead Box F1 gene (FOXF1), deletions of the gene, or its long-range enhancers on the maternal allele are responsible for this neonatal lethal disorder. Here, we describe monozygotic twins and one full-term newborn with ACD and gastrointestinal malformations caused by de novo mutations of FOXF1 on the maternal-inherited alleles. Since this parental transmission is consistent with genomic imprinting, the parent-of-origin specific monoallelic expression of genes, we have undertaken a detailed analysis of both allelic expression and DNA methylation. FOXF1 and its neighboring gene FENDRR were both biallelically expressed in a wide range of fetal tissues, including lung and intestine. Furthermore, detailed methylation screening within the 16q24.1 regions failed to identify regions of allelic methylation, suggesting that disrupted imprinting is not responsible for ACDMPV.]]>
Fri, 03 Mar 2017 00:00:00 PST
Modeling complex patterns of differential DNA methylation that associate with gene expression changes. Schlosberg CE, VanderKraats ND, Edwards JR
Nucleic Acids Res (May 2017)

Numerous genomic studies are underway to determine which genes are abnormally regulated by DNA methylation in disease. However, we have a poor understanding of how disease-specific methylation changes affect expression. We thus developed an integrative analysis tool, Methylation-based Gene Expression Classification (ME-Class), to explain specific variation in methylation that associates with expression change. This model captures the complexity of methylation changes around a gene promoter. Using 17 whole-genome bisulfite sequencing and RNA-seq datasets from different tissues from the Roadmap Epigenomics Project, ME-Class significantly outperforms standard methods using methylation to predict differential gene expression change. To demonstrate its utility, we used ME-Class to analyze 32 datasets from different hematopoietic cell types from the Blueprint Epigenome project. Expression-associated methylation changes were predominantly found when comparing cells from distantly related lineages, implying that changes in the cell's transcriptional program precede associated methylation changes. Training ME-Class on normal-tumor pairs from The Cancer Genome Atlas indicated that cancer-specific expression-associated methylation changes differ from tissue-specific changes. We further show that ME-Class can detect functionally relevant cancer-specific, expression-associated methylation changes that are reversed upon the removal of methylation. ME-Class is thus a powerful tool to identify genes that are dysregulated by DNA methylation in disease.]]>
Tue, 07 Feb 2017 00:00:00 PST
LncRNA/DNA binding analysis reveals losses and gains and lineage specificity of genomic imprinting in mammals. Liu H, Shang X, Zhu H
Bioinformatics (May 2017)

Genomic imprinting is regulated by lncRNAs and is important for embryogenesis, physiology and behaviour in mammals. Aberrant imprinting causes diseases and disorders. Experimental studies have examined genomic imprinting primarily in humans and mice, thus leaving some fundamental issues poorly addressed. The cost of experimentally examining imprinted genes in many tissues in diverse species makes computational analysis of lncRNAs' DNA binding sites valuable.]]>
Thu, 05 Jan 2017 00:00:00 PST
Three intronic lncRNAs with monoallelic expression derived from the MEG8 gene in cattle. Yang W, Li D, Wang G, Zhang C, Zhang M, Zhang W, Li S
Anim Genet (Jun 2017)

The field of long noncoding RNA (lncRNA) research has been rapidly advancing in recent years. Antisense lncRNAs, intergenetic lncRNAs and enhancer lncRNAs can regulate genomic imprinting, which leads to parent-origin-specific monoalletic expression of genes. However, the function of intronic ncRNAs in genomic imprinting remains unclear. Previously, we obtained the cDNA sequence of cattle MEG8 gene, which is located in the DLK1-DIO3 imprinted clusters of cattle chromosome 21. In this study, we undertook a systematic search for transcripts mapping to the MEG8 intronic region and identified three novel lncRNAs, named MEG8 intronic RNA 1 (MEG8-IT1), MEG8 intronic RNA 2 (MEG8-IT2) and MEG8 intronic RNA 3 (MEG8-IT3) according to the GENCODE annotated bibliography. We characterized the expression pattern of these lncRNAs using RT-PCR in adult cattle tissues, and they were expressed in all tested eight tissues, similar to the expression pattern of MEG8. The allele-specific expression of three novel lncRNAs was assessed using a polymorphism-based sequencing approach. Three single nucleotide polymorphism sites were identified in these three lncRNAs. We found that the three lncRNAs showed monoallelic expression in the analyzed tissues, suggesting that they may be imprinted in cattle. These results expand the number of known monoallelically expressed lncRNAs from the DLK1-DIO3 domain and contribute to further investigation of lncRNA regulatory mechanisms and function.]]>
Wed, 07 Dec 2016 00:00:00 PST