'; ?> 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 Thu, 12 Dec 2019 20:27:27 EST Thu, 12 Dec 2019 20:27:27 EST jirtle@radonc.duke.edu james001@jirtle.com Improved detection of epigenomic marks with mixed-effects hidden Markov models. Baldoni PL, Rashid NU, Ibrahim JG
Biometrics (Dec 2019)

Chromatin immunoprecipitation followed by next-generation sequencing (ChIP-seq) is a technique to detect genomic regions containing protein-DNA interaction, such as transcription factor binding sites or regions containing histone modifications. One goal of the analysis of ChIP-seq experiments is to identify genomic loci enriched for sequencing reads pertaining to DNA bound to the factor of interest. The accurate identification of such regions aids in the understanding of epigenomic marks and gene regulatory mechanisms. Given the reduction of massively parallel sequencing costs, methods to detect consensus regions of enrichment across multiple samples are of interest. Here, we present a statistical model to detect broad consensus regions of enrichment from ChIP-seq technical or biological replicates through a class of zero-inflated mixed-effects hidden Markov models. We show that the proposed model outperforms existing methods for consensus peak calling in common epigenomic marks by accounting for the excess zeros and sample-specific biases. We apply our method to data from the Encyclopedia of DNA Elements and Roadmap Epigenomics projects and also from an extensive simulation study.]]>
Wed, 31 Dec 1969 19:00:00 EST
Stability and Lability of Parental Methylation Imprints in Development and Disease. Farhadova S, Gomez-Velazquez M, Feil R
Genes (Basel) (Dec 2019)

DNA methylation plays essential roles in mammals. Of particular interest are parental methylation marks that originate from the oocyte or the sperm, and bring about mono-allelic gene expression at defined chromosomal regions. The remarkable somatic stability of these parental imprints in the pre-implantation embryo-where they resist global waves of DNA demethylation-is not fully understood despite the importance of this phenomenon. After implantation, some methylation imprints persist in the placenta only, a tissue in which many genes are imprinted. Again here, the underlying epigenetic mechanisms are not clear. Mouse studies have pinpointed the involvement of transcription factors, covalent histone modifications, and histone variants. These and other features linked to the stability of methylation imprints are instructive as concerns their conservation in humans, in which different congenital disorders are caused by perturbed parental imprints. Here, we discuss DNA and histone methylation imprints, and why unravelling maintenance mechanisms is important for understanding imprinting disorders in humans.]]>
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
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
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
Schaaf-Yang syndrome shows a Prader-Willi syndrome-like phenotype during infancy. Negishi Y, Ieda D, Hori I, Nozaki Y, Yamagata T, Komaki H, Tohyama J, Nagasaki K, Tada H, Saitoh S
Orphanet J Rare Dis (Dec 2019)

Schaaf-Yang syndrome (SYS) is a newly recognized imprinting related syndrome, which is caused by a truncating variant in maternally imprinted MAGEL2 located in 15q11-q13. Yet, precise pathomechanism remains to be solved. We sequenced MAGEL2 in patients suspected Prader-Willi syndrome (PWS) to delineate clinical presentation of SYS. We examined 105 patients with clinically suspected PWS but without a specific PWS genetic alteration. Sanger sequencing of the entire MAGEL2 gene and methylation-specific restriction enzyme treatment to detect the parent of origin were performed. Clinical presentation was retrospectively assessed in detail.]]>
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
The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma: A systematic review. Fussey JM, Vaidya B, Kim D, Clark J, Ellard S, Smith JA
Clin Endocrinol (Oxf) (Dec 2019)

The significant variation in the clinical behaviour of sporadic medullary thyroid carcinoma (sMTC) causes uncertainty when planning the management of these patients. Several tumour genetic and epigenetic markers have been described, but their clinical usefulness remains unclear. The aim of this review was to evaluate the evidence for the use of molecular genetic and epigenetic profiles in the risk stratification and management of sMTC.]]>
Wed, 31 Dec 1969 19:00:00 EST
The epigenomic landscape of transposable elements across normal human development and anatomy. Pehrsson EC, Choudhary MNK, Sundaram V, Wang T
Nat Commun (Dec 2019)

Transposable elements (TEs) have deposited functional regulatory elements throughout the human genome. Although most are silenced, certain TEs have been co-opted by the host. However, a comprehensive, multidimensional picture of the contribution of TEs to normal human gene regulation is still lacking. Here, we quantify the epigenomic status of TEs across human anatomy and development using data from the Roadmap Epigenomics Project. We find that TEs encompass a quarter of the human regulatory epigenome, and 47% of elements can be in an active regulatory state. We demonstrate that SINEs are enriched relative to other classes for active and transcribed marks, that TEs encompass a higher proportion of enhancer states in the hematopoietic lineage, and that DNA methylation of Alu elements decreases with age, corresponding with a loss of CpG islands. Finally, we identify TEs that may perform an evolutionarily conserved regulatory function, providing a systematic profile of TE activity in normal human tissue.]]>
Wed, 31 Dec 1969 19:00:00 EST
Understanding osteoarthritis pathogenesis: a multiomics system-based approach. Ratneswaran A, Rockel JS, Kapoor M
Curr Opin Rheumatol (Jan 2020)

Osteoarthritis is a heterogeneous, multifactorial condition regulated by complex biological interactions at multiple levels. Comprehensive understanding of these regulatory interactions is required to develop feasible advances to improve patient outcomes. Improvements in technology have made extensive genomic, transcriptomic, epigenomic, proteomic, and metabolomic profiling possible. This review summarizes findings over the past 20 months related to omics technologies in osteoarthritis and examines how using a multiomics approach is necessary for advancing our understanding of osteoarthritis as a disease to improve precision osteoarthritis treatments.]]>
Wed, 31 Dec 1969 19:00:00 EST
Epigenetics/epigenomics and prevention by curcumin of early stages of inflammatory-driven colon cancer. Wu R, Wang L, Yin R, Hudlikar R, Li S, Kuo HD, Peter R, Sargsyan D, Guo Y, Liu X, Kong AT
Mol Carcinog (Dec 2019)

Colorectal cancer (CRC) is associated with significant morbidity and mortality in the US and worldwide. CRC is the second most common cancer-related death in both men and women globally. Chronic inflammation has been identified as one of the major risk factors of CRC. It may drive genetic and epigenetic/epigenomic alterations, such as DNA methylation, histone modification, and non-coding RNA regulation. Current prevention modalities for CRC are limited and some treatment regimens such as use the nonsteroidal anti-inflammatory drug aspirin may have severe side effects, namely gastrointestinal ulceration and bleeding. Therefore, there is an urgent need of developing alternative strategies. Recently, increasing evidence suggests that several dietary cancer chemopreventive phytochemicals possess anti-inflammation and antioxidative stress activities, and may prevent cancers including CRC. Curcumin (CUR) is the yellow pigment that is found in the rhizomes of turmeric (Curcuma longa). Many studies have demonstrated that CUR exhibit strong anticancer, antioxidative stress, and anti-inflammatory activities by regulating signaling pathways, such as nuclear factor erythroid-2-related factor 2, nuclear factor-κB, and epigenetics/epigenomics pathways of histones modifications, and DNA methylation. In this review, we will discuss the latest evidence in epigenetics/epigenomics alterations by CUR in CRC and their potential contribution in the prevention of CRC.]]>
Wed, 31 Dec 1969 19:00:00 EST
A road map for understanding molecular and genetic determinants of osteoporosis. Yang TL, Shen H, Liu A, Dong SS, Zhang L, Deng FY, Zhao Q, Deng HW
Nat Rev Endocrinol (Dec 2019)

Osteoporosis is a highly prevalent disorder characterized by low bone mineral density and an increased risk of fracture, termed osteoporotic fracture. Notably, bone mineral density, osteoporosis and osteoporotic fracture are highly heritable; however, determining the genetic architecture, and especially the underlying genomic and molecular mechanisms, of osteoporosis in vivo in humans is still challenging. In addition to susceptibility loci identified in genome-wide association studies, advances in various omics technologies, including genomics, transcriptomics, epigenomics, proteomics and metabolomics, have all been applied to dissect the pathogenesis of osteoporosis. However, each technology individually cannot capture the entire view of the disease pathology and thus fails to comprehensively identify the underlying pathological molecular mechanisms, especially the regulatory and signalling mechanisms. A change to the status quo calls for integrative multi-omics and inter-omics analyses with approaches in 'systems genetics and genomics'. In this Review, we highlight findings from genome-wide association studies and studies using various omics technologies individually to identify mechanisms of osteoporosis. Furthermore, we summarize current studies of data integration to understand, diagnose and inform the treatment of osteoporosis. The integration of multiple technologies will provide a road map to illuminate the complex pathogenesis of osteoporosis, especially from molecular functional aspects, in vivo in humans.]]>
Wed, 31 Dec 1969 19:00:00 EST
Optimized Combination of Multiple Graphs with Application to the Integration of Brain Imaging and (epi)Genomics Data. Bai Y, Pascal Z, Calhoun V, Wang YP
IEEE Trans Med Imaging (Dec 2019)

With the rapid development of high-throughput technologies, a growing amount of multi-omics data are collected, giving rise to a great demand for combining such data for biomedical discovery. Due to the cost and time to label the data manually, the number of labelled samples is limited. This motivated the need for semi-supervised learning algorithms. In this work, we applied a graph-based semi-supervised learning (GSSL) to classify a severe chronic mental disorder, schizophrenia (SZ). An advantage of GSSL is that it can simultaneously analyse more than two types of data, while many existing models focus on pairwise data analysis. In particular, we applied GSSL to the analysis of single nucleotide polymorphism (SNP), functional magnetic resonance imaging (fMRI) and DNA methylation data, which accounts for genetics, brain imaging (endophenotypes), and environmental factors (epigenomics) respectively. While parameter selection has been an open challenge for most models, another key contribution of this work is that we explored the parameter space to interpret their meaning and established practical guidelines. Based on the practical significance of each hyper-parameter, a relatively small range of candidate values can be determined in a data-driven way to both optimize and speed up the parameter tuning process. We validated the model through both synthetic data and a real SZ dataset of 184 subjects from the Mental Illness and Neuroscience Discovery (MIND) Clinical Imaging Consortium. In comparison to several existing approaches, our algorithm achieved better performance in terms of classification accuracy. We also confirmed the significance of several brain regions associated with SZ.]]>
Wed, 31 Dec 1969 19:00:00 EST
Loss of p57 expression confers resistance to contact inhibition in human androgenetic trophoblast stem cells. Takahashi S, Okae H, Kobayashi N, Kitamura A, Kumada K, Yaegashi N, Arima T
Proc Natl Acad Sci U S A (Dec 2019)

A complete hydatidiform mole (CHM) is androgenetic in origin and characterized by enhanced trophoblastic proliferation and the absence of fetal tissue. In 15 to 20% of cases, CHMs are followed by malignant gestational trophoblastic neoplasms including choriocarcinoma. Aberrant genomic imprinting may be responsible for trophoblast hypertrophy in CHMs, but the detailed mechanisms are still elusive, partly due to the lack of suitable animal or in vitro models. We recently developed a culture system of human trophoblast stem (TS) cells. In this study, we apply this system to CHMs for a better understanding of their molecular pathology. CHM-derived TS cells, designated as TS cells, are morphologically similar to biparental TS (TS) cells and express TS-specific markers such as GATA3, KRT7, and TFAP2C. Interestingly, TS cells have a growth advantage over TS cells only after they reach confluence. We found that p57, a maternally expressed gene encoding a cyclin-dependent kinase inhibitor, is strongly induced by increased cell density in TS cells, but not in TS cells. Knockout and overexpression studies suggest that loss of p57 expression would be the major cause of the reduced sensitivity to contact inhibition in CHMs. Our findings shed light on the molecular mechanism underlying the pathogenesis of CHMs and could have broad implications in tumorigenesis beyond CHMs because silencing of is frequently observed in a variety of human tumors.]]>
Wed, 31 Dec 1969 19:00:00 EST
Special volume: The genomics and epigenomics of schizophrenia. Akbarian S
Schizophr Res (Dec 2019)

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Wed, 31 Dec 1969 19:00:00 EST
Epigenetics of lung cancer: a translational perspective. Quintanal-Villalonga Ã, Molina-Pinelo S
Cell Oncol (Dordr) (Dec 2019)

Lung cancer remains the most common cause of cancer-related death, with a 5-year survival rate of only 18%. In recent years, the development of targeted pharmacological agents and immunotherapies has substantially increased the survival of a subset of patients. However, most patients lack such efficacious therapy and are, thus, treated with classical chemotherapy with poor clinical outcomes. Therefore, novel therapeutic strategies are urgently needed. In recent years, the development of epigenetic assays and their application to cancer research have highlighted the relevance of epigenetic regulation in the initiation, development, progression and treatment of lung cancer.]]>
Wed, 31 Dec 1969 19:00:00 EST
The Arms Race Between KRAB-Zinc Finger Proteins and Endogenous Retroelements and Its Impact on Mammals. Bruno M, Mahgoub M, Macfarlan TS
Annu Rev Genet (Dec 2019)

Nearly half of the human genome consists of endogenous retroelements (EREs) and their genetic remnants, a small fraction of which carry the potential to propagate in the host genome, posing a threat to genome integrity and cell/organismal survival. The largest family of transcription factors in tetrapods, the Krüppel-associated box domain zinc finger proteins (KRAB-ZFPs), binds to specific EREs and represses their transcription. Since their first appearance over 400 million years ago, KRAB-ZFPs have undergone dramatic expansion and diversification in mammals, correlating with the invasions of new EREs. In this article we review our current understanding of the structure, function, and evolution of KRAB-ZFPs and discuss growing evidence that the arms race between KRAB-ZFPs and the EREs they target is a major driving force for the evolution of new traits in mammals, often accompanied by domestication of EREs themselves.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genetic and epigenetic control of retinal development in zebrafish. Seritrakul P, Gross JM
Curr Opin Neurobiol (Dec 2019)

The vertebrate retina is a complex structure composed of seven cell types (six neuron and one glia), and all of which originate from a seemingly homogeneous population of proliferative multipotent retinal progenitor cells (RPCs) that exit the cell cycle and differentiate in a spatio-temporally regulated and stereotyped fashion. This neurogenesis process requires intricate genetic regulation involving a combination of cell intrinsic transcription factors and extrinsic signaling molecules, and many critical factors have been identified that influence the timing and composition of the developing retina. Adding complexity to the process, over the past decade, a variety of epigenetic regulatory mechanisms have been shown to influence neurogenesis, and these include changes in histone modifications and the chromatin landscape and changes in DNA methylation and hydroxymethylation patterns. This review summarizes recent findings in the genetic and epigenetic regulation of retinal development, with an emphasis on the zebrafish model system, and it outlines future areas of investigation that will continue to push the field forward into the epigenomics era.]]>
Wed, 31 Dec 1969 19:00:00 EST
Early epigenomic and transcriptional changes reveal Elk-1 transcription factor as a therapeutic target in Huntington's disease. Yildirim F, Ng CW, Kappes V, Ehrenberger T, Rigby SK, Stivanello V, Gipson TA, Soltis AR, Vanhoutte P, Caboche J, Housman DE, Fraenkel E
Proc Natl Acad Sci U S A (Dec 2019)

Huntington's disease (HD) is a chronic neurodegenerative disorder characterized by a late clinical onset despite ubiquitous expression of the mutant Huntingtin gene () from birth. Transcriptional dysregulation is a pivotal feature of HD. Yet, the genes that are altered in the prodromal period and their regulators, which present opportunities for therapeutic intervention, remain to be elucidated. Using transcriptional and chromatin profiling, we found aberrant transcription and changes in histone H3K27acetylation in the striatum of R6/1 mice during the presymptomatic disease stages. Integrating these data, we identified the Elk-1 transcription factor as a candidate regulator of prodromal changes in HD. Exogenous expression of Elk-1 exerted beneficial effects in a primary striatal cell culture model of HD, and adeno-associated virus-mediated Elk-1 overexpression alleviated transcriptional dysregulation in R6/1 mice. Collectively, our work demonstrates that aberrant gene expression precedes overt disease onset in HD, identifies the Elk-1 transcription factor as a key regulator linked to early epigenetic and transcriptional changes in HD, and presents evidence for Elk-1 as a target for alleviating molecular pathology in HD.]]>
Wed, 31 Dec 1969 19:00:00 EST
The ENCODE Portal as an Epigenomics Resource. Jou J, Gabdank I, Luo Y, Lin K, Sud P, Myers Z, Hilton JA, Kagda MS, Lam B, O'Neill E, Adenekan P, Graham K, Baymuradov UK, R Miyasato S, Strattan JS, Jolanki O, Lee JW, Litton C, Y Tanaka F, Hitz BC, Cherry JM
Curr Protoc Bioinformatics (Dec 2019)

The Encyclopedia of DNA Elements (ENCODE) web portal hosts genomic data generated by the ENCODE Consortium, Genomics of Gene Regulation, The NIH Roadmap Epigenomics Consortium, and the modENCODE and modERN projects. The goal of the ENCODE project is to build a comprehensive map of the functional elements of the human and mouse genomes. Currently, the portal database stores over 500 TB of raw and processed data from over 15,000 experiments spanning assays that measure gene expression, DNA accessibility, DNA and RNA binding, DNA methylation, and 3D chromatin structure across numerous cell lines, tissue types, and differentiation states with selected genetic and molecular perturbations. The ENCODE portal provides unrestricted access to the aforementioned data and relevant metadata as a service to the scientific community. The metadata model captures the details of the experiments, raw and processed data files, and processing pipelines in human and machine-readable form and enables the user to search for specific data either using a web browser or programmatically via REST API. Furthermore, ENCODE data can be freely visualized or downloaded for additional analyses. © 2019 The Authors. Basic Protocol: Query the portal Support Protocol 1: Batch downloading Support Protocol 2: Using the cart to download files Support Protocol 3: Visualize data Alternate Protocol: Query building and programmatic access.]]>
Wed, 31 Dec 1969 19:00:00 EST