'; ?> 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 Tue, 26 Sep 2017 03:54:47 PDT Tue, 26 Sep 2017 03:54:47 PDT jirtle@radonc.duke.edu james001@jirtle.com The Role of N-α-acetyltransferase 10 Protein in DNA Methylation and Genomic Imprinting. Lee CC, Peng SH, Shen L, Lee CF, Du TH, Kang ML, Xu GL, Upadhyay AK, Cheng X, Yan YT, Zhang Y, Juan LJ
Mol Cell (Sep 2017)

Genomic imprinting is an allelic gene expression phenomenon primarily controlled by allele-specific DNA methylation at the imprinting control region (ICR), but the underlying mechanism remains largely unclear. N-α-acetyltransferase 10 protein (Naa10p) catalyzes N-α-acetylation of nascent proteins, and mutation of human Naa10p is linked to severe developmental delays. Here we report that Naa10-null mice display partial embryonic lethality, growth retardation, brain disorders, and maternal effect lethality, phenotypes commonly observed in defective genomic imprinting. Genome-wide analyses further revealed global DNA hypomethylation and enriched dysregulation of imprinted genes in Naa10p-knockout embryos and embryonic stem cells. Mechanistically, Naa10p facilitates binding of DNA methyltransferase 1 (Dnmt1) to DNA substrates, including the ICRs of the imprinted allele during S phase. Moreover, the lethal Ogden syndrome-associated mutation of human Naa10p disrupts its binding to the ICR of H19 and Dnmt1 recruitment. Our study thus links Naa10p mutation-associated Ogden syndrome to defective DNA methylation and genomic imprinting.]]>
Mon, 25 Sep 2017 00:00:00 PDT
The Role of Epigenomics in Aquatic Toxicology. Brander SM, Biales AD, Connon RE
Environ Toxicol Chem (Oct 2017)

Over the past decade, the field of molecular biology has rapidly incorporated epigenetic studies to evaluate organism-environment interactions that can result in chronic effects. Such responses arise from early life stage stress, the utilization of genetic information over an individual's life time, and transgenerational inheritance. Knowledge of epigenetic mechanisms provides the potential for a comprehensive evaluation of multigenerational and heritable effects from environmental stressors, such as contaminants. Focused studies have provided a greater understanding of how many responses to environmental stressors are driven by epigenetic modifiers. We discuss the promise of epigenetics and suggest future research directions within the field of aquatic toxicology, with a particular focus on the potential for identifying key heritable marks with consequential impacts at the organism and population levels. Environ Toxicol Chem 2017;36:2565-2573. © 2017 SETAC.]]>
Mon, 25 Sep 2017 00:00:00 PDT
The Role of KRAB-ZFPs in Transposable Element Repression and Mammalian Evolution. Yang P, Wang Y, Macfarlan TS
Trends Genet (Sep 2017)

Kruppel-associated box zinc-finger proteins (KRAB-ZFPs) make up the largest family of transcription factors in humans. These proteins emerged in the last common ancestor of coelacanth and tetrapods, and have expanded and diversified in the mammalian lineage. Although their mechanism of transcriptional repression has been well studied for over a decade, the DNA-binding activities and the biological functions of these proteins have been largely unexplored. Recent large-scale ChIP-seq studies and loss-of-function experiments have revealed that KRAB-ZFPs play a major role in the recognition and transcriptional silencing of transposable elements (TEs), consistent with an 'arms race model' of KRAB-ZFP evolution against invading TEs. However, this model is insufficient to explain the evolution of many KRAB-ZFPs that appear to domesticate TEs for novel host functions. We highlight some of the mammalian regulatory innovations driven by specific KRAB-ZFPs, including genomic imprinting, meiotic recombination hotspot choice, and placental growth.]]>
Fri, 22 Sep 2017 00:00:00 PDT
RNA-Seq Analyses Identify Frequent Allele Specific Expression and No Evidence of Genomic Imprinting in Specific Embryonic Tissues of Chicken. Zhuo Z, Lamont SJ, Abasht B
Sci Rep (Sep 2017)

Epigenetic and genetic cis-regulatory elements in diploid organisms may cause allele specific expression (ASE) - unequal expression of the two chromosomal gene copies. Genomic imprinting is an intriguing type of ASE in which some genes are expressed monoallelically from either the paternal allele or maternal allele as a result of epigenetic modifications. Imprinted genes have been identified in several animal species and are frequently associated with embryonic development and growth. Whether genomic imprinting exists in chickens remains debatable, as previous studies have reported conflicting evidence. Albeit no genomic imprinting has been reported in the chicken embryo as a whole, we interrogated the existence or absence of genomic imprinting in the 12-day-old chicken embryonic brain and liver by examining ASE in F1 reciprocal crosses of two highly inbred chicken lines (Fayoumi and Leghorn). We identified 5197 and 4638 ASE SNPs, corresponding to 18.3% and 17.3% of the genes with a detectable expression in the embryonic brain and liver, respectively. There was no evidence detected of genomic imprinting in 12-day-old embryonic brain and liver. While ruling out the possibility of imprinted Z-chromosome inactivation, our results indicated that Z-linked gene expression is partially compensated between sexes in chickens.]]>
Thu, 21 Sep 2017 00:00:00 PDT
Allele specific expression and methylation in the bumblebee, Bombus terrestris. Lonsdale Z, Lee K, Kiriakidu M, Amarasinghe H, Nathanael D, O'Connor CJ, Mallon EB
PeerJ (2017)

The social hymenoptera are emerging as models for epigenetics. DNA methylation, the addition of a methyl group, is a common epigenetic marker. In mammals and flowering plants methylation affects allele specific expression. There is contradictory evidence for the role of methylation on allele specific expression in social insects. The aim of this paper is to investigate allele specific expression and monoallelic methylation in the bumblebee, Bombus terrestris. We found nineteen genes that were both monoallelically methylated and monoallelically expressed in a single bee. Fourteen of these genes express the hypermethylated allele, while the other five express the hypomethylated allele. We also searched for allele specific expression in twenty-nine published RNA-seq libraries. We found 555 loci with allele-specific expression. We discuss our results with reference to the functional role of methylation in gene expression in insects and in the as yet unquantified role of genetic cis effects in insect allele specific methylation and expression.]]>
Wed, 20 Sep 2017 00:00:00 PDT
Genomic imprinting beyond DNA methylation: a role for maternal histones. Hanna CW, Kelsey G
Genome Biol (Sep 2017)

Inheritance of DNA methylation states from gametes determines genomic imprinting in mammals. A new study shows that repressive chromatin in oocytes can also confer imprinting.]]>
Wed, 20 Sep 2017 00:00:00 PDT
Transcription-driven DNA methylation setting on the mouse Peg3 locus. Bretz CL, Kim J
Epigenetics (Sep 2017)

The imprinting of the mouse Peg3 domain is controlled through the Peg3-DMR, which obtains its maternal-specific DNA methylation during oogenesis. In the current study, we deleted an oocyte-specific alternative promoter, termed U1, which is localized 20 kb upstream of the Peg3-DMR. Deletion of this alternative promoter resulted in complete removal of the maternal-specific DNA methylation on the Peg3-DMR. Consequently, the imprinted genes in the Peg3 domain become biallelic in the mutants with maternal transmission of the deletion. Expression levels of the imprinted genes were also affected in the mutants: 2-fold upregulation of Peg3 and Usp29 and downregulation of Zim1 to basal levels. Breeding experiments further indicated under-representation of females among the surviving mutants, a potential sex-biased outcome from the biallelic expression of the Peg3 domain. Overall, the results suggest that U1-driven transcription may be required for establishing oocyte-specific DNA methylation on the Peg3 domain.]]>
Tue, 19 Sep 2017 00:00:00 PDT
Methods for discovering genomic loci exhibiting complex patterns of differential methylation. Hardcastle TJ
BMC Bioinformatics (Sep 2017)

Cytosine methylation is widespread in most eukaryotic genomes and is known to play a substantial role in various regulatory pathways. Unmethylated cytosines may be converted to uracil through the addition of sodium bisulphite, allowing genome-wide quantification of cytosine methylation via high-throughput sequencing. The data thus acquired allows the discovery of methylation 'loci'; contiguous regions of methylation consistently methylated across biological replicates. The mapping of these loci allows for associations with other genomic factors to be identified, and for analyses of differential methylation to take place.]]>
Tue, 19 Sep 2017 00:00:00 PDT
NLRPs, the subcortical maternal complex and genomic imprinting. Monk D, Sanchez-Delgado M, Fisher R
Reproduction (Sep 2017)

Before activation of the embryonic genome, the oocyte provides many of the RNAs and proteins required for the epigenetic reprogramming and the transition to a totipotent state. Targeted disruption of a subset of oocyte-derived transcripts in mice results in early embryonic lethality and cleavage stage embryonic arrest as highlighted by the members of the Subcortical Maternal Complex (SCMC). Maternal-effect recessive mutations of NLRP7, KHDC3L and NLRP5 in humans are associated with variable reproductive outcomes, biparental hydatidiform moles (BiHM) and widespread multi-locus imprinting disturbances. The precise mechanism of action of these genes is unknown, but the maternal effect phenomenon suggests a function during early pre-implantation development, while biochemical and genetic studies implement them as SCMC members or interacting partners. In this review article we discuss the role of the NLRP family members and the SCMC proteins in the establishment of genomic imprints and post-zygotic methylation maintenance, the recent advances made in the understanding of the biology involved in BiHM formation and the wider roles of the SCMC in mammalian reproduction.]]>
Sat, 16 Sep 2017 00:00:00 PDT
Evolving DNA methylation and gene expression markers of B-cell chronic lymphocytic leukemia are present in pre-diagnostic blood samples more than 10 years prior to diagnosis. Georgiadis P, Liampa I, Hebels DG, Krauskopf J, Chatziioannou A, Valavanis I, de Kok TMCM, Kleinjans JCS, Bergdahl IA, Melin B, Spaeth F, Palli D, Vermeulen RCH, Vlaanderen J, Chadeau-Hyam M, Vineis P, Kyrtopoulos SA,  
BMC Genomics (Sep 2017)

B-cell chronic lymphocytic leukemia (CLL) is a common type of adult leukemia. It often follows an indolent course and is preceded by monoclonal B-cell lymphocytosis, an asymptomatic condition, however it is not known what causes subjects with this condition to progress to CLL. Hence the discovery of prediagnostic markers has the potential to improve the identification of subjects likely to develop CLL and may also provide insights into the pathogenesis of the disease of potential clinical relevance.]]>
Thu, 14 Sep 2017 00:00:00 PDT
Disturbed Placental Imprinting in Preeclampsia Leads to Altered Expression of DLX5, a Human-Specific Early Trophoblast Marker. Zadora J, Singh M, Herse F, Przybyl L, Haase N, Golic M, Yung HW, Huppertz B, Cartwright JE, Whitley GS, Johnsen GM, Levi G, Isbruch A, Schulz H, Luft FC, Müller DN, Staff AC, Hurst LD, Dechend R, Izsvák Z
Circulation (Sep 2017)

Background -Preeclampsia (PE) is a complex and common human-specific pregnancy syndrome associated with placental pathology. The human-specificity provides both intellectual and methodological challenges, lacking a robust model system. Given the role of imprinted genes in human placentation and the vulnerability of imprinted genes to loss of imprinting changes, there has been extensive speculation, but no robust evidence, that imprinted genes are involved in PE. Our study aims at investigating whether disturbed imprinting contributes to PE. Methods -We first aimed at confirming that PE is a disease of the placenta by generating and analysing genome-wide molecular data on well-characterized patient material. We performed high-throughput transcriptome analyses of multiple placenta samples from normal and PE patients. Next, we identified differentially expressed genes (DEGs) in PE placenta, and intersected them with the list of human imprinted genes. We employed bioinformatics/statistical analyses to confirm association between imprinting and PE, and to predict biological processes affected in PE. Validation included epigenetic and cellular assays. Regarding human-specificity, we established an in vitro invasion-differentiation trophoblast model. Our comparative phylogenetic analysis involved single-cell transcriptome data of human, macaque and mouse preimplantation embryogenesis. Results -We found disturbed placental imprinting in PE and revealed potential candidates, including GATA3 and DLX5, with poorly explored imprinted status and no prior association with PE. Due to loss of imprinting DLX5 was upregulated in 69% of PE placentas. Levels of DLX5 correlated with classical PE marker. DLX5 is expressed in human, but not in murine trophoblast. The DLX5(high) phenotype resulted in reduced proliferation, increased metabolism and ER stress-response activation in trophoblasts in vitro The transcriptional profile of such cells mimics the transcriptome of PE placentas. Pan-mammalian comparative analysis identified DLX5 as a part of the human-specific regulatory network of trophoblast differentiation. Conclusions -Our analysis provides evidence of a true association between disturbed imprinting, gene expression and PE. Due to disturbed imprinting, the upregulated DLX5 affects trophoblast proliferation. Our in vitro model might fill a vital niche in PE research. Human-specific regulatory circuitry of DLX5 might help to explain certain aspects of PE.]]>
Thu, 14 Sep 2017 00:00:00 PDT
Tissue-specific DNA methylation is conserved across human, mouse, and rat, and driven by primary sequence conservation. Zhou J, Sears RL, Xing X, Zhang B, Li D, Rockweiler NB, Jang HS, Choudhary MNK, Lee HJ, Lowdon RF, Arand J, Tabers B, Gu CC, Cicero TJ, Wang T
BMC Genomics (Sep 2017)

Uncovering mechanisms of epigenome evolution is an essential step towards understanding the evolution of different cellular phenotypes. While studies have confirmed DNA methylation as a conserved epigenetic mechanism in mammalian development, little is known about the conservation of tissue-specific genome-wide DNA methylation patterns.]]>
Wed, 13 Sep 2017 00:00:00 PDT
Chronic Cigarette Smoke-Induced Epigenomic Changes Precede Sensitization of Bronchial Epithelial Cells to Single-Step Transformation by KRAS Mutations. Vaz M, Hwang SY, Kagiampakis I, Phallen J, Patil A, O'Hagan HM, Murphy L, Zahnow CA, Gabrielson E, Velculescu VE, Easwaran HP, Baylin SB
Cancer Cell (Sep 2017)

We define how chronic cigarette smoke-induced time-dependent epigenetic alterations can sensitize human bronchial epithelial cells for transformation by a single oncogene. The smoke-induced chromatin changes include initial repressive polycomb marking of genes, later manifesting abnormal DNA methylation by 10 months. At this time, cells exhibit epithelial-to-mesenchymal changes, anchorage-independent growth, and upregulated RAS/MAPK signaling with silencing of hypermethylated genes, which normally inhibit these pathways and are associated with smoking-related non-small cell lung cancer. These cells, in the absence of any driver gene mutations, now transform by introducing a single KRAS mutation and form adenosquamous lung carcinomas in mice. Thus, epigenetic abnormalities may prime for changing oncogene senescence to addiction for a single key oncogene involved in lung cancer initiation.]]>
Tue, 12 Sep 2017 00:00:00 PDT
Assay of DNA methyltransferase 1 activity based on uracil-specific excision reagent digestion induced G-quadruplex formation. Li J, He G, Mu C, Wang K, Xiang Y
Anal Chim Acta (Sep 2017)

DNA methylation catalyzed by DNA methyltransferase plays an important role in many biological processes including gene transcription, genomic imprinting and cellular differentiation. Herein, a novel and effective electrochemical method for the assay of DNA methyltransferase 1(DNMT1) activity has been successfully developed by using uracil-specific excision reagent (USER) induced G-quadruplex formation. Briefly, double stranded DNA containing the recognition sequence of DNMT1 is immobilized on the electrode. Among them, one strand (DNA S1) contains G-rich sequence and a cytosine base, while the supplement strand (DNA S2) cotains C-rich sequence and a methylated cytosine. Through the activity of DNMT1, the hemimethylated CG recognition sequence of the double stranded DNA are methylated and DNA S2 strand is cleaved and removed after the subsequently treatment with EpiTect fast bisulfite conversion kits and USER, leaving the DNA S1 to form the G-quadruplex-hemin DNAzyme for signal amplification. Under optimal-conditions, the method shows wide linear range of 0.1-40 U mL(-1) with a detection limit of 0.06 U mL(-1). Furthermore, the inhibition assay study demonstrates that SGI-1027 can inhibit the DNMT 1 activity with the IC50 values of 6 μM in the presence of 160 μM S-adenosylmethionine. Since this method can detect human DNMT1 activity effectively and has successfully been applied in complex biological samples, it may have great potential in the applications in DNA methylation related clinical practices and biochemical researches.]]>
Tue, 05 Sep 2017 00:00:00 PDT
A statistical test for detecting parent-of-origin effects when parental information is missing. Sacco C, Viroli C, Falchi M
Stat Appl Genet Mol Biol (Sep 2017)

Genomic imprinting is an epigenetic mechanism that leads to differential contributions of maternal and paternal alleles to offspring gene expression in a parent-of-origin manner. We propose a novel test for detecting the parent-of-origin effects (POEs) in genome wide genotype data from related individuals (twins) when the parental origin cannot be inferred. The proposed method exploits a finite mixture of linear mixed models: the key idea is that in the case of POEs the population can be clustered in two different groups in which the reference allele is inherited by a different parent. A further advantage of this approach is the possibility to obtain an estimation of parental effect when the parental information is missing. We will also show that the approach is flexible enough to be applicable to the general scenario of independent data. The performance of the proposed test is evaluated through a wide simulation study. The method is finally applied to known imprinted genes of the MuTHER twin study data.]]>
Fri, 01 Sep 2017 00:00:00 PDT
Type I interferons and the cytokine TNF cooperatively reprogram the macrophage epigenome to promote inflammatory activation. Park SH, Kang K, Giannopoulou E, Qiao Y, Kang K, Kim G, Park-Min KH, Ivashkiv LB
Nat Immunol (Oct 2017)

Cross-regulation of Toll-like receptor (TLR) responses by cytokines is essential for effective host defense, avoidance of toxicity and homeostasis, but the underlying mechanisms are not well understood. Our comprehensive epigenomics approach to the analysis of human macrophages showed that the proinflammatory cytokines TNF and type I interferons induced transcriptional cascades that altered chromatin states to broadly reprogram responses induced by TLR4. TNF tolerized genes encoding inflammatory molecules to prevent toxicity while preserving the induction of genes encoding antiviral and metabolic molecules. Type I interferons potentiated the inflammatory function of TNF by priming chromatin to prevent the silencing of target genes of the transcription factor NF-κB that encode inflammatory molecules. The priming of chromatin enabled robust transcriptional responses to weak upstream signals. Similar chromatin regulation occurred in human diseases. Our findings reveal that signaling crosstalk between interferons and TNF is integrated at the level of chromatin to reprogram inflammatory responses, and identify previously unknown functions and mechanisms of action of these cytokines.]]>
Mon, 21 Aug 2017 00:00:00 PDT
Human imprinting disorders: Principles, practice, problems and progress. Mackay DJG, Temple IK
Eur J Med Genet (Nov 2017)

Epigenetic regulation orchestrates gene expression with exquisite precision, over a huge dynamic range and across developmental space and time, permitting genomically-homogeneous humans to develop and adapt to their surroundings. Every generation, these epigenetic marks are re-set twice: in the germline, to enable differentiation of sperm and eggs, and at fertilisation, to create the totipotent zygote that then begins growth and differentiation into a new human. A small group of genes evades the second, zygotic wave of epigenetic reprogramming, and these genes retain an epigenetic 'imprint' of the parent from whom they were inherited. Imprinted genes are (as a general rule) expressed from one parental allele only. Some imprinted genes are critical regulators of growth and development, and thus disruption of their normal monoallelic expression causes congenital imprinting disorders, with clinical features impacting growth, development, behaviour and metabolism. Imprinting disorders as a group have characteristics that challenge diagnosis and management, including clinical and molecular heterogeneity, overlapping clinical features, somatic mosaicism, and multi-locus involvement. New insights into the biology and epigenomics of the early embryo offers new clues about the origin and importance of imprinting disorders.]]>
Fri, 18 Aug 2017 00:00:00 PDT
Characterization of the human thyroid epigenome. Siu C, Wiseman S, Gakkhar S, Heravi-Moussavi A, Bilenky M, Carles A, Sierocinski T, Tam A, Zhao E, Kasaian K, Moore RA, Mungall AJ, Walker B, Thomson T, Marra MA, Hirst M, Jones SJM
J Endocrinol (Nov 2017)

The thyroid gland, necessary for normal human growth and development, functions as an essential regulator of metabolism by the production and secretion of appropriate levels of thyroid hormone. However, assessment of abnormal thyroid function may be challenging suggesting a more fundamental understanding of normal function is needed. One way to characterize normal gland function is to study the epigenome and resulting transcriptome within its constituent cells. This study generates the first published reference epigenomes for human thyroid from four individuals using ChIP-seq and RNA-seq. We profiled six histone modifications (H3K4me1, H3K4me3, H3K27ac, H3K36me3, H3K9me3, H3K27me3), identified chromatin states using a hidden Markov model, produced a novel quantitative metric for model selection and established epigenomic maps of 19 chromatin states. We found that epigenetic features characterizing promoters and transcription elongation tend to be more consistent than regions characterizing enhancers or Polycomb-repressed regions and that epigenetically active genes consistent across all epigenomes tend to have higher expression than those not marked as epigenetically active in all epigenomes. We also identified a set of 18 genes epigenetically active and consistently expressed in the thyroid that are likely highly relevant to thyroid function. Altogether, these epigenomes represent a powerful resource to develop a deeper understanding of the underlying molecular biology of thyroid function and provide contextual information of thyroid and human epigenomic data for comparison and integration into future studies.]]>
Tue, 15 Aug 2017 00:00:00 PDT
The Epigenomic Revolution in Breast Cancer: From Single-Gene to Genome-Wide Next-Generation Approaches. Davalos V, Martinez-Cardus A, Esteller M
Am J Pathol (Oct 2017)

From the first identification of aberrant DNA methylation in primary tumors in humans more than 3 decades ago, progress in cancer epigenetics research has been exponential. For many years, cancer epigenetics studies relied on the identification of DNA methylation and histone modifications at specific genes. Those studies laid the foundation for the field and revealed the epigenetic alterations as hallmarks of cancer, as well as the crucial role of epigenetic mechanisms in tumorigenesis. The introduction of next-generation sequencing and array-based technologies for analyzing epigenetic states has accelerated our understanding about cancer and have become potent tools in our fight against the disease. Findings emerging from epigenome-wide analyses have led to new discoveries with remarkable clinical applications. This review summarizes the gene-specific epigenetic alterations common in breast cancer and discusses the recent advances in breast cancer epigenomics, focusing on their contribution to diagnosis, prognosis, patient stratification, and treatment of the disease.]]>
Sun, 23 Jul 2017 00:00:00 PDT
Multicellular Transcriptional Analysis of Mammalian Heart Regeneration. Quaife-Ryan GA, Sim CB, Ziemann M, Kaspi A, Rafehi H, Ramialison M, El-Osta A, Hudson JE, Porrello ER
Circulation (Sep 2017)

The inability of the adult mammalian heart to regenerate following injury represents a major barrier in cardiovascular medicine. In contrast, the neonatal mammalian heart retains a transient capacity for regeneration, which is lost shortly after birth. Defining the molecular mechanisms that govern regenerative capacity in the neonatal period remains a central goal in cardiac biology. Here, we assemble a transcriptomic framework of multiple cardiac cell populations during postnatal development and following injury, which enables comparative analyses of the regenerative (neonatal) versus nonregenerative (adult) state for the first time.]]>
Sat, 22 Jul 2017 00:00:00 PDT