'; ?> 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, 21 Oct 2019 14:25:31 EDT Mon, 21 Oct 2019 14:25:31 EDT jirtle@radonc.duke.edu james001@jirtle.com AIKYATAN: mapping distal regulatory elements using convolutional learning on GPU. Fang CH, Theera-Ampornpunt N, Roth MA, Grama A, Chaterji S
BMC Bioinformatics (Oct 2019)

The data deluge can leverage sophisticated ML techniques for functionally annotating the regulatory non-coding genome. The challenge lies in selecting the appropriate classifier for the specific functional annotation problem, within the bounds of the hardware constraints and the model's complexity. In our system AIKYATAN, we annotate distal epigenomic regulatory sites, e.g., enhancers. Specifically, we develop a binary classifier that classifies genome sequences as distal regulatory regions or not, given their histone modifications' combinatorial signatures. This problem is challenging because the regulatory regions are distal to the genes, with diverse signatures across classes (e.g., enhancers and insulators) and even within each class (e.g., different enhancer sub-classes).]]>
Wed, 31 Dec 1969 19:00:00 EST
Body Mass Index Drives Changes in DNA Methylation: A Longitudinal Study. Sun D, Zhang T, Su S, Hao G, Chen T, Li QZ, Bazzano L, He J, Wang X, Li S, Chen W
Circ Res (Oct 2019)

Previous EWASs (Epigenome-Wide Association Studies) suggest that obesity may be the cause, not a consequence, of changes in DNA methylation (DNAm). However, longitudinal observations are lacking.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genome-Wide Identification of Allele-Specific Gene Expression in a Parent-of-Origin Specific Manner. Chen C, Begcy K
Methods Mol Biol (2020)

Upon fertilization, normal endosperm and embryo development require the contribution of both the maternal and paternal genomes. However, certain genes are expressed in a parent-of-origin-dependent manner, an epigenetic phenomenon known as genomic imprinting. Despite the blast of new technologies and the crucial advances of the past decades in the epigenetics field, novel imprinted genes are yet to be discovered and thus key regulators of early seed development. Using rice plant as a model, we describe a method for the identification of imprinted genes based on an RNA-Seq approach, which allows the identification of maternal and paternal gene expression in a parent-of-origin-specific manner.]]>
Wed, 31 Dec 1969 19:00:00 EST
Epigenomics and Single-Cell Sequencing Define a Developmental Hierarchy in Langerhans Cell Histiocytosis. Halbritter F, Farlik M, Schwentner R, Jug G, Fortelny N, Schnöller T, Pisa H, Schuster LC, Reinprecht A, Czech T, Gojo J, Holter W, Minkov M, Bauer WM, Simonitsch-Klupp I, Bock C, Hutter C
Cancer Discov (Oct 2019)

Langerhans cell histiocytosis (LCH) is a rare neoplasm predominantly affecting children. It occupies a hybrid position between cancers and inflammatory diseases, which makes it an attractive model for studying cancer development. To explore the molecular mechanisms underlying the pathophysiology of LCH and its characteristic clinical heterogeneity, we investigated the transcriptomic and epigenomic diversity in primary LCH lesions. Using single-cell RNA sequencing, we identified multiple recurrent types of LCH cells within these biopsies, including putative LCH progenitor cells and several subsets of differentiated LCH cells. We confirmed the presence of proliferative LCH cells in all analyzed biopsies using IHC, and we defined an epigenomic and gene-regulatory basis of the different LCH-cell subsets by chromatin-accessibility profiling. In summary, our single-cell analysis of LCH uncovered an unexpected degree of cellular, transcriptomic, and epigenomic heterogeneity among LCH cells, indicative of complex developmental hierarchies in LCH lesions. SIGNIFICANCE: This study sketches a molecular portrait of LCH lesions by combining single-cell transcriptomics with epigenome profiling. We uncovered extensive cellular heterogeneity, explained in part by an intrinsic developmental hierarchy of LCH cells. Our findings provide new insights and hypotheses for advancing LCH research and a starting point for personalizing therapy...]]>
Wed, 31 Dec 1969 19:00:00 EST
Genome-Wide Profiling of Histone Modifications with ChIP-Seq. Ricci WA, Levin L, Zhang X
Methods Mol Biol (2020)

Chromatin immunoprecipitation coupled with sequencing (ChIP-seq) is a widely used method for mapping the genome-wide locations of chromatin-associated proteins. This protocol has been developed and utilized to perform ChIP on histone covalent modifications in various plant species including cereals. DNA and chromatin-associated proteins are crosslinked with formaldehyde. Chromatin is then isolated from nuclei and sheared via sonication. Antibodies targeting the histone modification of interest are incubated with the sheared chromatin and nonspecific interactions are washed away. DNA is purified via phenol-chloroform extraction, end-repaired, ligated to sequencing adapters, and PCR-amplified.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genome-wide allele-specific methylation is enriched at gene regulatory regions in a multi-generation pedigree from the Norfolk Island isolate. Benton MC, Lea RA, Macartney-Coxson D, Sutherland HG, White N, Kennedy D, Mengersen K, Haupt LM, Griffiths LR
Epigenetics Chromatin (Oct 2019)

Allele-specific methylation (ASM) occurs when DNA methylation patterns exhibit asymmetry among alleles. ASM occurs at imprinted loci, but its presence elsewhere across the human genome is indicative of wider importance in terms of gene regulation and disease risk. Here, we studied ASM by focusing on blood-based DNA collected from 24 subjects comprising a 3-generation pedigree from the Norfolk Island genetic isolate. We applied a genome-wide bisulphite sequencing approach with a genotype-independent ASM calling method to map ASM across the genome. Regions of ASM were then tested for enrichment at gene regulatory regions using Genomic Association Test (GAT) tool.]]>
Wed, 31 Dec 1969 19:00:00 EST
Next generation sequencing data for use in risk assessment. Merrick BA
Curr Opin Toxicol (Dec 2019)

Next generation sequencing (NGS) represents several powerful platforms that have revolutionized RNA and DNA analysis. The parallel sequencing of millions of DNA molecules can provide mechanistic insights into toxicology and provide new avenues for biomarker discovery with growing relevance for risk assessment. The evolution of NGS technologies has improved over the last decade with increased sensitivity and accuracy to foster new biomarker assays from tissue, blood and other biofluids. NGS sequencing technologies can identify transcriptional changes and genomic targets with base pair precision in response to chemical exposure. Further, there are several exciting movements within the toxicology community that incorporate NGS platforms into new strategies for more rapid toxicological characterizations. These include the Tox21 in vitro high throughput transcriptomic screening program, development of organotypic spheroids, alternative animal models, mining archival tissues, liquid biopsy and epigenomics. This review will describe NGS-based technologies, demonstrate how they can be used as tools for target discovery in tissue and blood, and suggest how they might be applied for risk assessment.]]>
Wed, 31 Dec 1969 19:00:00 EST
Aberrant Methylation of Tumor Suppressive miRNAs in Bile from Patients With Pancreaticobiliary Diseases. Ohtsubo K, Miyake K, Arai S, Fukuda K, Yanagimura N, Suzuki C, Otani S, Adachi Y, Tanimoto A, Nishiyama A, Yamashita K, Takeuchi S, Notohara K, Yoshimura K, Yano S
Anticancer Res (Oct 2019)

Epigenetic abnormalities in microRNAs (miRNAs) have not been analyzed in samples other than pancreaticobiliary tissues in patients with pancreaticobiliary cancer (PBC). To identify miRNAs specific for PBC, the present study analyzed the methylation of tumor-suppressive miRNAs in bile from patients with pancreaticobiliary diseases.]]>
Wed, 31 Dec 1969 19:00:00 EST
Altered expression of epigenetic regulators and imprinted genes in human placenta and fetal tissues from second trimester spontaneous pregnancy losses. Vasconcelos S, Ramalho C, Marques CJ, Doria S
Epigenetics (Dec 2019)

Epigenetic mechanisms such as genomic imprinting have a fundamental role in embryo and fetal development. Hence, we here studied expression levels of epigenetic modifiers and imprinted genes in cases of ididopathic spontaneous abortion (SA). Thirty-five placental samples and 35 matched fetal tissues from second trimester SA were analysed; including 16 controls (placental and fetal infections as the known cause of spontaneous abortion) and 19 idiopathic SA cases. Transcript levels of epigenetic regulators and imprinted genes were measured by qRT-PCR and methylation at imprinted genes was studied by bisulfite genomic sequencing and MS-MLPA. Global DNA hydroxymethylation (5-hmC) levels were measured by an ELISA-based assay. We observed an upregulation of and in placental samples from idiopathic SA cases; however, no significant difference in global 5-hmC levels was observed. On the contrary, in fetal tissues, was markedly downregulated in idiopathic SA, showing an opposite trend to that observed in placental tissue. and were upregulated and downregulated in placentas from idiopathic SA cases; concordantly, was also upregulated in fetal tissues from idiopathic SA cases. Although not reaching statistical significance, an increase in methylation levels of , KvDMR1 and H19 DMRs was observed in idiopathic SA cases, concordantly with the observed changes in expression. Our study reveals, for the first time, deregulation of epigenetic modifiers and imprinted genes in both placental and fetal tissues from idiopathic SA cases in the second trimester of pregnancy, indicating a critical role during pregnancy.]]>
Wed, 31 Dec 1969 19:00:00 EST
The systems medicine of neonatal abstinence syndrome. Stone WL, Wood DL, Justice NA, Shah DS, Olsen ME, Bharti D
Front Biosci (Landmark Ed) (Jan 2020)

This review will focus on a systems medicine approach to neonatal abstinence syndrome (NAS). Systems medicine utilizes information gained from the application of "omics" technology and bioinformatics (1). The omic approaches we will emphasize include genomics, epigenomics, proteomics, and metabolomics. The goals of systems medicine are to provide clinically relevant and objective insights into disease diagnosis, prognosis, and stratification as well as pharmacological strategies and evidence-based individualized clinical guidance. Despite the increasing incidence of NAS and its societal and economic costs, there has been only a very modest emphasis on utilizing a systems medicine approach, and this has been primarily in the areas of genomics and epigenomics. As detailed below, proteomics and metabolomics hold great promise in advancing our knowledge of NAS and its treatment. Metabolomics, in particular, can provide a quantitative assessment of the exposome, which is a comprehensive picture of both internal and external environmental factors affecting health.]]>
Wed, 31 Dec 1969 19:00:00 EST
Meg3-DMR, not the Meg3 gene, regulates imprinting of the Dlk1-Dio3 locus. Zhu W, Botticelli EM, Kery RE, Mao Y, Wang X, Yang A, Wang X, Zhou J, Zhang X, Soberman RJ, Klibanski A, Zhou Y
Dev Biol (Nov 2019)

The imprinted delta like 1 homolog (DLK1) - thyroxine deiodinase type III (DIO3) locus regulates development and growth. Its imprinting regulation involves two differentially methylated regions (DMRs), intergenic-DMR (IG-DMR) and maternally expressed gene 3-DMR (Meg3-DMR). In mice, a maternal deletion of the IG-DMR leads to LOI in the locus, proving that the IG-DMR is a cis-acting imprinting control region of the locus. However, the Meg3-DMR overlaps with the promoter, exon 1 and intron 1 of the Meg3 gene. Because deletion of the Meg3-DMR inactivates the Meg3 gene, their roles in imprinting regulation of Meg3-DMR mice is unknown. Therefore, we generated two mouse models: Meg3 and Meg3, respectively targeting exons 1-4 and exons 2-4 of the Meg3 gene. A maternal deletion of Meg3 caused embryonic death and LOI in both embryos and placentas, but did not affect methylation status of the IG-DMR. In contrast, mice carrying a maternal deletion of Meg3 were born normally and did not have LOI. These data indicate that it is the Meg3-DMR, not the Meg3 gene, which regulates imprinting of the Dlk1-Dio3 locus.]]>
Wed, 31 Dec 1969 19:00:00 EST
Characterization of Button Loci that Promote Homologous Chromosome Pairing and Cell-Type-Specific Interchromosomal Gene Regulation. Viets K, Sauria MEG, Chernoff C, Rodriguez Viales R, Echterling M, Anderson C, Tran S, Dove A, Goyal R, Voortman L, Gordus A, Furlong EEM, Taylor J, Johnston RJ
Dev Cell (Oct 2019)

Homologous chromosomes colocalize to regulate gene expression in processes including genomic imprinting, X-inactivation, and transvection. In Drosophila, homologous chromosomes pair throughout development, promoting transvection. The "button" model of pairing proposes that specific regions along chromosomes pair with high affinity. Here, we identify buttons interspersed across the fly genome that pair with their homologous sequences, even when relocated to multiple positions in the genome. A majority of transgenes that span a full topologically associating domain (TAD) function as buttons, but not all buttons contain TADs. Additionally, buttons are enriched for insulator protein clusters. Fragments of buttons do not pair, suggesting that combinations of elements within a button are required for pairing. Pairing is necessary but not sufficient for transvection. Additionally, pairing and transvection are stronger in some cell types than in others, suggesting that pairing strength regulates transvection efficiency between cell types. Thus, buttons pair homologous chromosomes to facilitate cell-type-specific interchromosomal gene regulation.]]>
Wed, 31 Dec 1969 19:00:00 EST
Urban environment and psychiatric disorders: a review of the neuroscience and biology. Costa E Silva JA, Steffen RE
Metabolism (Nov 2019)

Most of the world's population now lives in cities. While living in cities have both health risks and benefits, mental health has been usually considered to be negatively affected by urbanicity. While mental health disorders have complex etiology and multiple causes, it has been shown in multiple observational studies that mood and anxiety disorders are more prevalent in urban centers and incidence has been increasing. In addition, the incidence of schizophrenia is strongly increased in people born and raised in cities. Studies on the effects of urbanicity on the brain, however, are more challenging to conduct, since individual and environmental factors are hard to distinguish. The main objective of this article is to review studies on how specific neural processes mediate those associations between urbanicity and psychiatric disorders and how environmental factors affect genetic regulation (epigenetics). Neuroimaging studies have shown how urban stressors might affect the brain by conducting experiments using functional magnetic resonance imaging (fMRI). There have been demonstrations that urban upbringing and city living have dissociable impacts on social evaluative stress processing in humans. City living was associated with increased amygdala activity and the urban upbringing has been shown to affect the perigenual anterior cingulate cortex, a key region for regulation of amygdala activity, negative affect and stress. In addition, studies on epigenetics have shown associations between exposure to features of the environment and methylation patterns. The goal of understanding how urban environments act as a risk factor for mental disorders may be pursued on several levels. It can be approached by measuring the effects of economic factors (unemployment, socioeconomic status), social condition (social network support), environmental exposures (toxins, air pollution, noise, light), that must be weighed to identify how it contributes to mental disorders.]]>
Wed, 31 Dec 1969 19:00:00 EST
Base-Resolution Methylome of Retinal Pigment Epithelial Cells Used in the First Trial of Human Induced Pluripotent Stem Cell-Based Autologous Transplantation. Araki H, Miura F, Watanabe A, Morinaga C, Kitaoka F, Kitano Y, Sakai N, Shibata Y, Terada M, Goto S, Yamanaka S, Takahashi M, Ito T
Stem Cell Reports (Oct 2019)

The first-in-human trial of induced pluripotent stem cell (iPSC)-based autologous transplantation was successfully performed on a female patient with age-related macular degeneration. Here we delineated the base-resolution methylome of the iPSC-derived retinal pigment epithelium (iRPE) used in this trial. The methylome of iRPE closely resembled that of native RPE (nRPE), although partially methylated domains (PMDs) emerged in iRPE but not nRPE. Most differentially methylated regions between iRPE and nRPE appeared to originate from (de)methylation errors during differentiation, whereas errors at reprogramming resulted in aberrant genomic imprinting and X chromosome reactivation. Moreover, non-CpG methylation was prominent in nRPE but not iRPE. Intriguingly, xenotransplantation to mouse remodeled the iRPE methylome to demethylate a subset of suppressed genes and accumulate non-CpG methylation, but failed to resolve PMDs and hypermethylated CpG islands. Although the impacts of these alterations remain elusive, our findings should provide a useful guide for methylome analyses of other iPSC-derived cells.]]>
Wed, 31 Dec 1969 19:00:00 EST
Short AIP1 (ASK1-Interacting Protein-1) Isoform Localizes to the Mitochondria and Promotes Vascular Dysfunction. Li Z, Li L, Zhang H, Zhou HJ, Ji W, Min W
Arterioscler Thromb Vasc Biol (Oct 2019)

Vascular endothelial cells (ECs) normally maintain vascular homeostasis and are regulated by proinflammatory cytokines and reactive oxygen species. A human genome-wide association study identified that (; also identified as ) gene variants confer susceptibility to cardiovascular disease, but the underlying mechanism is unknown. Approach and Results: We detected a normal AIP1 form (named AIP1A) in the healthy aorta, but a shorter form of AIP1 (named AIP1B) was found in diseased aortae that contained atherosclerotic plaques and graft arteriosclerosis. AIP1B transcription in resting ECs was suppressed through epigenetic inhibition by RIF1 (Rap1-interacting factor 1)/H3K9 (histone H3 lysine 9) methyltransferase-mediated H3K9 trimethylation, and this inhibition was released by proinflammatory cytokines. AIP1A, but not AIP1B, was downregulated by proteolytic degradation through a Smurf1 (SMAD ubiquitylation regulatory factor 1)-dependent pathway in ECs under inflammation. Therefore, AIP1B was the major form present during inflammatory conditions. AIP1B, which lacks the N-terminal pleckstrin homology domain of AIP1A, localized to the mitochondria and augmented TNF (tumor necrosis factor)-induced mitochondrial reactive oxygen species generation and EC activation. AIP1B-ECTG (EC-specific AIP1B transgenic) mice exhibited augmented reactive oxygen species production, EC activation, and neointima formation in vascular remodeling models.]]>
Wed, 31 Dec 1969 19:00:00 EST
CoBATCH for High-Throughput Single-Cell Epigenomic Profiling. Wang Q, Xiong H, Ai S, Yu X, Liu Y, Zhang J, He A
Mol Cell (Oct 2019)

An efficient, generalizable method for genome-wide mapping of single-cell histone modifications or chromatin-binding proteins is lacking. Here, we develop CoBATCH, combinatorial barcoding and targeted chromatin release, for single-cell profiling of genomic distribution of chromatin-binding proteins in cell culture and tissue. Protein A in fusion to Tn5 transposase is enriched through specific antibodies to genomic regions, and Tn5 generates indexed chromatin fragments ready for library preparation and sequencing. Importantly, this strategy enables not only low-input epigenomic profiling in intact tissues but also measures scalable up to tens of thousands of single cells per experiment under both native and cross-linked conditions. CoBATCH produces ∼12,000 reads/cell with extremely low background. Mapping of endothelial cell lineages from ten embryonic mouse organs through CoBATCH allows for efficient deciphering of epigenetic heterogeneity of cell populations and cis-regulatory mechanisms. Thus, obviating specialized devices, CoBATCH is broadly applicable and easily deployable for single-cell profiling of protein-DNA interactions.]]>
Wed, 31 Dec 1969 19:00:00 EST
Hemimethylation of CpG dyads is characteristic of secondary DMRs associated with imprinted loci and correlates with 5-hydroxymethylcytosine at paternally methylated sequences. Nechin J, Tunstall E, Raymond N, Hamagami N, Pathmanabhan C, Forestier S, Davis TL
Epigenetics Chromatin (Oct 2019)

In mammals, the regulation of imprinted genes is controlled by differential methylation at imprinting control regions which acquire parent of origin-specific methylation patterns during gametogenesis and retain differences in allelic methylation status throughout fertilization and subsequent somatic cell divisions. In addition, many imprinted genes acquire differential methylation during post-implantation development; these secondary differentially methylated regions appear necessary to maintain the imprinted expression state of individual genes. Despite the requirement for both types of differentially methylated sequence elements to achieve proper expression across imprinting clusters, methylation patterns are more labile at secondary differentially methylated regions. To understand the nature of this variability, we analyzed CpG dyad methylation patterns at both paternally and maternally methylated imprinted loci within multiple imprinting clusters.]]>
Wed, 31 Dec 1969 19:00:00 EST
Single-Cell RNA Sequencing Reveals a Developmental Hierarchy in Langerhans Cell Histiocytosis. Gruber TA
Cancer Discov (Oct 2019)

In this issue of , Halbritter and colleagues utilize single-cell RNA sequencing to dissect the cellular hierarchy in Langerhans cell histiocytosis. They identified a remarkably consistent composition of 14 cellular subsets across all patients with a range of clinical spectrums consistent with a shared developmental hierarchy driven by key transcriptional regulators..]]>
Wed, 31 Dec 1969 19:00:00 EST
The Many Facets of Tumor Heterogeneity: Is Metabolism Lagging Behind? Loponte S, Lovisa S, Deem AK, Carugo A, Viale A
Cancers (Basel) (Oct 2019)

Tumor functional heterogeneity has been recognized for decades, and technological advancements are fueling renewed interest in uncovering the cell-intrinsic and extrinsic factors that influence tumor development and therapeutic response. Intratumoral heterogeneity is now arguably one of the most-studied topics in tumor biology, leading to the discovery of new paradigms and reinterpretation of old ones, as we aim to understand the profound implications that genomic, epigenomic, and functional heterogeneity hold with regard to clinical outcomes. In spite of our improved understanding of the biological complexity of cancer, characterization of tumor metabolic heterogeneity has lagged behind, lost in a century-old controversy debating whether glycolysis or mitochondrial respiration is more influential. But is tumor metabolism really so simple? Here, we review historical and current views of intratumoral heterogeneity, with an emphasis on summarizing the emerging data that begin to illuminate just how vast the spectrum of metabolic strategies a tumor can employ may be, and what this means for how we might interpret other tumor characteristics, such as mutational landscape, contribution of microenvironmental influences, and treatment resistance.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genomic imprinting and its effects on postnatal growth and adult metabolism. Millership SJ, Van de Pette M, Withers DJ
Cell Mol Life Sci (Oct 2019)

Imprinted genes display parent-of-origin-specific expression with this epigenetic system of regulation found exclusively in therian mammals. Historically, defined imprinted gene functions were almost solely focused on pregnancy and the influence on the growth parameters of the developing embryo and placenta. More recently, a number of postnatal functions have been identified which converge on resource allocation, both for animals in the nest and in adults. While many of the prenatal functions of imprinted genes that have so far been described adhere to the "parental conflict" hypothesis, no clear picture has yet emerged on the functional role of imprints on postnatal metabolism. As these roles are uncovered, interest in the potential for these genes to influence postnatal metabolism and associated adult-onset disease outcomes when dysregulated has gathered pace. Here, we review the published data on imprinted genes and their influence on postnatal metabolism, starting in the nest, and then progressing through to adulthood. When observing the functional effects of these genes on adult metabolism, we must always be careful to acknowledge the influence both of direct expression in the relevant metabolic tissue, but also indirect metabolic programming effects caused by their modulation of both in utero and postnatal growth trajectories.]]>
Wed, 31 Dec 1969 19:00:00 EST