'; ?> 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 Wed, 04 May 2016 18:41:09 PDT Wed, 04 May 2016 18:41:09 PDT jirtle@radonc.duke.edu james001@jirtle.com Integrative genomic deconvolution of rheumatoid arthritis GWAS loci into gene and cell type associations. Walsh AM, Whitaker JW, Huang CC, Cherkas Y, Lamberth SL, Brodmerkel C, Curran ME, Dobrin R
Genome Biol (2016)

Although genome-wide association studies (GWAS) have identified over 100 genetic loci associated with rheumatoid arthritis (RA), our ability to translate these results into disease understanding and novel therapeutics is limited. Most RA GWAS loci reside outside of protein-coding regions and likely affect distal transcriptional enhancers. Furthermore, GWAS do not identify the cell types where the associated causal gene functions. Thus, mapping the transcriptional regulatory roles of GWAS hits and the relevant cell types will lead to better understanding of RA pathogenesis.]]>
Wed, 04 May 2016 00:00:00 PDT
Properties and reactivity of nucleic acids relevant to epigenomics, transcriptomics, and therapeutics. Gillingham D, Geigle S, Anatole von Lilienfeld O
Chem Soc Rev (May 2016)

Developments in epigenomics, toxicology, and therapeutic nucleic acids all rely on a precise understanding of nucleic acid properties and chemical reactivity. In this review we discuss the properties and chemical reactivity of each nucleobase and attempt to provide some general principles for nucleic acid targeting or engineering. For adenine-thymine and guanine-cytosine base pairs, we review recent quantum chemical estimates of their Watson-Crick interaction energy, π-π stacking energies, as well as the nuclear quantum effects on tautomerism. Reactions that target nucleobases have been crucial in the development of new sequencing technologies and we believe further developments in nucleic acid chemistry will be required to deconstruct the enormously complex transcriptome.]]>
Wed, 04 May 2016 00:00:00 PDT
Nongenomic regulation of gene expression. Iglesias-Platas I, Monk D
Curr Opin Pediatr (Jun 2016)

The purpose of this review is to highlight the recent advances in epigenetic regulation and chromatin biology for a better understanding of gene regulation related to human disease.]]>
Tue, 03 May 2016 00:00:00 PDT
Multi-omic data integration and analysis using systems genomics approaches: methods and applications in animal production, health and welfare. Suravajhala P, Kogelman LJ, Kadarmideen HN
Genet Sel Evol (2016)

In the past years, there has been a remarkable development of high-throughput omics (HTO) technologies such as genomics, epigenomics, transcriptomics, proteomics and metabolomics across all facets of biology. This has spearheaded the progress of the systems biology era, including applications on animal production and health traits. However, notwithstanding these new HTO technologies, there remains an emerging challenge in data analysis. On the one hand, different HTO technologies judged on their own merit are appropriate for the identification of disease-causing genes, biomarkers for prevention and drug targets for the treatment of diseases and for individualized genomic predictions of performance or disease risks. On the other hand, integration of multi-omic data and joint modelling and analyses are very powerful and accurate to understand the systems biology of healthy and sustainable production of animals. We present an overview of current and emerging HTO technologies each with a focus on their applications in animal and veterinary sciences before introducing an integrative systems genomics framework for analysing and integrating multi-omic data towards improved animal production, health and welfare. We conclude that there are big challenges in multi-omic data integration, modelling and systems-level analyses, particularly with the fast emerging HTO technologies. We highlight existing and emerging systems genomics approaches and discuss how they contribute to our understanding of the biology of complex traits or diseases and holistic improvement of production performance, disease resistance and welfare.]]>
Sat, 30 Apr 2016 00:00:00 PDT
Alterations in expression of imprinted genes from the H19/IGF2 loci in a multigenerational model of intrauterine growth restriction (IUGR). Gonzalez-Rodriguez P, Cantu J, O'Neil D, Seferovic MD, Goodspeed DM, Suter MA, Aagaard KM
Am J Obstet Gynecol (May 2016)

The H19/IGF2 imprinted loci have attracted recent attention because of their role in cellular differentiation and proliferation, heritable gene regulation, and in utero or early postnatal growth and development. Expression from the imprinted H19/IGF2 locus involves a complex interplay of 3 means of epigenetic regulation: proper establishment of DNA methylation, promoter occupancy of CTCF, and expression of microRNA-675. We have demonstrated previously in a multigenerational rat model of intrauterine growth restriction the epigenetic heritability of adult metabolic syndrome in a F2 generation. We have further demonstrated abrogation of the F2 adult metabolic syndrome phenotype with essential nutrient supplementation of intermediates along the 1-carbon pathway and shown that alterations in the metabolome precede the adult onset of metabolic syndrome. The upstream molecular and epigenomic mediators underlying these observations, however, have yet to be elucidated fully.]]>
Fri, 29 Apr 2016 00:00:00 PDT
Altered Expression of Imprinted Genes in Squamous Cell Carcinoma of the Head and Neck. Hsu CM, Lin PM, Lin HC, Lai CC, Yang CH, Lin SF, Yang MY
Anticancer Res (May 2016)

Genomic imprinting is associated with many human diseases, including various types of cancers, however, no studies on gene imprinting are related to squamous cell carcinoma of the head and neck (SCCHN) directly.]]>
Fri, 29 Apr 2016 00:00:00 PDT
Precision Medicine and Oncology: An Overview of the Opportunities Presented by Next-Generation Sequencing and Big Data and the Challenges Posed to Conventional Drug Development and Regulatory Approval Pathways. Doherty M, Metcalfe T, Guardino E, Peters E, Ramage L
Ann Oncol (Apr 2016)

Recent studies have begun to describe the vast extent of inter- and intra-tumor genomic diversity and the ability of the tumor genome to evolve over time and in response to selective pressures exerted by therapy, Gerlinger et al [1], Greaves and Maley [2]. Techniques allowing the systematic evaluation of the tumor genome, particularly Next-Generation Sequencing (NGS), now have performance characteristics and costs which allow them to be integrated into routine clinical care and drug development, Frampton et al [3]. It is therefore pertinent to reevaluate the drug development and approval process of oncology therapies in light of these developments.Although it is too early to predict the extent to which NGS will transform oncology, it will likely become an important tool in routine diagnostics and, when combined with the use of treatment/matching algorithms(1) based on the clinical relevance of mutational profiles, will have a beneficial effect on patient outcomes. Along with advances in immunotherapy, NGS, as a basis of selecting targeted therapies for cancer patients, should be incorporated into strategic planning for the future of oncology drug development. In the future, integrative systems biology approaches encompassing epigenomics, pathway analysis, and insights derived from the tumor microenvironment, in addition to genomics, are expected to lead to improved decision making. The use of NGS to elucidate the impact of somatic genomic alterations on treatment outcomes is an important first step, even if current attempts to match patients to targeted therapies have yielded low rates of actionability (13%, Andre et al [4]) for rare variants.Clinical trials will need to become more patient-centric (as opposed to drug-centric) when NGS- or molecular profiling-driven trials are conducted, since treatments will become more individualized.We recommend that NGS-driven trials and the development of treatment algorithms are further explored, potentially including public-private partnerships and multi-sponsor collaborations.]]>
Wed, 27 Apr 2016 00:00:00 PDT
Parental epigenetic asymmetry of PRC2-mediated histone modifications in the Arabidopsis endosperm. Moreno-Romero J, Jiang H, Santos-González J, Köhler C
EMBO J (Apr 2016)

Parental genomes in the endosperm are marked by differential DNA methylation and are therefore epigenetically distinct. This epigenetic asymmetry is established in the gametes and maintained after fertilization by unknown mechanisms. In this manuscript, we have addressed the key question whether parentally inherited differential DNA methylation affects de novo targeting of chromatin modifiers in the early endosperm. Our data reveal that polycomb-mediated H3 lysine 27 trimethylation (H3K27me3) is preferentially localized to regions that are targeted by the DNA glycosylase DEMETER (DME), mechanistically linking DNA hypomethylation to imprinted gene expression. Our data furthermore suggest an absence of de novo DNA methylation in the early endosperm, providing an explanation how DME-mediated hypomethylation of the maternal genome is maintained after fertilization. Lastly, we show that paternal-specific H3K27me3-marked regions are located at pericentromeric regions, suggesting that H3K27me3 and DNA methylation are not necessarily exclusive marks at pericentromeric regions in the endosperm.]]>
Tue, 26 Apr 2016 00:00:00 PDT
Separating the wheat from the chaff: systematic identification of functionally relevant noncoding variants in ADHD. Tong JH, Hawi Z, Dark C, Cummins TD, Johnson BP, Newman DP, Lau R, Vance A, Heussler HS, Matthews N, Bellgrove MA, Pang KC
Mol Psychiatry (Apr 2016)

Attention deficit hyperactivity disorder (ADHD) is a highly heritable psychiatric condition with negative lifetime outcomes. Uncovering its genetic architecture should yield important insights into the neurobiology of ADHD and assist development of novel treatment strategies. Twenty years of candidate gene investigations and more recently genome-wide association studies have identified an array of potential association signals. In this context, separating the likely true from false associations ('the wheat' from 'the chaff') will be crucial for uncovering the functional biology of ADHD. Here, we defined a set of 2070 DNA variants that showed evidence of association with ADHD (or were in linkage disequilibrium). More than 97% of these variants were noncoding, and were prioritised for further exploration using two tools-genome-wide annotation of variants (GWAVA) and Combined Annotation-Dependent Depletion (CADD)-that were recently developed to rank variants based upon their likely pathogenicity. Capitalising on recent efforts such as the Encyclopaedia of DNA Elements and US National Institutes of Health Roadmap Epigenomics Projects to improve understanding of the noncoding genome, we subsequently identified 65 variants to which we assigned functional annotations, based upon their likely impact on alternative splicing, transcription factor binding and translational regulation. We propose that these 65 variants, which possess not only a high likelihood of pathogenicity but also readily testable functional hypotheses, represent a tractable shortlist for future experimental validation in ADHD. Taken together, this study brings into sharp focus the likely relevance of noncoding variants for the genetic risk associated with ADHD, and more broadly suggests a bioinformatics approach that should be relevant to other psychiatric disorders.Molecular Psychiatry advance online publication, 26 April 2016; doi:10.1038/mp.2016.2.]]>
Tue, 26 Apr 2016 00:00:00 PDT
Field Cancerization in Sporadic Colon Cancer. Park SK, Song CS, Yang HJ, Jung YS, Choi KY, Koo DH, Kim KE, Jeong KU, Kim HO, Kim H, Chun HK, Park DI
Gut Liver (Apr 2016)

Aberrant DNA methylation has a specific role in field cancerization. Certain molecular markers, including secreted frizzled-related protein 2 (SFRP2), tissue factor pathway inhibitor 2 (TFPI2), N-Myc downstream-regulated gene 4 (NDRG4) and bone morphogenic protein 3 (BMP3), have previously been shown to be hypermethylated in colorectal cancer (CRC). We aim to examine field cancerization in CRC based on the presence of aberrant DNA methylation in normal-appearing tissue from CRC patients.]]>
Tue, 26 Apr 2016 00:00:00 PDT
Interplay between PREX2 mutations and the PI3K pathway and its effect on epigenetic regulation of gene expression in NRAS-mutant melanoma. Deribe YL
Small GTPases (Apr 2016)

PREX2 is a PTEN interacting protein that is significantly mutated in melanoma and pancreatic ductal adenocarcinoma. Recently, we reported the mechanistic basis of melanomagenesis by PREX2 mutations. Truncating PREX2 mutations activate its guanine nucleotide exchange factor activity for its substrate RAC1. This leads to increased PI3K/AKT signaling associated with reduced DNA methylation and increased cell proliferation in NRAS-mutant melanoma. Here, we provide additional data that indicates a reciprocal regulation of PREX2 by PTEN whereby loss of PTEN results in a dramatic increase in expression of PREX2 at the protein level. Pharmacologic studies revealed destabilization of PREX2 by inhibition of PI3K/AKT signaling. Additionally, we provide data to show a selective decrease in a particular histone mark, H4 Lys20 trimethylation, in cells expressing PREX2 (E824*) truncating mutation globally and at the imprint control region of CDKN1C (also known as p57) and IGF2. The decrease in H4K20 trimethylation coupled with DNA hypomethylation at this particular locus is associated with genomic imprinting and regulation of expression of p57 and IGF2. Taken together, these results demonstrate the complex signaling mechanisms that involve PREX2, PI3K/AKT/PTEN and downstream epigenetic machinery to deregulate expression of key cell cycle regulators.]]>
Mon, 25 Apr 2016 00:00:00 PDT
Evolution of Epigenetic Regulation in Vertebrate Genomes. Lowdon RF, Jang HS, Wang T
Trends Genet (May 2016)

Empirical models of sequence evolution have spurred progress in the field of evolutionary genetics for decades. We are now realizing the importance and complexity of the eukaryotic epigenome. While epigenome analysis has been applied to genomes from single-cell eukaryotes to human, comparative analyses are still relatively few and computational algorithms to quantify epigenome evolution remain scarce. Accordingly, a quantitative model of epigenome evolution remains to be established. We review here the comparative epigenomics literature and synthesize its overarching themes. We also suggest one mechanism, transcription factor binding site (TFBS) turnover, which relates sequence evolution to epigenetic conservation or divergence. Lastly, we propose a framework for how the field can move forward to build a coherent quantitative model of epigenome evolution.]]>
Sun, 24 Apr 2016 00:00:00 PDT
Comparative DNA methylation analysis to decipher common and cell type-specific patterns among multiple cell types. Yang X, Shao X, Gao L, Zhang S
Brief Funct Genomics (Apr 2016)

DNA methylation has been proved to play important roles in cell development and complex diseases through comparative studies of DNA methylation profiles across different tissues and samples. Current studies indicate that the regulation of DNA methylation to gene expression depends on the genomic locations of CpGs. Common DNA methylation patterns shared across different cell types and tissues are abundant, and they are likely involved in the basic functions of cell development, such as housekeeping functions. By way of contrast, cell type-specific DNA methylation patterns show distinct functional relevance with cell type specificity. Additionally, abnormal DNA methylation patterns are extensively involved in tumour development. Pan-cancer methylation patterns reveal common mechanisms and new similarities of different cancers, while cancer-specific patterns are relating to tumour heterogeneity and patient survival. Moreover, DNA methylation patterns in specific cancer are relevant with diverse regulatory elements such as enhancers and long non-coding RNAs. In this review, we survey the recent advances on DNA methylation patterns in normal or tumour states to illustrate their potential roles in cell development and cell canceration.]]>
Sat, 23 Apr 2016 00:00:00 PDT
The evolving landscape of imprinted genes in humans and mice: Conflict among alleles, genes, tissues, and kin. Wilkins JF, Úbeda F, Van Cleve J
Bioessays (May 2016)

Three recent genome-wide studies in mice and humans have produced the most definitive map to date of genomic imprinting (gene expression that depends on parental origin) by incorporating multiple tissue types and developmental stages. Here, we explore the results of these studies in light of the kinship theory of genomic imprinting, which predicts that imprinting evolves due to differential genetic relatedness between maternal and paternal relatives. The studies produce a list of imprinted genes with around 120-180 in mice and ∼100 in humans. The studies agree on broad patterns across mice and humans including the complex patterns of imprinted expression at loci like Igf2 and Grb10. We discuss how the kinship theory provides a powerful framework for hypotheses that can explain these patterns. Finally, since imprinting is rare in the genome despite predictions from the kinship theory that it might be common, we discuss evolutionary factors that could favor biallelic expression.]]>
Fri, 22 Apr 2016 00:00:00 PDT
Childhood obesity: a systems medicine approach. Stone WL, Schetzina K, Stuart C
Front Biosci (Landmark Ed) (2016)

Childhood obesity and its sequelae are a major public health problem in both the USA and globally. This review will focus on a systems medicine approach to obesity. Systems medicine is an integrative approach utilizing the vast amount of data garnered from "omics" technology and integrating these data with conventional pathophysiology as well as diverse environmental factors such as diet, exercise, community dynamics and the intestinal microbiome. Omics technology includes genomics, epigenomics, metagenomics, metabolomics and proteomics. In addition to unraveling etiology, the goals of a systems medicine approach are to provide actionable and evidenced-based clinical approaches. In the case of childhood obesity, an additional goal is characterizing measureable risk factors/biomarkers for obesity at the earliest possible age and devising age-appropriate optimal intervention strategies. It is also important to establish the age at which interventions could be critical. As discussed below, it is possible that some of the pathophysiological and epigenetic changes resulting from childhood obesity could become more irreversible the longer the obesity remains untreated.]]>
Fri, 22 Apr 2016 00:00:00 PDT
Pathogenetics of alveolar capillary dysplasia with misalignment of pulmonary veins. Szafranski P, Gambin T, Dharmadhikari AV, Akdemir KC, Jhangiani SN, Schuette J, Godiwala N, Yatsenko SA, Sebastian J, Madan-Khetarpal S, Surti U, Abellar RG, Bateman DA, Wilson AL, Markham MH, Slamon J, Santos-Simarro F, Palomares M, Nevado J, Lapunzina P, Chung BH, Wong WL, Chu YW, Mok GT, Kerem E, Reiter J, Ambalavanan N, Anderson SA, Kelly DR, Shieh J, Rosenthal TC, Scheible K, Steiner L, Iqbal MA, McKinnon ML, Hamilton SJ, Schlade-Bartusiak K, English D, Hendson G, Roeder ER, DeNapoli TS, Littlejohn RO, Wolff DJ, Wagner CL, Yeung A, Francis D, Fiorino EK, Edelman M, Fox J, Hayes DA, Janssens S, De Baere E, Menten B, Loccufier A, Vanwalleghem L, Moerman P, Sznajer Y, Lay AS, Kussmann JL, Chawla J, Payton DJ, Phillips GE, Brosens E, Tibboel D, de Klein A, Maystadt I, Fisher R, Sebire N, Male A, Chopra M, Pinner J, Malcolm G, Peters G, Arbuckle S, Lees M, Mead Z, Quarrell O, Sayers R, Owens M, Shaw-Smith C, Lioy J, McKay E, de Leeuw N, Feenstra I, Spruijt L, Elmslie F, Thiruchelvam T, Bacino CA, Langston C, Lupski JR, Sen P, Popek E, Stankiewicz P
Hum Genet (May 2016)

Alveolar capillary dysplasia with misalignment of pulmonary veins (ACDMPV) is a lethal lung developmental disorder caused by heterozygous point mutations or genomic deletion copy-number variants (CNVs) of FOXF1 or its upstream enhancer involving fetal lung-expressed long noncoding RNA genes LINC01081 and LINC01082. Using custom-designed array comparative genomic hybridization, Sanger sequencing, whole exome sequencing (WES), and bioinformatic analyses, we studied 22 new unrelated families (20 postnatal and two prenatal) with clinically diagnosed ACDMPV. We describe novel deletion CNVs at the FOXF1 locus in 13 unrelated ACDMPV patients. Together with the previously reported cases, all 31 genomic deletions in 16q24.1, pathogenic for ACDMPV, for which parental origin was determined, arose de novo with 30 of them occurring on the maternally inherited chromosome 16, strongly implicating genomic imprinting of the FOXF1 locus in human lungs. Surprisingly, we have also identified four ACDMPV families with the pathogenic variants in the FOXF1 locus that arose on paternal chromosome 16. Interestingly, a combination of the severe cardiac defects, including hypoplastic left heart, and single umbilical artery were observed only in children with deletion CNVs involving FOXF1 and its upstream enhancer. Our data demonstrate that genomic imprinting at 16q24.1 plays an important role in variable ACDMPV manifestation likely through long-range regulation of FOXF1 expression, and may be also responsible for key phenotypic features of maternal uniparental disomy 16. Moreover, in one family, WES revealed a de novo missense variant in ESRP1, potentially implicating FGF signaling in the etiology of ACDMPV.]]>
Tue, 19 Apr 2016 00:00:00 PDT
Maintaining memory of silencing at imprinted differentially methylated regions. Voon HP, Gibbons RJ
Cell Mol Life Sci (May 2016)

Imprinted genes are an exceptional cluster of genes which are expressed in a parent-of-origin dependent fashion. This allele-specific expression is dependent on differential DNA methylation which is established in the parental germlines in a sex-specific manner. The DNA methylation imprint is accompanied by heterochromatin modifications which must be continuously maintained through development. This review summarises the factors which are important for protecting the epigenetic modifications at imprinted differentially methylated regions (DMRs), including PGC7, ZFP57 and the ATRX/Daxx/H3.3 complex. We discuss how these factors maintain heterochromatin silencing, not only at imprinted DMRs, but also other heterochromatic regions in the genome.]]>
Mon, 04 Apr 2016 00:00:00 PDT
Biomarkers in neonatology: the new "omics" of bronchopulmonary dysplasia. Piersigilli F, Bhandari V
J Matern Fetal Neonatal Med (Jun 2016)

Bronchopulmonary dysplasia (BPD) is a complex disorder resulting from gene-environmental interactions. An improved understanding of the pathogenesis of this most common chronic lung disease in infants has been made by utilizing animal models and correlating with human data. Currently, while some (vitamin A, caffeine) pharmacotherapeutic options are being utilized to ameliorate this condition, there is still no specific or effective treatment for BPD. It would be helpful for prognostication and targeted potential novel therapeutic strategies to identify those babies accurately who are at risk for developing this disease. A reliable biomarker would have the capacity to be detected in the initial phase of the disease, to allow early interventions to avoid or minimize the detrimental effects of the disease. This review will focus on human studies performed with the "omic" techniques, specifically genomics, epigenomics, microbiomics, transciptomics, proteomics and metabolomics, and summarize the information available in the literature, as it pertains to biomarker identification for BPD. Using "omics" technologies, investigators have reported markers that have the potential to be used as biomarkers of BPD: SPOCK2, VEGF -624C > G, VEGF -460T > C, mast cells specific markers, miR-219 pathway, miR-152, -30a-3p, -133b, -206, -7, lactate, taurine, trimethylamine-N-oxide, gluconate, myoinositol and alterations in surfactant lipid profile.]]>
Fri, 25 Mar 2016 00:00:00 PDT
DNA methylation analysis in constitutional disorders: Clinical implications of the epigenome. Schenkel LC, Rodenhiser DI, Ainsworth PJ, Paré G, Sadikovic B
Crit Rev Clin Lab Sci (Jun 2016)

Genomic, chromosomal, and gene-specific changes in the DNA sequence underpin both phenotypic variations in populations as well as disease associations, and the application of genomic technologies for the identification of constitutional (inherited) or somatic (acquired) alterations in DNA sequence forms a cornerstone of clinical and molecular genetics. In addition to the disruption of primary DNA sequence, the modulation of DNA function by epigenetic phenomena, in particular by DNA methylation, has long been known to play a role in the regulation of gene expression and consequent pathogenesis. However, these epigenetic factors have been identified only in a handful of pediatric conditions, including imprinting disorders. Technological advances in the past decade that have revolutionized clinical genomics are now rapidly being applied to the emerging discipline of clinical epigenomics. Here, we present an overview of epigenetic mechanisms with a focus on DNA modifications, including the molecular mechanisms of DNA methylation and subtypes of DNA modifications, and we describe the classic and emerging genomic technologies that are being applied to this study. This review focuses primarily on constitutional epigenomic conditions associated with a spectrum of developmental and intellectual disabilities. Epigenomic disorders are discussed in the context of global genomic disorders, imprinting disorders, and single gene disorders. We include a section focused on integration of genetic and epigenetic mechanisms together with their effect on clinical phenotypes. Finally, we summarize emerging epigenomic technologies and their impact on diagnostic aspects of constitutional genetic and epigenetic disorders.]]>
Tue, 16 Feb 2016 00:00:00 PST
Key Signaling Events for Committing Mouse Pluripotent Stem Cells to the Germline Fate. Wang JQ, Cao WG
Biol Reprod (Dec 2016)

The process of germline development carries genetic information and preparatory totipotency across generations. The last decade has witnessed remarkable successes in the generation of germline cells from mouse pluripotent stem cells, especially induced germline cells with the capacity for producing viable offspring, suggesting clinical applications of induced germline cells in humans. However, to date, the culture systems for germline induction with accurate sex-specific meiosis and epigenetic reprogramming have not been well-established. In this study, we primarily focus on the mouse model to discuss key signaling events for germline induction. We review mechanisms of competent regulators on primordial germ cell induction and discuss current achievements and difficulties in inducing sex-specific germline development. Furthermore, we review the developmental identities of mouse embryonic stem cells and epiblast stem cells under certain defined culture conditions as it relates to the differentiation process of becoming germline cells.]]>
Fri, 29 Jan 2016 00:00:00 PST