'; ?> 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, 20 Sep 2019 08:27:16 EDT Fri, 20 Sep 2019 08:27:16 EDT jirtle@radonc.duke.edu james001@jirtle.com Panoptic View of Prognostic Models for Personalized Breast Cancer Management. Saini G, Mittal K, Rida P, Janssen EAM, Gogineni K, Aneja R
Cancers (Basel) (Sep 2019)

The efforts to personalize treatment for patients with breast cancer have led to a focus on the deeper characterization of genotypic and phenotypic heterogeneity among breast cancers. Traditional pathology utilizes microscopy to profile the morphologic features and organizational architecture of tumor tissue for predicting the course of disease, and is the first-line set of guiding tools for customizing treatment decision-making. Currently, clinicians use this information, combined with the disease stage, to predict patient prognosis to some extent. However, tumoral heterogeneity stubbornly persists among patient subgroups delineated by these clinicopathologic characteristics, as currently used methodologies in diagnostic pathology lack the capability to discern deeper genotypic and subtler phenotypic differences among individual patients. Recent advancements in molecular pathology, however, are poised to change this by joining forces with multiple-omics technologies (genomics, transcriptomics, epigenomics, proteomics, and metabolomics) that provide a wealth of data about the precise molecular complement of each patient's tumor. In addition, these technologies inform the drivers of disease aggressiveness, the determinants of therapeutic response, and new treatment targets in the individual patient. The tumor architecture information can be integrated with the knowledge of the detailed mutational, transcriptional, and proteomic phenotypes of cancer cells within individual tumors to derive a new level of biologic insight that enables powerful, data-driven patient stratification and customization of treatment for each patient, at each stage of the disease. This review summarizes the prognostic and predictive insights provided by commercially available gene expression-based tests and other multivariate or clinical -omics-based prognostic/predictive models currently under development, and proposes a more inclusive multiplatform approach to tackling the challenging heterogeneity of breast cancer to individualize its management. "The future is already here-it's just not very evenly distributed."-William Ford Gibson.]]>
Wed, 31 Dec 1969 19:00:00 EST
Heart Failure in the Era of Precision Medicine: A Scientific Statement From the American Heart Association. Cresci S, Pereira NL, Ahmad F, Byku M, de Las Fuentes L, Lanfear DE, Reilly CM, Owens AT, Wolf MJ,  
Circ Genom Precis Med (Sep 2019)

One of 5 people will develop heart failure over his or her lifetime. Early diagnosis and better understanding of the pathophysiology of this disease are critical to optimal treatment. The "omics"-genomics, pharmacogenomics, epigenomics, proteomics, metabolomics, and microbiomics- of heart failure represent rapidly expanding fields of science that have, to date, not been integrated into a single body of work. The goals of this statement are to provide a comprehensive overview of the current state of these omics as they relate to the development and progression of heart failure and to consider the current and potential future applications of these data for precision medicine with respect to prevention, diagnosis, and therapy.]]>
Wed, 31 Dec 1969 19:00:00 EST
Aberrant expression of imprinted lncRNA MEG8 causes trophoblast dysfunction and abortion. Sheng F, Sun N, Ji Y, Ma Y, Ding H, Zhang Q, Yang F, Li W
J Cell Biochem (Oct 2019)

Long noncoding RNAs (lncRNAs) are a group of noncoding RNAs whose nucleotides are longer than 200 bp. Previous studies have shown that they play an important regulatory role in many developmental processes and biological pathways. However, the contributions of lncRNAs to placental development are largely unknown. Here, our study aimed to investigate the lncRNA expression signatures in placental development by performing a microarray lncRNA screen. Placental samples were obtained from pregnant C57BL/6 female mice at three key developmental time points (embryonic day E7.5, E13.5, and E19.5). Microarrays were used to analyze the differential expression of lncRNAs during placental development. In addition to the genomic imprinting region and the dynamic DNA methylation status during placental development, we screened imprinted lncRNAs whose expression was controlled by DNA methylation during placental development. We found that the imprinted lncRNA Rian may play an important role during placental development. Its homologous sequence lncRNA MEG8 (RIAN) was abnormally highly expressed in human spontaneous abortion villi. Upregulation of MEG8 expression in trophoblast cell lines decreased cell proliferation and invasion, whereas downregulation of MEG8 expression had the opposite effect. Furthermore, DNA methylation results showed that the methylation of the MEG8 promoter region was increased in spontaneous abortion villi. There was dynamic spatiotemporal expression of imprinted lncRNAs during placental development. The imprinted lncRNA MEG8 is involved in the regulation of early trophoblast cell function. Promoter methylation abnormalities can cause trophoblastic cell defects, which may be one of the factors that occurs in early unexplained spontaneous abortion.]]>
Wed, 31 Dec 1969 19:00:00 EST
Genetic variation and temperature affects hybrid barriers during interspecific hybridization. Bjerkan KN, Hornslien KS, Johannessen IM, Krabberød AK, van Ekelenburg YS, Kalantarian M, Shirzadi R, Comai L, Brysting AK, Bramsiepe J, Grini PE
Plant J (Sep 2019)

Genomic imprinting regulates parent-specific transcript dosage during seed development and is mainly confined to the endosperm. Elucidation of the function of many imprinted genes has been hampered by the lack of corresponding mutant phenotypes, and the role of imprinting is mainly associated with genome dosage regulation or allocation of resources. Disruption of imprinted genes has also been suggested to mediate endosperm based post-zygotic hybrid barriers depending on genetic variation and gene dosage. Here, we have analyzed the conservation of a clade from the MADS-box type I class transcription factors in the closely related species Arabidopsis arenosa, A. lyrata and A. thaliana, and show that AGL36-like genes are imprinted and maternally expressed in seeds of Arabidopsis species and in hybrid seeds between outbreeding species. In hybridizations between outbreeding and inbreeding species the paternally silenced allele of the AGL36-like gene is reactivated in the hybrid, demonstrating that also maternally expressed imprinted genes are perturbed during hybridization and that such effects on imprinted genes are specific to the species combination. Furthermore, we also demonstrate a quantitative effect of genetic diversity and temperature on the strength of the post-zygotic hybridization barrier. Remarkably, a small decrease in temperature during seed development increases survival of hybrid F1 seeds, suggesting that abiotic and genetic parameters play important roles in post-zygotic species barriers, pointing at evolutionary scenarios favoring such effects. This article is protected by copyright. All rights reserved.]]>
Wed, 31 Dec 1969 19:00:00 EST
The crossroads of psychiatric epigenomics. Petronis A, Labrie V
World Psychiatry (Oct 2019)

Wed, 31 Dec 1969 19:00:00 EST
The Evolving Field Of Genetic Epidemiology: From Familial Aggregation To Genomic Sequencing. Duggal P, Ladd-Acosta C, Ray D, Beaty TH
Am J Epidemiol (Sep 2019)

The field of genetic epidemiology is relatively young and brings together genetics, epidemiology and biostatistics to identify and implement the best study designs and statistical analyses for identifying genes controlling risk to complex and heterogeneous diseases (i.e. those where genes and environmental risk factors both contribute to etiology). The field has moved quickly over the past 40 years partly because the technology of genotyping and sequencing has forced it to adapt while adhering to the fundamental principles of genetics. In the last two decades, the available tools for genetic epidemiology have expanded from a genetic focus (i.e. considering one gene at a time) to a genomic focus (i.e. considering the entire genome), and now they must further expand to integrate information from other "-omics" (e.g. epigenomics, transcriptomics as measured by RNA expression) both at the individual level and at the population level. Additionally, we can now also evaluate gene and environmental interactions across populations to better understand exposure and the heterogeneity in disease risk. The future challenges facing genetic epidemiology are considerable both in scale and techniques, but the importance of the field will not diminish because by design it ties scientific goals with public health applications.]]>
Wed, 31 Dec 1969 19:00:00 EST
Whole-exome sequencing identifies a GREB1L variant in a three-generation family with Müllerian and renal agenesis: a novel candidate gene in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. A case report. Herlin MK, Le VQ, Højland AT, Ernst A, Okkels H, Petersen AC, Petersen MB, Pedersen IS
Hum Reprod (Sep 2019)

The aetiology of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome, characterized by uterovaginal agenesis in 46,XX women, remains poorly understood. Since familial occurrences are rare, genetic findings reported so far only apply to a minority of mainly sporadic cases and most studies have not included other family members enabling segregation analysis. Herein, we report on the investigation of a unique three-generation family of two female cousins with MRKH syndrome and unilateral renal agenesis (RA) and two deceased male relatives with RA. We performed whole-exome sequencing (WES) in eight family members leading to the identification of a novel pathogenic (CADD = 33) c.705G>T missense variant in GREB1L, a gene recently identified as a novel cause of RA. Previous reports include several cases of female fetuses with bilateral RA and uterus agenesis, which support GREB1L as an important gene in both kidney and female genital tract development. The pedigree is compatible with autosomal dominant inheritance with incomplete penetrance following a parent-origin-specific manner, which could be due to imprinting. To our knowledge, this is the first investigation of a larger MRKH syndrome pedigree using WES, and we suggest GREB1L as a novel and promising candidate gene in the aetiology of MRKH syndrome.]]>
Wed, 31 Dec 1969 19:00:00 EST
The Current State of Omics Technologies in the Clinical Management of Asthma and Allergic Diseases. Donovan BM, Bastarache L, Turi KN, Zutter MM, Hartert TV
Ann Allergy Asthma Immunol (Sep 2019)

To review the state of omics science specific to asthma and allergic diseases and discuss the current and potential applicability of omics in clinical disease prediction, treatment, and management Data Sources: Studies and reviews focused on the use of omics technologies in asthma and allergic disease research and clinical management were identified using PubMed STUDY SELECTIONS: Publications were included based on relevance, with emphasis placed on the most recent findings RESULTS: Omics-based research is increasingly being used to differentiate asthma and allergic disease subtypes, identify biomarkers and pathological mediators, predict patient responsiveness to specific therapies, and monitor disease control. While most studies have focused on genomics and transcriptomics approaches, increasing attention is being placed on omics technologies that assess the effect of environmental exposures on disease initiation and progression. Studies utilizing omics data to identify biological targets and pathways involved in asthma and allergic disease pathogenesis have primarily focused on a specific omics subtype, providing only a partial view of the disease process.]]>
Wed, 31 Dec 1969 19:00:00 EST
DNA methylation and mRNA expression of imprinted genes in blastocysts derived from an improved in vitro maturation method for oocytes from small antral follicles in polycystic ovary syndrome patients. Saenz-de-Juano MD, Ivanova E, Romero S, Lolicato F, Sánchez F, Van Ranst H, Krueger F, Segonds-Pichon A, De Vos M, Andrews S, Smitz J, Kelsey G, Anckaert E
Hum Reprod (Sep 2019)

Does imprinted DNA methylation or imprinted gene expression differ between human blastocysts from conventional ovarian stimulation (COS) and an optimized two-step IVM method (CAPA-IVM) in age-matched polycystic ovary syndrome (PCOS) patients?]]>
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
Neuroendocrine prostate cancer: long noncoding RNAs to treat an incurable cancer - an interview with Dr Francesco Crea. Crea F
Epigenomics (Sep 2019)

Dr Crea's lab studies the role of epigenetic factors and noncoding RNA in cancer initiation and progression. While working at the National Cancer Institute (USA), Dr Crea has demonstrated that polycomb-targeting drugs eradicate prostate cancer stem cells. While working at the BC Cancer Agency (Canada), Dr Crea discovered and patented , a long noncoding RNA involved in prostate cancer metastasis. Dr Crea has received awards from the American Society of Clinical Oncology, from the Prostate Cancer Program and from Prostate Cancer Foundation BC. He is also an Editorial Board member for . His team is currently working on developing new biomarkers and therapeutic targets for incurable prostate and breast cancers.]]>
Wed, 31 Dec 1969 19:00:00 EST
Loss of methylation of H19-imprinted gene derived from assisted reproductive technologies can be mitigated by cleavage-stage embryo transfer in mice. Chen S, Zhang M, Li L, Wang M, Shi Y, Zhang H, Kang B, Tang N, Li B
J Assist Reprod Genet (Sep 2019)

Studies on rodents have shown that assisted reproductive technologies (ARTs) are associated with perturbation of genomic imprinting in blastocyst-stage embryos. However, the vulnerable developmental window for ART influence on the genomic imprinting of embryos is still undetermined. The purpose of this study was to establish the specific embryonic development stage at which the loss of methylation of H19 imprinting control regions (ICRs) was caused by ART occurrence. Additionally, we explored protocols to safeguard against possible negative impacts of ART on embryo H19 imprinting.]]>
Wed, 31 Dec 1969 19:00:00 EST
Xist RNA in action: Past, present, and future. Loda A, Heard E
PLoS Genet (Sep 2019)

In mammals, dosage compensation of sex chromosomal genes between females (XX) and males (XY) is achieved through X-chromosome inactivation (XCI). The X-linked X-inactive-specific transcript (Xist) long noncoding RNA is indispensable for XCI and initiates the process early during development by spreading in cis across the X chromosome from which it is transcribed. During XCI, Xist RNA triggers gene silencing, recruits a plethora of chromatin modifying factors, and drives a major structural reorganization of the X chromosome. Here, we review our knowledge of the multitude of epigenetic events orchestrated by Xist RNA to allow female mammals to survive through embryonic development by establishing and maintaining proper dosage compensation. In particular, we focus on recent studies characterizing the interaction partners of Xist RNA, and we discuss how they have affected the field by addressing long-standing controversies or by giving rise to new research perspectives that are currently being explored. This review is dedicated to the memory of Denise Barlow, pioneer of genomic imprinting and functional long noncoding RNAs (lncRNAs), whose work has revolutionized the epigenetics field and continues to inspire generations of scientists.]]>
Wed, 31 Dec 1969 19:00:00 EST
Conserved NPPB+ Border Zone Switches From MEF2- to AP-1-Driven Gene Program. van Duijvenboden K, de Bakker DEM, Man JCK, Janssen R, Günthel M, Hill MC, Hooijkaas IB, van der Made I, van der Kraak PH, Vink A, Creemers EE, Martin JF, Barnett P, Bakkers J, Christoffels VM
Circulation (Sep 2019)

Surviving cells in the postinfarction border zone are subjected to intense fluctuations of their microenvironment. Recently, border zone cardiomyocytes have been specifically implicated in cardiac regeneration. Here, we defined their unique transcriptional and regulatory properties, and comprehensively validated new molecular markers, including Nppb, encoding B-type natriuretic peptide, after infarction.]]>
Wed, 31 Dec 1969 19:00:00 EST
A method for identifying allele-specific hydroxymethylation. Yamada Y, Sasaki S
Epigenetics (Sep 2019)

We previously identified sequence-dependent allele-specific methylation (sd-ASM) in adult human peripheral blood leukocytes, in which ASM occurs in cis depending on adjacent polymorphic sequences. A number of groups have identified sd-ASM sites in the human and mouse genomes, illustrating the prevalence of sd-ASM in mammalian genomes. In addition, sd-ASM can lead to sequence-dependent allele-specific expression of neighbouring genes. Imprinted genes also often exhibit parent-of-origin-dependent allele-specific methylation (pd-ASM), which causes parent-of-origin-dependent allele-specific expression. However, whether most of the already known sd-ASM and pd-ASM sites are methylated or hydroxymethylated remains unclear due to technical restrictions. Accordingly, a novel method that enables examination of allelic methylation and hydroxymethylation status and also overcomes the drawbacks of conventional methods is needed. Such a method could also be used to elucidate the mechanisms underlying polymorphism-associated inter-individual differences in disease susceptibility and the mechanism of genomic imprinting. Here, we developed a simple method to determine allelic hydroxymethylation status and identified novel sequence- and parent-of-origin-dependent allele-specific hydroxymethylation sites. Correlation analyses of TF binding sequences and methylation or hydroxymethylation between three mouse strains revealed the involvement of in strain-specific methylation and hydroxymethylation in exon 7 of .]]>
Wed, 31 Dec 1969 19:00:00 EST
Classification of early and late stage liver hepatocellular carcinoma patients from their genomics and epigenomics profiles. Kaur H, Bhalla S, Raghava GPS
PLoS One (2019)

Liver Hepatocellular Carcinoma (LIHC) is one of the major cancers worldwide, responsible for millions of premature deaths every year. Prediction of clinical staging is vital to implement optimal therapeutic strategy and prognostic prediction in cancer patients. However, to date, no method has been developed for predicting the stage of LIHC from the genomic profile of samples.]]>
Wed, 31 Dec 1969 19:00:00 EST
Quantitative Multiplexed ChIP Reveals Global Alterations that Shape Promoter Bivalency in Ground State Embryonic Stem Cells. Kumar B, Elsässer SJ
Cell Rep (Sep 2019)

To understand the epigenomic foundation of naive pluripotency, we implement a quantitative multiplexed chromatin immunoprecipitation sequencing (ChIP-seq) method comparing mouse embryonic stem cells (ESCs) grown in 2i versus 2i/serum and serum conditions. MINUTE-ChIP has a large linear dynamic range for accurately quantifying relative differences in genome-wide histone modification patterns across multiple pooled samples. We find compelling evidence for a broad H3 lysine 27 trimethylation (H3K27me3) hypermethylation of the genome, while bivalent promoters stably retain high H3K27me3 levels in 2i. We show that DNA hypomethylation, as observed in 2i, is a contributor to genome-wide gain of H3K27me3, while active demethylation by JMJD3/UTX counteracts further accumulation of H3K27me3. In parallel, we find hypomethylation of H3 lysine 4 trimethylation (H3K4me3), particularly at bivalent promoters, to be a characteristic of the 2i ground state. Serum stimulates H3K4me3 independent of GSK-3b and ERK signaling, suggesting that low H3K4me3 and high H3K27me3 levels at bivalent promoters are a product of two independent mechanisms that safeguard naive pluripotency.]]>
Wed, 31 Dec 1969 19:00:00 EST
Distinct Imprinting Signatures and Biased Differentiation of Human Androgenetic and Parthenogenetic Embryonic Stem Cells. Sagi I, De Pinho JC, Zuccaro MV, Atzmon C, Golan-Lev T, Yanuka O, Prosser R, Sadowy A, Perez G, Cabral T, Glaser B, Tsang SH, Goland R, Sauer MV, Lobo R, Benvenisty N, Egli D
Cell Stem Cell (Sep 2019)

Genomic imprinting is an epigenetic mechanism that results in parent-of-origin monoallelic expression of specific genes, which precludes uniparental development and underlies various diseases. Here, we explored molecular and developmental aspects of imprinting in humans by generating exclusively paternal human androgenetic embryonic stem cells (aESCs) and comparing them with exclusively maternal parthenogenetic ESCs (pESCs) and bi-parental ESCs, establishing a pluripotent cell system of distinct parental backgrounds. Analyzing the transcriptomes and methylomes of human aESCs, pESCs, and bi-parental ESCs enabled the characterization of regulatory relations at known imprinted regions and uncovered imprinted gene candidates within and outside known imprinted regions. Investigating the consequences of uniparental differentiation, we showed the known paternal-genome preference for placental contribution, revealed a similar bias toward liver differentiation, and implicated the involvement of the imprinted gene IGF2 in this process. Our results demonstrate the utility of parent-specific human ESCs for dissecting the role of imprinting in human development and disease.]]>
Wed, 31 Dec 1969 19:00:00 EST
Prader-Willi syndrome imprinting centre deletion mice have impaired baseline and 5-HT2CR-mediated response inhibition. Davies JR, Wilkinson LS, Isles AR, Humby T
Hum Mol Genet (Sep 2019)

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder caused by deletion or inactivation of paternally expressed imprinted genes on human chromosome 15q11-q13. In addition to endocrine and developmental issues, PWS presents with behavioural problems including stereotyped behaviour, impulsiveness and cognitive deficits. The PWS genetic interval contains several brain-expressed small nucleolar (sno) RNA species that are subject to genomic imprinting, including snord115 that negatively regulates post-transcriptional modification of the serotonin 2C receptor (5-HT2CR) pre-mRNA potentially leading to a reduction in 5-HT2CR function. Using the imprinting centre deletion mouse model for PWS (PWSICdel) we have previously shown impairments in a number of behaviours, some of which are abnormally sensitive to 5-HT2CR-selective drugs. In the stop-signal reaction time task test of impulsivity, PWSICdel mice showed increased impulsivity relative to wild-type (WT) littermates. Challenge with the selective 5-HT2CR agonist WAY163909 reduced impulsivity in PWSICdel mice but had no effect on WT behaviour. This behavioural dissociation in was also reflected in differential patterns of immunoreactivity of the immediate early gene c-Fos, with a blunted response to the drug in the orbitofrontal cortex of PWSICdel mice, but no difference in c-Fos activation in the nucleus accumbens. These findings suggest specific facets of response inhibition are impaired in PWSICdel mice and that abnormal 5-HT2CR function may mediate this dissociation. These data have implications for our understanding of the aetiology of PWS-related behavioural traits and translational relevance for individuals with PWS who may seek to control appetite with the new obesity treatment 5-HT2CR agonist lorcaserin.]]>
Wed, 31 Dec 1969 19:00:00 EST
Identification of the expressome by machine learning on omics data. Sartor RC, Noshay J, Springer NM, Briggs SP
Proc Natl Acad Sci U S A (Sep 2019)

Accurate annotation of plant genomes remains complex due to the presence of many pseudogenes arising from whole-genome duplication-generated redundancy or the capture and movement of gene fragments by transposable elements. Machine learning on genome-wide epigenetic marks, informed by transcriptomic and proteomic training data, could be used to improve annotations through classification of all putative protein-coding genes as either constitutively silent or able to be expressed. Expressed genes were subclassified as able to express both mRNAs and proteins or only RNAs, and CG gene body methylation was associated only with the former subclass. More than 60,000 protein-coding genes have been annotated in the reference genome of maize inbred B73. About two-thirds of these genes are transcribed and are designated the filtered gene set (FGS). Classification of genes by our trained random forest algorithm was accurate and relied only on histone modifications or DNA methylation patterns within the gene body; promoter methylation was unimportant. Other inbred lines are known to transcribe significantly different sets of genes, indicating that the FGS is specific to B73. We accurately classified the sets of transcribed genes in additional inbred lines, arising from inbred-specific DNA methylation patterns. This approach highlights the potential of using chromatin information to improve annotations of functional genes.]]>
Wed, 31 Dec 1969 19:00:00 EST