'; ?> 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 Sat, 24 Sep 2016 23:15:51 PDT Sat, 24 Sep 2016 23:15:51 PDT jirtle@radonc.duke.edu james001@jirtle.com Epigenomic engineering for Down syndrome. Mentis AA
Neurosci Biobehav Rev (Sep 2016)

Down syndrome (DS; trisomy 21), the commonest genetic cause of mental disability, affects approximately 250,000 families in the United States alone. Despite milestones in understanding the specific genetic causes of the syndrome, the major symptoms of DS - not least those related to neurocognitive function - are incurable. DS phenotypes are highly variable, and gene expression patterns cannot be explained by trisomy alone, implicating epigenetics in DS pathophysiology. DNA and histone modifications appear to contribute to DS pathology and cognitive defects, and epigenomic, and genome editing research have very recently opened up novel therapeutic avenues for several diseases including DS. Here, we discuss how epigenomic therapies might be used to ameliorate DS-related phenotypes with a particular focus on the CRISPR-Cas 9 system for targeted epigenomic engineering in DS. This approach is likely to reap rewards in terms of understanding the pathophysiology of DS, especially when combined with animal models, but significant technical and ethical challenges must be overcome for clinical translation.]]>
Sat, 24 Sep 2016 00:00:00 PDT
Using genomic information to improve soybean adaptability to climate change. Li MW, Xin D, Gao Y, Li KP, Fan K, Muñoz NB, Yung WS, Lam HM
J Exp Bot (Sep 2016)

Climate change has brought severe challenges to agriculture. It is anticipated that there will be a drop in crop yield - including that of soybean - due to climatic stress factors that include drastic fluctuations in temperature, drought, flooding and high salinity. Genomic information on soybean has been accumulating rapidly since initial publication of its reference genome, providing a valuable tool for the improvement of cultivated soybean. Not only are many molecular markers that are associated with important quantitative trait loci now identified, but we also have a more detailed picture of the genomic variations among soybean germplasms, enabling us to utilize these as tools to assist crop breeding. In this review, we will summarize and discuss the currently available soybean genomic approaches, including whole-genome sequencing, sequencing-based genotyping, functional genomics, proteomics, and epigenomics. The information uncovered through these techniques will help further pinpoint important gene candidates and genomic loci associated with adaptive traits, as well as achieving a better understanding of how soybeans cope with the changing climate.]]>
Fri, 23 Sep 2016 00:00:00 PDT
Establishment and functions of DNA methylation in the germline. Stewart KR, Veselovska L, Kelsey G
Epigenomics (Sep 2016)

Epigenetic modifications established during gametogenesis regulate transcription and other nuclear processes in gametes, but also have influences in the zygote, embryo and postnatal life. This is best understood for DNA methylation which, established at discrete regions of the oocyte and sperm genomes, governs genomic imprinting. In this review, we describe how imprinting has informed our understanding of de novo DNA methylation mechanisms, highlight how recent genome-wide profiling studies have provided unprecedented insights into establishment of the sperm and oocyte methylomes and consider the fate and function of gametic methylation and other epigenetic modifications after fertilization.]]>
Fri, 23 Sep 2016 00:00:00 PDT
Increased dosage of the imprinted Ascl2 gene restrains two key endocrine lineages of the mouse Placenta. Tunster SJ, McNamara GI, Creeth HD, John RM
Dev Biol (Oct 2016)

Imprinted genes are expressed primarily from one parental allele by virtue of a germ line epigenetic process. Achaete-scute complex homolog 2 (Ascl2 aka Mash2) is a maternally expressed imprinted gene that plays a key role in placental and intestinal development. Loss-of-function of Ascl2 results in an expansion of the parietal trophoblast giant cell (P-TGC) lineage, an almost complete loss of Trophoblast specific protein alpha (Tpbpa) positive cells in the ectoplacental cone and embryonic failure by E10.5. Tpbpa expression marks the progenitors of some P-TGCs, two additional trophoblast giant cell lineages (spiral artery and canal), the spongiotrophoblast and the glycogen cell lineage. Using a transgenic model, here we show that elevated expression of Ascl2 reduced the number of P-TGC cells by 40%. Elevated Ascl2 also resulted in a marked loss of the spongiotrophoblast and a substantial mislocalisation of glycogen cells into the labyrinth. In addition, Ascl2-Tg placenta contained considerably more placental glycogen than wild type. Glycogen cells are normally located within the junctional zone in close contact with spongiotrophoblast cells, before migrating through the P-TGC layer into the maternal decidua late in gestation where their stores of glycogen are released. The failure of glycogen cells to release their stores of glycogen may explain both the inappropriate accumulation of glycogen and fetal growth restriction observed late in gestation in this model. In addition, using in a genetic cross we provide evidence that Ascl2 requires the activity of a second maternally expressed imprinted gene, Pleckstrin homology-like domain, family a, member 2 (Phlda2) to limit the expansion of the spongiotrophoblast. This "belts and braces" approach demonstrates the importance of genomic imprinting in regulating the size of the placental endocrine compartment for optimal placental development and fetal growth.]]>
Wed, 21 Sep 2016 00:00:00 PDT
Computational inference of a genomic pluripotency signature in human and mouse stem cells. Kurum E, Benayoun BA, Malhotra A, George J, Ucar D
Biol Direct (2016)

Recent analyses of next-generation sequencing datasets have shown that cell-specific regulatory elements in stem cells are marked with distinguishable patterns of transcription factor (TF) binding and epigenetic marks. For example, we recently demonstrated that promoters of cell-specific genes are covered with expanded trimethylation of histone H3 at lysine 4 (H3K4me3) marks (i.e., broad H3K4me3 domains). Moreover, binding of specific TFs, such as OCT4, NANOG, and SOX2, have been shown to play a critical role in maintaining the pluripotency of stem cells. Despite these observations, a systematic exploration of genomic and epigenomic features of stem-cell-specific gene promoters has not been conducted. Advanced machine-learning models can capture distinguishable genomic and epigenomic characteristics of stem-cell-specific promoters by taking advantage of the wealth of publicly available datasets. Here, we propose a three-step framework to discover novel data characteristics of high-throughput next generation sequencing datasets that distinguish pluripotency genes in human and mouse embryonic stem cells (ESCs). Our framework involves: i) feature extraction to identify novel features of genomic datasets; ii) feature selection using a logistic regression model combined with the Least Absolute Shrinkage and Selection Operator (LASSO) method to find the most critical datasets and features; and iii) cross validation with features selected using LASSO method to assess the predictive power of selected data features in distinguishing pluripotency genes. We show that specific epigenetic marks, and specific features of these marks, are enriched at pluripotency gene promoters. Moreover, we also assess both the individual and combined effect of TF binding, epigenetic mark deposition, gene expression datasets for marking pluripotency genes. Our findings are consistent with the existence of a conserved, complex and integrative genomic signature in ESCs that can be exploited to flag important candidate pluripotency genes. They also validate our computational framework for fostering a deeper understanding of genomic datasets in stem cells, in the future, could be extended to study cell-type-specific genomic landscapes in other cell types.]]>
Mon, 19 Sep 2016 00:00:00 PDT
Opposite differential risks for autism and schizophrenia based on maternal age, paternal age, and parental age differences. Byars SG, Boomsma JJ
Evol Med Public Health (2016)

Effects of maternal and paternal age on offspring autism and schizophrenia risks have been studied for over three decades, but inconsistent risks have often been found, precluding well-informed speculation on why these age-related risks might exist.]]>
Sat, 17 Sep 2016 00:00:00 PDT
The epigenome in Alzheimer's disease: current state and approaches for a new path to gene discovery and understanding disease mechanism. Klein HU, Bennett DA, De Jager PL
Acta Neuropathol (Oct 2016)

The advent of new technologies and analytic approaches is beginning to provide an unprecedented look at features of the human genome that affect RNA expression. These "epigenomic" features are found in a number of different forms: they include DNA methylation, covalent modifications of histone proteins and non-coding RNAs. Some of these features have now been implicated in Alzheimer's disease (AD). Here, we focus on recent studies that have identified robust observations relating to DNA methylation and chromatin in human brain tissue; these findings will ground the next generation of studies and provide a model for the design of such studies. Stemming from observations that compounds with histone deacetylase activity may be beneficial in AD, epigenome-wide studies in cortical samples from large numbers of human subjects have now shown that AD-associated epigenomic changes are reproducible, are not driven by genetic risk factors, and are widespread at specific locations in the genome. A fundamental question of whether such changes are causal remains to be demonstrated, but it is already clear that well-powered investigations of the human epigenome in the target organ of a neurodegenerative disease are feasible, are implicating new areas of the genome in the disease, and will be an important tool for future studies. We are now at an inflection point: as genome-wide association studies of genetic variants come to an end, a new generation of studies exploring the epigenome will provide an important new layer of information with which to enrich our understanding of AD pathogenesis and to possibly guide development of new therapeutic targets.]]>
Sat, 17 Sep 2016 00:00:00 PDT
Sierra platinum: a fast and robust peak-caller for replicated ChIP-seq experiments with visual quality-control and -steering. Müller L, Gerighausen D, Farman M, Zeckzer D
BMC Bioinformatics (2016)

Histone modifications play an important role in gene regulation. Their genomic locations are of great interest. Usually, the location is measured by ChIP-seq and analyzed with a peak-caller. Replicated ChIP-seq experiments become more and more available. However, their analysis is based on single-experiment peak-calling or on tools like PePr which allows peak-calling of replicates but whose underlying model might not be suitable for the conditions under which the experiments are performed.]]>
Fri, 16 Sep 2016 00:00:00 PDT
Interspecific hybrids of dwarf hamsters and Phasianidae birds as animal models for studying the genetic and developmental basis of hybrid incompatibility. Ishishita S, Matsuda Y
Genes Genet Syst (Sep 2016)

Hybrid incompatibility is important in speciation as it prevents gene flow between closely related populations. Reduced fitness from hybrid incompatibility may also reinforce prezygotic reproductive isolation between sympatric populations. However, the genetic and developmental basis of hybrid incompatibility in higher vertebrates remains poorly understood. Mammals and birds, both amniotes, have similar developmental processes, but marked differences in development such as the XY/ZW sex determination systems and the presence or absence of genomic imprinting. Here, we review the sterile phenotype of hybrids between the Phodopus dwarf hamsters P. campbelli and P. sungorus, and the inviable phenotype of hybrids between two birds of the family Phasianidae, chicken (Gallus gallus domesticus) and Japanese quail (Coturnix japonica). We propose hypotheses for developmental defects that are associated with these hybrid incompatibilities. In addition, we discuss the genetic and developmental basis for these defects in conjunction with recent findings from mouse and avian models of genetics, reproductive biology and genomics. We suggest that these hybrids are ideal animal models for studying the genetic and developmental basis of hybrid incompatibility in amniotes.]]>
Thu, 15 Sep 2016 00:00:00 PDT
Protocol Outlines for Parts 1 and 2 of the Prospective Endoscopy III Study for the Early Detection of Colorectal Cancer: Validation of a Concept Based on Blood Biomarkers. Rasmussen L, Wilhelmsen M, Christensen IJ, Andersen J, Jørgensen LN, Rasmussen M, Hendel JW, Madsen MR, Vilandt J, Hillig T, Klærke M, Münster AM, Andersen LM, Andersen B, Hornung N, Erlandsen EJ, Khalid A, Nielsen HJ
JMIR Res Protoc (2016)

Programs for population screening of colorectal cancer (CRC) have been implemented in several countries with fecal immunochemical testing (FIT) as the preferred platform. However, the major obstacle for a feces-based testing method is the limited compliance that reduces the clinical sensitivity for detection of participants with non-symptomatic CRC. Therefore, research approaches have been initiated to develop screening concepts based on biomarkers in blood. Preliminary results show that protein, genetic, epigenetic, and metabolomic components may be valuable in blood-based screening concepts, particularly when combinations of the various components appear to lead to significant improvements.]]>
Wed, 14 Sep 2016 00:00:00 PDT
Methods of epigenome editing for probing the function of genomic imprinting. Rienecker KD, Hill MJ, Isles AR
Epigenomics (Sep 2016)

The curious patterns of imprinted gene expression draw interest from several scientific disciplines to the functional consequences of genomic imprinting. Methods of probing the function of imprinting itself have largely been indirect and correlational, relying heavily on conventional transgenics. Recently, the burgeoning field of epigenome editing has provided new tools and suggested strategies for asking causal questions with site specificity. This perspective article aims to outline how these new methods may be applied to questions of functional imprinting and, with this aim in mind, to suggest new dimensions for the expansion of these epigenome-editing tools.]]>
Wed, 14 Sep 2016 00:00:00 PDT
Maps of context-dependent putative regulatory regions and genomic signal interactions. Diamanti K, Umer HM, Kruczyk M, Dąbrowski MJ, Cavalli M, Wadelius C, Komorowski J
Nucleic Acids Res (Sep 2016)

Gene transcription is regulated mainly by transcription factors (TFs). ENCODE and Roadmap Epigenomics provide global binding profiles of TFs, which can be used to identify regulatory regions. To this end we implemented a method to systematically construct cell-type and species-specific maps of regulatory regions and TF-TF interactions. We illustrated the approach by developing maps for five human cell-lines and two other species. We detected ∼144k putative regulatory regions among the human cell-lines, with the majority of them being ∼300 bp. We found ∼20k putative regulatory elements in the ENCODE heterochromatic domains suggesting a large regulatory potential in the regions presumed transcriptionally silent. Among the most significant TF interactions identified in the heterochromatic regions were CTCF and the cohesin complex, which is in agreement with previous reports. Finally, we investigated the enrichment of the obtained putative regulatory regions in the 3D chromatin domains. More than 90% of the regions were discovered in the 3D contacting domains. We found a significant enrichment of GWAS SNPs in the putative regulatory regions. These significant enrichments provide evidence that the regulatory regions play a crucial role in the genomic structural stability. Additionally, we generated maps of putative regulatory regions for prostate and colorectal cancer human cell-lines.]]>
Wed, 14 Sep 2016 00:00:00 PDT
Genomic prediction using models with dominance and imprinting effects for backfat thickness and average daily gain in Danish Duroc pigs. Guo X, Christensen OF, Ostersen T, Wang Y, Lund MS, Su G
Genet Sel Evol (2016)

Dominance and imprinting genetic effects have been shown to contribute to genetic variance for certain traits but are usually ignored in genomic prediction of complex traits in livestock. The objectives of this study were to estimate variances of additive, dominance and imprinting genetic effects and to evaluate predictions of genetic merit based on genomic data for average daily gain (DG) and backfat thickness (BF) in Danish Duroc pigs.]]>
Wed, 14 Sep 2016 00:00:00 PDT
Endosperm turgor pressure decreases during early Arabidopsis seed development. Beauzamy L, Fourquin C, Dubrulle N, Boursiac Y, Boudaoud A, Ingram G
Development (Sep 2016)

In Arabidopsis, rapid expansion of the coenocytic endosperm after fertilisation has been proposed to drive early seed growth, which is in turn constrained by the seed coat. This hypothesis implies physical heterogeneity between the endosperm and seed coat compartments during early seed development, which to date has not been demonstrated. Here, we combine tissue indentation with modelling to show that the physical properties of the developing seed are consistent with the hypothesis that elevated endosperm-derived turgor pressure drives early seed expansion. We provide evidence that whole-seed turgor is generated by the endosperm at early developmental stages. Furthermore, we show that endosperm cellularisation and seed growth arrest are associated with a drop in endosperm turgor pressure. Finally, we demonstrate that this decrease is perturbed when the function of POLYCOMB REPRESSIVE COMPLEX 2 is lost, suggesting that turgor pressure changes could be a target of genomic imprinting. Our results indicate a developmental role for changes in endosperm turgor pressure in the Arabidopsis seed.]]>
Wed, 14 Sep 2016 00:00:00 PDT
Humanized H19/Igf2 locus reveals diverged imprinting mechanism between mouse and human and reflects Silver-Russell syndrome phenotypes. Hur SK, Freschi A, Ideraabdullah F, Thorvaldsen JL, Luense LJ, Weller AH, Berger SL, Cerrato F, Riccio A, Bartolomei MS
Proc Natl Acad Sci U S A (Sep 2016)

Genomic imprinting affects a subset of genes in mammals, such that they are expressed in a monoallelic, parent-of-origin-specific manner. These genes are regulated by imprinting control regions (ICRs), cis-regulatory elements that exhibit allele-specific differential DNA methylation. Although genomic imprinting is conserved in mammals, ICRs are genetically divergent across species. This raises the fundamental question of whether the ICR plays a species-specific role in regulating imprinting at a given locus. We addressed this question at the H19/insulin-like growth factor 2 (Igf2) imprinted locus, the misregulation of which is associated with the human imprinting disorders Beckwith-Wiedemann syndrome (BWS) and Silver-Russell syndrome (SRS). We generated a knock-in mouse in which the endogenous H19/Igf2 ICR (mIC1) is replaced by the orthologous human ICR (hIC1) sequence, designated H19(hIC1) We show that hIC1 can functionally replace mIC1 on the maternal allele. In contrast, paternally transmitted hIC1 leads to growth restriction, abnormal hIC1 methylation, and loss of H19 and Igf2 imprinted expression. Imprint establishment at hIC1 is impaired in the male germ line, which is associated with an abnormal composition of histone posttranslational modifications compared with mIC1. Overall, this study reveals evolutionarily divergent paternal imprinting at IC1 between mice and humans. The conserved maternal imprinting mechanism and function at IC1 demonstrates the possibility of modeling maternal transmission of hIC1 mutations associated with BWS in mice. In addition, we propose that further analyses in the paternal knock-in H19(+/hIC1) mice will elucidate the molecular mechanisms that may underlie SRS.]]>
Tue, 13 Sep 2016 00:00:00 PDT
Pre-analytical variables of circulating cell-free nucleosomes containing 5-methylcytosine DNA or histone modification H3K9Me3. Rasmussen L, Herzog M, Rømer E, Micallef J, Bulut O, Wilhelmsen M, Christensen IJ, Nielsen HJ
Scand J Clin Lab Invest (Oct 2016)

To evaluate pre-analytical variables of circulating cell-free nucleosomes containing 5-methylcytosine DNA (5mC) or histone modification H3K9Me3 (H3K9Me3).]]>
Sat, 10 Sep 2016 00:00:00 PDT
Symptom Science: Repurposing Existing Omics Data. Osier ND, Imes CC, Khalil H, Zelazny J, Johansson AE, Conley YP
Biol Res Nurs (Sep 2016)

Omics approaches, including genomics, transcriptomics, proteomics, epigenomics, microbiomics, and metabolomics, generate large data sets. Once they have been used to address initial study aims, these large data sets are extremely valuable to the greater research community for ancillary investigations. Repurposing available omics data sets provides data to address research questions, generate and test hypotheses, replicate findings, and conduct mega-analyses. Many well-characterized, longitudinal, epidemiological studies collected extensive phenotype data related to symptom occurrence and severity. While the main phenotype of interest for many of these studies was often not symptom related, these data were collected to better understand the primary phenotype of interest. A search for symptom data (i.e., cognitive impairment, fatigue, gastrointestinal distress/nausea, sleep, and pain) in the database of genotypes and phenotypes (dbGaP) revealed many studies that collected symptom and omics data. There is thus a real possibility for nurse scientists to be able to look at symptom data over time from thousands of individuals and use omics data to identify key biological underpinnings that account for the development and severity of symptoms without recruiting participants or generating any new data. The purpose of this article is to introduce the reader to resources that provide omics data to the research community for repurposing, provide guidance on using these databases, and encourage the use of these data to move symptom science forward.]]>
Sat, 10 Sep 2016 00:00:00 PDT
Parental Genome Imbalance Causes Post-Zygotic Seed Lethality and Deregulates Imprinting in Rice. Zhang HY, Luo M, Johnson SD, Zhu XW, Liu L, Huang F, Liu YT, Xu PZ, Wu XJ
Rice (N Y) (Dec 2016)

Reproductive isolation between rice of different ploidy levels is manifested as endosperm and embryo abortion in seeds produced by interploidy crosses. Genomic imprinting is considered to be the underlying mechanism establishing the post-zygotic hybridization barrier. We characterized disrupted seed development in reciprocal crosses between a diploid Japonica rice and a tetraploid Indica rice.]]>
Mon, 29 Aug 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 (Sep 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.]]>
Fri, 26 Aug 2016 00:00:00 PDT
Fine-scale mapping of 8q24 locus identifies multiple independent risk variants for breast cancer. Shi J, Zhang Y, Zheng W, Michailidou K, Ghoussaini M, Bolla MK, Wang Q, Dennis J, Lush M, Milne RL, Shu XO, Beesley J, Kar S, Andrulis IL, Anton-Culver H, Arndt V, Beckmann MW, Zhao Z, Guo X, Benitez J, Beeghly-Fadiel A, Blot W, Bogdanova NV, Bojesen SE, Brauch H, Brenner H, Brinton L, Broeks A, Brüning T, Burwinkel B, Cai H, Canisius S, Chang-Claude J, Choi JY, Couch FJ, Cox A, Cross SS, Czene K, Darabi H, Devilee P, Droit A, Dork T, Fasching PA, Fletcher O, Flyger H, Fostira F, Gaborieau V, García-Closas M, Giles GG, Grip M, Guenel P, Haiman CA, Hamann U, Hartman M, Miao H, Hollestelle A, Hopper JL, Hsiung CN,  , Ito H, Jakubowska A, Johnson N, Torres D, Kabisch M, Kang D, Khan S, Knight JA, Kosma VM, Lambrechts D, Li J, Lindblom A, Lophatananon A, Lubinski J, Mannermaa A, Manoukian S, Le Marchand L, Margolin S, Marme F, Matsuo K, McLean C, Meindl A, Muir K, Neuhausen SL, Nevanlinna H, Nord S, Børresen-Dale AL, Olson JE, Orr N, van den Ouweland AM, Peterlongo P, Choudary Putti T, Rudolph A, Sangrajrang S, Sawyer EJ, Schmidt MK, Schmutzler RK, Shen CY, Hou MF, Shrubsole MJ, Southey MC, Swerdlow A, Hwang Teo S, Thienpont B, Toland AE, Tollenaar RA, Tomlinson I, Truong T, Tseng CC, Wen W, Winqvist R, Wu AH, Har Yip C, Zamora PM, Zheng Y, Floris G, Cheng CY, Hooning MJ, Martens JW, Seynaeve C, Kristensen VN, Hall P, Pharoah PD, Simard J, Chenevix-Trench G, Dunning AM, Antoniou AC, Easton DF, Cai Q, Long J
Int J Cancer (Sep 2016)

Previous genome-wide association studies among women of European ancestry identified two independent breast cancer susceptibility loci represented by single nucleotide polymorphisms (SNPs) rs13281615 and rs11780156 at 8q24. A fine-mapping study across 2.06 Mb (chr8:127,561,724-129,624,067, hg19) in 55,540 breast cancer cases and 51,168 controls within the Breast Cancer Association Consortium was conducted. Three additional independent association signals in women of European ancestry, represented by rs35961416 (OR = 0.95, 95% CI = 0.93-0.97, conditional p = 5.8 × 10(-6) ), rs7815245 (OR = 0.94, 95% CI = 0.91-0.96, conditional p = 1.1 × 10(-6) ) and rs2033101 (OR = 1.05, 95% CI = 1.02-1.07, conditional p = 1.1 × 10(-4) ) were found. Integrative analysis using functional genomic data from the Roadmap Epigenomics, the Encyclopedia of DNA Elements project, the Cancer Genome Atlas and other public resources implied that SNPs rs7815245 in Signal 3, and rs1121948 in Signal 5 (in linkage disequilibrium with rs11780156, r(2)  = 0.77), were putatively functional variants for two of the five independent association signals. The results highlighted multiple 8q24 variants associated with breast cancer susceptibility in women of European ancestry.]]>
Sat, 09 Jul 2016 00:00:00 PDT