'; ?> 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 Fri, 22 Mar 2019 08:22:48 EDT Fri, 22 Mar 2019 08:22:48 EDT jirtle@radonc.duke.edu james001@jirtle.com The immune milieu of cholangiocarcinoma: From molecular pathogenesis to precision medicine. Rimassa L, Personeni N, Aghemo A, Lleo A
J Autoimmun (Mar 2019)

Cholangiocarcinoma (CCA) is a deadly cancer of the biliary epithelium with limited therapeutic options. It is a heterogeneous group of cancer that could develop at any level from the biliary tree and is currently classified into intrahepatic, perihilar and distal based on its anatomical location. With incidence and mortality rates currently increasing, it is now the second most common type of primary liver cancer and represents up to 3% of all gastrointestinal malignancies. High-throughput genomics and epigenomics have greatly increased our understanding of CCA underlying biology, however its pathogenesis remains largely unknown. CCA is characterized by a highly desmoplastic microenvironment containing stromal cells, mainly cancer-associated fibroblasts, infiltrating tumor epithelium. Tumor microenvironment in CCA is a highly dynamic environment that, besides stromal and endothelial cells, encompass also an abundance of immune cells, of both the innate and adaptive immune system (including tumor-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes) and abundant proliferative factors. It is orchestrated by multiple soluble factors and signals, that eventually define a tumor growth-permissive microenvironment. Through complicate interactions with CCA cells, tumor microenvironment profoundly affects the proliferative and invasive abilities of epithelial cancer cells and plays an important role in accelerating neovascularization and preventing apoptosis of neoplastic cells. In this review, we discuss recent developments regarding the characteristics of the tumor microenvironment, the role of each cellular population, and their multiarticulate interaction with the malignant population. Further we discuss innovative treatment approaches, including immunotherapy, and how identification of CCA secreted factors by both the stromal component and immune cell subsets are leading towards a precision medicine in CCA.]]>
Wed, 31 Dec 1969 19:00:00 EST
DMSO induces drastic changes in human cellular processes and epigenetic landscape in vitro. Verheijen M, Lienhard M, Schrooders Y, Clayton O, Nudischer R, Boerno S, Timmermann B, Selevsek N, Schlapbach R, Gmuender H, Gotta S, Geraedts J, Herwig R, Kleinjans J, Caiment F
Sci Rep (Mar 2019)

Though clinical trials for medical applications of dimethyl sulfoxide (DMSO) reported toxicity in the 1960s, later, the FDA classified DMSO in the safest solvent category. DMSO became widely used in many biomedical fields and biological effects were overlooked. Meanwhile, biomedical science has evolved towards sensitive high-throughput techniques and new research areas, including epigenomics and microRNAs. Considering its wide use, especially for cryopreservation and in vitro assays, we evaluated biological effect of DMSO using these technological innovations. We exposed 3D cardiac and hepatic microtissues to medium with or without 0.1% DMSO and analyzed the transcriptome, proteome and DNA methylation profiles. In both tissue types, transcriptome analysis detected >2000 differentially expressed genes affecting similar biological processes, thereby indicating consistent cross-organ actions of DMSO. Furthermore, microRNA analysis revealed large-scale deregulations of cardiac microRNAs and smaller, though still massive, effects in hepatic microtissues. Genome-wide methylation patterns also revealed tissue-specificity. While hepatic microtissues demonstrated non-significant changes, findings from cardiac microtissues suggested disruption of DNA methylation mechanisms leading to genome-wide changes. The extreme changes in microRNAs and alterations in the epigenetic landscape indicate that DMSO is not inert. Its use should be reconsidered, especially for cryopreservation of embryos and oocytes, since it may impact embryonic development.]]>
Wed, 31 Dec 1969 19:00:00 EST
How does homeostasis happen? Integrative physiological, systems biological, and evolutionary perspectives. Goldstein DS
Am J Physiol Regul Integr Comp Physiol (Apr 2019)

Homeostasis is a founding principle of integrative physiology. In current systems biology, however, homeostasis seems almost invisible. Is homeostasis a key goal driving body processes, or is it an emergent mechanistic fact? In this perspective piece, I propose that the integrative physiological and systems biological viewpoints about homeostasis reflect different epistemologies, different philosophies of knowledge. Integrative physiology is concept driven. It attempts to explain biological phenomena by continuous formation of theories that experimentation or observation can test. In integrative physiology, "function" refers to goals or purposes. Systems biology is data driven. It explains biological phenomena in terms of "omics"-i.e., genomics, gene expression, epigenomics, proteomics, and metabolomics-it depicts the data in computer models of complex cascades or networks, and it makes predictions from the models. In systems biology, "function" refers more to mechanisms than to goals. The integrative physiologist emphasizes homeostasis of internal variables such as Pco and blood pressure. The systems biologist views these emphases as teleological and unparsimonious in that the "regulated variable" (e.g., arterial Pco and blood pressure) and the "regulator" (e.g., the "carbistat" and "barostat") are unobservable constructs. The integrative physiologist views systems biological explanations as not really explanations but descriptions that cannot account for phenomena we humans believe exist, although they cannot be observed directly, such as feelings and, ultimately, the conscious mind. This essay reviews the history of the two epistemologies, emphasizing autonomic neuroscience. I predict rapprochement of integrative physiology with systems biology. The resolution will avoid teleological purposiveness, transcend pure mechanism, and incorporate adaptiveness in evolution, i.e., "Darwinian medicine."]]>
Wed, 31 Dec 1969 19:00:00 EST
Ectopic expression of DNA methyltransferases DNMT3A2 and DNMT3L leads to aberrant hypermethylation and postnatal lethality in mice. Sasaki K, Hara S, Yamakami R, Sato Y, Hasegawa S, Kono T, Morohaku K, Obata Y
Mol Reprod Dev (Mar 2019)

DNA methylation is generally known to inactivate gene expression. The DNA methyltransferases (DNMTs), DNMT3A and DNMT3B, catalyze somatic cell lineage-specific DNA methylation, while DNMT3A and DNMT3L catalyze germ cell lineage-specific DNA methylation. How such lineage- and gene-specific DNA methylation patterns are created remains to be elucidated. To better understand the regulatory mechanisms underlying DNA methylation, we generated transgenic mice that constitutively expressed DNMT3A and DNMT3L, and analyzed DNA methylation, gene expression, and their subsequent impact on ontogeny. All transgenic mice were born normally but died within 20 weeks accompanied with cardiac hypertrophy. Several genes were repressed in the hearts of transgenic mice compared with those in wild-type mice. CpG islands of these downregulated genes were highly methylated in the transgenic mice. This abnormal methylation occurred in the perinatal stage. Conversely, monoallelic DNA methylation at imprinted loci was faithfully maintained in all transgenic mice, except H19. Thus, the loci preferred by DNMT3A and DNMT3L differ between somatic and germ cell lineages.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genomic consequences of sleep restriction: the devil is in the details. Fuller PM, Eikermann M
Anaesthesia (Apr 2019)

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Wed, 31 Dec 1969 19:00:00 EST
Epigenomics in an extraterrestrial environment: organ-specific alteration of DNA methylation and gene expression elicited by spaceflight in Arabidopsis thaliana. Zhou M, Sng NJ, LeFrois CE, Paul AL, Ferl RJ
BMC Genomics (Mar 2019)

Plants adapted to diverse environments on Earth throughout their evolutionary history, and developed mechanisms to thrive in a variety of terrestrial habitats. When plants are grown in the novel environment of spaceflight aboard the International Space Station (ISS), an environment completely outside their evolutionary history, they respond with unique alterations to their gene expression profile. Identifying the genes important for physiological adaptation to spaceflight and dissecting the biological processes and pathways engaged by plants during spaceflight has helped reveal spaceflight adaptation, and has furthered understanding of terrestrial growth processes. However, the underlying regulatory mechanisms responsible for these changes in gene expression patterns are just beginning to be explored. Epigenetic modifications, such as DNA methylation at position five in cytosine, has been shown to play a role in the physiological adaptation to adverse terrestrial environments, and may play a role in spaceflight as well.]]>
Wed, 31 Dec 1969 19:00:00 EST
Simultaneous Targeted Methylation Sequencing (sTM-Seq). Asmus N, Papale LA, Madrid A, Alisch RS
Curr Protoc Hum Genet (Apr 2019)

Mapping patterns of DNA methylation throughout the epigenome are critical to our understanding of several important biological and regulatory functions, such as transcriptional regulation, genomic imprinting, and embryonic development. The development and rapid advancement of next-generation sequencing (NGS) technologies have provided clinicians and researchers with accurate and reliable read-outs of genomic and epigenomic information at the nucleotide level. Such improvements have significantly lowered the cost required for genome-wide sequencing, facilitating the vast acquisition of data that has led to many improvements in patient care. However, the torrid rate of NGS data generation has left targeted validation approaches behind, including the confirmation of epigenetic marks such as DNA methylation. To overcome these shortcomings, we present a rapid and robust protocol for the parallel examination of multiple methylated sequences that we have termed simultaneous targeted methylation sequencing (sTM-Seq). Key features of this technique include the elimination of the need for large amounts of high-molecular weight DNA and the nucleotide specific distinction of both 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). Moreover, sTM-Seq is scalable and can be used to investigate multiple loci in dozens of samples within a single sequencing run. By utilizing freely available web-based software and universal primers for multipurpose barcoding, library preparation, and customized sequencing, sTM-Seq is affordable, efficient, and widely applicable. Together, these features enable sTM-Seq to have wide-reaching clinical applications that will greatly improve turnaround rates for same-day procedures and allow clinicians to collect high-resolution data that can be used in a variety of patient settings. © 2019 by John Wiley & Sons, Inc.]]>
Wed, 31 Dec 1969 19:00:00 EST
Machine learning polymer models of three-dimensional chromatin organization in human lymphoblastoid cells. Al Bkhetan Z, Kadlof M, Kraft A, Plewczynski D
Methods (Mar 2019)

We present machine learning models of human genome three-dimensional structure that combine one dimensional (linear) sequence specificity, epigenomic information, and transcription factor binding profiles, with the polymer-based biophysical simulations in order to explain the extensive long-range chromatin looping observed in ChIA-PET experiments for lymphoblastoid cells. Random Forest, Gradient Boosting Machine (GBM), and Deep Learning models were constructed and evaluated, when predicting high-resolution interactions within Topologically Associating Domains (TADs). The predicted interactions are consistent with the experimental long-read ChIA-PET interactions mediated by CTCF and RNAPOL2 for GM12878 cell line. The contribution of sequence information and chromatin state defined by epigenomic features to the prediction task is analyzed and reported, when using them separately and combined. Furthermore, we design three-dimensional models of chromatin contact domains (CCDs) using real (ChIA-PET) and predicted looping interactions. Initial results show a similarity between both types of 3D computational models (constructed from experimental or predicted interactions). This observation confirms the association between genome sequence, epigenomic and transcription factor profiles, and three-dimensional interactions.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genetic editing of colonic organoids provides a molecularly distinct and orthotopic preclinical model of serrated carcinogenesis. Lannagan TRM, Lee YK, Wang T, Roper J, Bettington ML, Fennell L, Vrbanac L, Jonavicius L, Somashekar R, Gieniec K, Yang M, Ng JQ, Suzuki N, Ichinose M, Wright JA, Kobayashi H, Putoczki TL, Hayakawa Y, Leedham SJ, Abud HE, Yilmaz Ã–H, Marker J, Klebe S, Wirapati P, Mukherjee S, Tejpar S, Leggett BA, Whitehall VLJ, Worthley DL, Woods SL
Gut (04 2019)

Serrated colorectal cancer (CRC) accounts for approximately 25% of cases and includes tumours that are among the most treatment resistant and with worst outcomes. This CRC subtype is associated with activating mutations in the mitogen-activated kinase pathway gene, , and epigenetic modifications termed the CpG Island Methylator Phenotype, leading to epigenetic silencing of key tumour suppressor genes. It is still not clear which (epi-)genetic changes are most important in neoplastic progression and we begin to address this knowledge gap herein.]]>
Wed, 31 Dec 1969 19:00:00 EST
The peculiar aging of human liver: A geroscience perspective within transplant context. Morsiani C, Bacalini MG, Santoro A, Garagnani P, Collura S, D'Errico A, de Eguileor M, Grazi GL, Cescon M, Franceschi C, Capri M
Ageing Res Rev (May 2019)

An appraisal of recent data highlighting aspects inspired by the new Geroscience perspective are here discussed. The main findings are summarized as follows: i) liver has to be considered an immunological organ, and new studies suggest a role for the recently described cells named telocytes; ii) the liver-gut axis represents a crucial connection with environment and life style habits and may influence liver diseases onset; iii) the physiological aging of liver shows relatively modest alterations. Nevertheless, several molecular changes appear to be relevant: a) an increase of microRNA-31-5p; -141-3p; -200c-3p expressions after 60 years of age; b) a remodeling of genome-wide DNA methylation profile evident until 60 years of age and then plateauing; c) changes in transcriptome including the metabolic zones of hepatocyte lobules; d) liver undergoes an accelerated aging in presence of chronic inflammation/liver diseases in a sort of continuum, largely as a consequence of unhealthy life styles and exposure to environmental noxious agents. We argue that chronic liver inflammation has all the major characteristics of "inflammaging" and likely sustains the onset and progression of liver diseases. Finally, we propose to use a combination of parameters, mostly obtained by omics such as transcriptomics and epigenomics, to evaluate in deep both the biological age of liver (in comparison with the chronological age) and the effects of donor-recipient age-mismatches in the context of liver transplant.]]>
Wed, 31 Dec 1969 19:00:00 EST
Integration of microbiology, molecular pathology, and epidemiology: a new paradigm to explore the pathogenesis of microbiome-driven neoplasms. Hamada T, Nowak JA, Milner DA, Song M, Ogino S
J Pathol (Apr 2019)

Molecular pathological epidemiology (MPE) is an integrative transdisciplinary field that addresses heterogeneous effects of exogenous and endogenous factors (collectively termed 'exposures'), including microorganisms, on disease occurrence and consequences, utilising molecular pathological signatures of the disease. In parallel with the paradigm of precision medicine, findings from MPE research can provide aetiological insights into tailored strategies of disease prevention and treatment. Due to the availability of molecular pathological tests on tumours, the MPE approach has been utilised predominantly in research on cancers including breast, lung, prostate, and colorectal carcinomas. Mounting evidence indicates that the microbiome (inclusive of viruses, bacteria, fungi, and parasites) plays an important role in a variety of human diseases including neoplasms. An alteration of the microbiome may be not only a cause of neoplasia but also an informative biomarker that indicates or mediates the association of an epidemiological exposure with health conditions and outcomes. To adequately educate and train investigators in this emerging area, we herein propose the integration of microbiology into the MPE model (termed 'microbiology-MPE'), which could improve our understanding of the complex interactions of environment, tumour cells, the immune system, and microbes in the tumour microenvironment during the carcinogenic process. Using this approach, we can examine how lifestyle factors, dietary patterns, medications, environmental exposures, and germline genetics influence cancer development and progression through impacting the microbial communities in the human body. Further integration of other disciplines (e.g. pharmacology, immunology, nutrition) into microbiology-MPE would expand this developing research frontier. With the advent of high-throughput next-generation sequencing technologies, researchers now have increasing access to large-scale metagenomics as well as other omics data (e.g. genomics, epigenomics, proteomics, and metabolomics) in population-based research. The integrative field of microbiology-MPE will open new opportunities for personalised medicine and public health. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genetic variation of UBE3A is associated with schizotypy in a population of typical individuals. Salminen I, Read S, Hurd P, Crespi B
Psychiatry Res (Mar 2019)

The maternally expressed imprinted gene UBE3A has been implicated in autism, schizophrenia and psychosis. The phenotype of Angelman syndrome, caused by loss of UBE3A expression, involves autism spectrum traits, while Prader-Willi syndrome, where the genotype of maternal disomy increases dosage of UBE3A, shows high penetrance for the development of psychosis. Maternal duplications of the 15q11-q13 chromosome region that overlap the imprinted region also show an association with schizophrenia, further implying a connection between increased dosage of UBE3A and the development of schizophrenia and psychosis. We phenotyped a large population of typical individuals for autism spectrum and schizotypal traits and genotyped them for a set of SNPs in UBE3A. Genetic variation of rs732739, an intronic SNP tagging a large haplotype spanning nearly the entire range of UBE3A, was significantly associated with variation in total schizotypy. Our results provide an independent line of evidence, connecting the imprinted UBE3A gene to the schizophrenia spectrum.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genomic imprinting disorders: lessons on how genome, epigenome and environment interact. Monk D, Mackay DJG, Eggermann T, Maher ER, Riccio A
Nat Rev Genet (Apr 2019)

Genomic imprinting, the monoallelic and parent-of-origin-dependent expression of a subset of genes, is required for normal development, and its disruption leads to human disease. Imprinting defects can involve isolated or multilocus epigenetic changes that may have no evident genetic cause, or imprinting disruption can be traced back to alterations of cis-acting elements or trans-acting factors that control the establishment, maintenance and erasure of germline epigenetic imprints. Recent insights into the dynamics of the epigenome, including the effect of environmental factors, suggest that the developmental outcomes and heritability of imprinting disorders are influenced by interactions between the genome, the epigenome and the environment in germ cells and early embryos.]]>
Wed, 31 Dec 1969 19:00:00 EST
The hyper-activation of transcriptional enhancers in breast cancer. Li QL, Wang DY, Ju LG, Yao J, Gao C, Lei PJ, Li LY, Zhao XL, Wu M
Clin Epigenetics (Mar 2019)

Activation of transcription enhancers, especially super-enhancers, is one of the critical epigenetic features of tumorigenesis. However, very few studies have systematically identified the enhancers specific in cancer tissues.]]>
Wed, 31 Dec 1969 19:00:00 EST
Epigenetics and epigenomics in diabetic kidney disease and metabolic memory. Kato M, Natarajan R
Nat Rev Nephrol (Mar 2019)

The development and progression of diabetic kidney disease (DKD), a highly prevalent complication of diabetes mellitus, are influenced by both genetic and environmental factors. DKD is an important contributor to the morbidity of patients with diabetes mellitus, indicating a clear need for an improved understanding of disease aetiology to inform the development of more efficacious treatments. DKD is characterized by an accumulation of extracellular matrix, hypertrophy and fibrosis in kidney glomerular and tubular cells. Increasing evidence shows that genes associated with these features of DKD are regulated not only by classical signalling pathways but also by epigenetic mechanisms involving chromatin histone modifications, DNA methylation and non-coding RNAs. These mechanisms can respond to changes in the environment and, importantly, might mediate the persistent long-term expression of DKD-related genes and phenotypes induced by prior glycaemic exposure despite subsequent glycaemic control, a phenomenon called metabolic memory. Detection of epigenetic events during the early stages of DKD could be valuable for timely diagnosis and prompt treatment to prevent progression to end-stage renal disease. Identification of epigenetic signatures of DKD via epigenome-wide association studies might also inform precision medicine approaches. Here, we highlight the emerging role of epigenetics and epigenomics in DKD and the translational potential of candidate epigenetic factors and non-coding RNAs as biomarkers and drug targets for DKD.]]>
Wed, 31 Dec 1969 19:00:00 EST
Link between depression and cardiovascular diseases due to epigenomics and proteomics: Focus on energy metabolism. Kahl KG, Stapel B, Frieling H
Prog Neuropsychopharmacol Biol Psychiatry (03 2019)

Major depression is the most common mental disorder and a leading cause of years lived with disability. In addition to the burden attributed to depressive symptoms and reduced daily life functioning, people with major depression are at increased risk of premature mortality, particularly due to cardiovascular diseases. Several studies point to a bi-directional relation between major depression and cardiovascular diseases, thereby indicating that both diseases may share common pathophysiological pathways. These include lifestyle factors (e.g. physical activity, smoking behavior), dysfunctions of endocrine systems (e.g. hypothalamus-pituitary adrenal axis), and a dysbalance of pro- and anti-inflammatory factors. Furthermore, recent research point to the role of epigenomic and proteomic factors, that are reviewed here with a particular focus on the mitochondrial energy metabolism.]]>
Wed, 31 Dec 1969 19:00:00 EST
Single-Cell Omics Analyses Enabled by Microchip Technologies. Deng Y, Finck A, Fan R
Annu Rev Biomed Eng (Mar 2019)

The study of single-cell omics provides unique information regarding the heterogeneity of cellular populations at various levels of the central dogma of molecular biology. This knowledge facilitates a deeper understanding of how underlying molecular and architectural changes alter cell behavior, development, and disease processes. The emerging microchip-based tools for single-cell omics analysis are enabling the evaluation of cellular omics with high throughput, improved sensitivity, and reduced cost. We review state-of-the-art microchip platforms for profiling genomics, epigenomics, transcriptomics, proteomics, metabolomics, and multi-omics at single-cell resolution. We also discuss the background of and challenges in the analysis of each molecular layer and integration of multiple levels of omics data, as well as how microchip-based methodologies benefit these fields. Additionally, we examine the advantages and limitations of these approaches. Looking forward, we describe additional challenges and future opportunities that will facilitate the improvement and broad adoption of single-cell omics in life science and medicine. Expected final online publication date for the Annual Review of Biomedical Engineering Volume 21 is June 4, 2019. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.]]>
Wed, 31 Dec 1969 19:00:00 EST
Biomarkers: What Role Do They Play (If Any) for Diagnosis, Prognosis and Tumor Response Prediction for Hepatocellular Carcinoma? Harding JJ, Khalil DN, Abou-Alfa GK
Dig Dis Sci (Mar 2019)

Hepatocellular carcinoma (HCC) is a common illness that affects patients worldwide. The disease remains poorly understood though several recent advances have increased the understanding of HCC biology and treatment.]]>
Wed, 31 Dec 1969 19:00:00 EST
Shift work, DNA methylation and epigenetic age. White AJ, Kresovich JK, Xu Z, Sandler DP, Taylor JA
Int J Epidemiol (Mar 2019)

Shift work has been associated with increased risk of age-related morbidity and mortality. Biological age, estimated using DNA methylation (DNAm), may quantify the biological consequences of shift work on the risk of age-related disease. We examined whether prior employment in shift-working occupations was associated with epigenetic age acceleration.]]>
Wed, 31 Dec 1969 19:00:00 EST
The effects of Assisted Reproductive Technologies on genomic imprinting in the placenta. Rhon-Calderon EA, Vrooman LA, Riesche L, Bartolomei MS
Placenta (Mar 2019)

The placenta is a complex and poorly understood organ, which serves as the connection between the mother and the developing fetus. Genomic imprinting, defined as a regulatory process resulting in the expression of a gene in a parent-of-origin-specific manner, plays an important role in fetal development and placental function. Disturbances that occur during the establishment and maintenance of imprinting could compromise the placenta and fetus, and ultimately, offspring health. Assisted Reproductive Technologies (ART) have been widely used to overcome infertility, however experimental studies have shown that ART procedures affect placentation and the expression of imprinted genes. Here we briefly review the role of imprinted genes in placental development and the evidence from mouse and human studies suggesting ART disrupts imprinted gene regulation in the placenta.]]>
Wed, 31 Dec 1969 19:00:00 EST