'; ?> 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 Sun, 21 Jul 2019 14:46:19 EDT Sun, 21 Jul 2019 14:46:19 EDT jirtle@radonc.duke.edu james001@jirtle.com New insights into DNA methylation signatures: SMARCA2 variants in Nicolaides-Baraitser syndrome. Chater-Diehl E, Ejaz R, Cytrynbaum C, Siu MT, Turinsky A, Choufani S, Goodman SJ, Abdul-Rahman O, Bedford M, Dorrani N, Engleman K, Flores-Daboub J, Genevieve D, Mendoza-Londono R, Meschino W, Perrin L, Safina N, Townshend S, Scherer SW, Anagnostou E, Piton A, Deardorff M, Brudno M, Chitayat D, Weksberg R
BMC Med Genomics (Jul 2019)

Nicolaides-Baraitser syndrome (NCBRS) is a neurodevelopmental disorder caused by pathogenic sequence variants in SMARCA2 which encodes the catalytic component of the chromatin remodeling BAF complex. Pathogenic variants in genes that encode epigenetic regulators have been associated with genome-wide changes in DNA methylation (DNAm) in affected individuals termed DNAm signatures.]]> Wed, 31 Dec 1969 19:00:00 EST The role of molecular genetics in the clinical management of sporadic medullary thyroid carcinoma. Fussey JM, Vaidya B, Kim D, Clark J, Ellard S, Smith JA
Clin Endocrinol (Oxf) (Jul 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 Role of epigenetic regulation of Igf2 and H19 in 2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD)-induced ovarian toxicity in offspring rats. Zhang X, Ji M, Tan X, Yu K, Xu L, Chen G, Yu Z
Toxicol Lett (Sep 2019)

2,3,7,8-Tetrachlorobenzo-p-dioxin (TCDD) exposure during embryonic gonadal sex determination had been demonstrated to harm the ovarian development. However, its mechanism was unclear and possibly related to epigenetic regulation. In the present study, the pregnant rats were treated with TCDD (100 ng/kg/day or 500 ng/kg/day) or only vehicle and corn oil on the day 8-14 of gestation through the gavage with a stainless-steel feeding needle. The vaginal opening time and estrous cycle of female offspring rats (F1) were monitored twice a day. The ovarian histology, follicle count, real-time PCR, Western Blotting and DNA methylation analysis for Igf2 and H19 were carried out. The results showed that maternal TCDD exposure disrupted estrous cyclicity, resulted in aberrant concentration of serum E2 and FSH, and affected the number of primordial follicles, secondary follicles and corpus luteum. However, TCDD had no effect on the number of primary follicles and atresia follicles. Furthermore, the mRAN expression of imprinted genes Igf2 and H19 was down-regulated, and the IGF2 protein was also down-regulated. TCDD exposure did not alter the mean methylation rate of Igf2 DMR2 and H19 ICR, and only some CpG sites throughout them were hypermethylated in high-dose TCDD rats. In conclusion, maternal exposure of TCDD could affect the ovary development and functions which were possibly associated with down-regulation expression of IGF2 and H19. However, it was not entirely clear whether the impairment of ovary by TCDD was related to the methylation pattern of Igf2 and H19 ICR.]]> 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 (Jul 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 Origins of DNA methylation defects in Wilms tumors. Anvar Z, Acurzio B, Roma J, Cerrato F, Verde G
Cancer Lett (Aug 2019)

Wilms tumor is an embryonic renal cancer that typically presents in early childhood and accounts for 7% of all paediatric cancers. Different genetic alterations have been described in this malignancy, however, only a few of them are associated with a majority of Wilms tumors. Alterations in DNA methylation, in contrast, are frequent molecular defects observed in most cases of Wilms tumors. How these epimutations are established in this tumor is not yet completely clear. The recent identification of the molecular actors required for the epigenetic reprogramming during embryogenesis suggests novel possible mechanisms responsible for the DNA methylation defects in Wilms tumor. Here, we provide an overview of the DNA methylation alterations observed in this malignancy and discuss the distinct molecular mechanisms by which these epimutations can arise.]]> Wed, 31 Dec 1969 19:00:00 EST Biological underpinnings from psychosocial stress towards appetite and obesity during youth: research implications towards metagenomics, epigenomics and metabolomics. Michels N
Nutr Res Rev (Jul 2019)

Psychosocial stress, uncontrolled eating and obesity are three interrelated epidemiological phenomena already present during youth. This broad narrative conceptual review summarises main biological underpinnings of the stress-diet-obesity pathway and how new techniques can further knowledge. Cortisol seems the main biological factor from stress towards central adiposity; and diet, physical activity and sleep are the main behavioural pathways. Within stress-diet, the concepts of comfort food and emotional eating are highlighted, as cortisol affects reward pathways and appetite brain centres with a role for insulin, leptin, neuropeptide Y (NPY), endocannabinoids, orexin and gastrointestinal hormones. More recently researched biological underpinnings are microbiota, epigenetic modifications and metabolites. First, the gut microbiota reaches the stress-regulating and appetite-regulating brain centres via the gut-brain axis. Second, epigenetic analyses are recommended as diet, obesity, stress and gut microbiota can change gene expression which then affects appetite, energy homeostasis and stress reactivity. Finally, metabolomics would be a good technique to disentangle stress-diet-obesity interactions as multiple biological pathways are involved. Saliva might be an ideal biological matrix as it allows metagenomic (oral microbiota), epigenomic and metabolomic analyses. In conclusion, stress and diet/obesity research should be combined in interdisciplinary collaborations with implementation of several -omics analyses.]]> Wed, 31 Dec 1969 19:00:00 EST Paternal benzo[a]pyrene exposure alters the sperm DNA methylation levels of imprinting genes in F0 generation mice and their unexposed F1-2 male offspring. Zhang W, Yang J, Lv Y, Li S, Qiang M
Chemosphere (Aug 2019)

Benzo[a]pyrene (BaP) is an environmental pollutant known to cause teratogenesis. However, the mechanism underlying this teratogenic effect is not fully understood. Recently, the alteration of DNA methylation of imprinting genes has emerged as a specific epigenetic mechanism linking the impact of environmental pollutants on embryonic development to paternal exposures. The aim of this study was to investigate the transgenerational effects of paternal BaP exposure on the imprinting genes in mouse sperm DNA.]]> Wed, 31 Dec 1969 19:00:00 EST Mechanisms of resistance to a PI3K inhibitor in gastrointestinal stromal tumors: an approach to identify novel druggable targets. Ravegnini G, Sammarini G, Moran S, Calice G, Indio V, Urbini M, Astolfi A, Zanotti F, Pantaleo MA, Hrelia P, Angelini S
Cancer Manag Res (2019)

Gastrointestinal stromal tumors (GISTs) represent a worldwide paradigm of target therapy. The introduction of tyrosine kinase inhibitors has deeply changed the prognosis of GIST patients, however, the majority of them acquire secondary mutations and progress. Unfortunately, besides tyrosine-kinase inhibitors, no other therapeutic options are available. Therefore, it is mandatory to identify novel molecules and/or strategies to overcome the inevitable resistance. In this context, after promising preclinical data on the novel PI3K inhibitor BYL719, the NCT01735968 trial in GIST patients who had previously failed treatment with imatinib and sunitinib started. BYL719 has attracted our attention, and we comprehensively characterized genomic and transcriptomic changes taking place during resistance. For this purpose, we generated two in vitro GIST models of acquired resistance to BYL719 and performed an omic-based analysis by integrating RNA-sequencing, miRNA, and methylation profiles in sensitive and resistant cells. We identified novel epigenomic mechanisms of pharmacological resistance in GISTs suggesting the existence of pathways involved in drug resistance and alternatively acquired mutations. Therefore, epigenomics should be taken into account as an alternative adaptive mechanism. Despite the fact that currently we do not have patients in treatment with BYL719 to verify this hypothesis, the most intriguing result is the involvement of H19 and PSTA1 in GIST resistance, which might represent druggable targets.]]> Wed, 31 Dec 1969 19:00:00 EST Absence of an embryonic stem cell DNA methylation signature in human cancer. Zhang Z, Wiencke JK, Koestler DC, Salas LA, Christensen BC, Kelsey KT
BMC Cancer (Jul 2019)

Differentiated cells that arise from stem cells in early development contain DNA methylation features that provide a memory trace of their fetal cell origin (FCO). The FCO signature was developed to estimate the proportion of cells in a mixture of cell types that are of fetal origin and are reminiscent of embryonic stem cell lineage. Here we implemented the FCO signature estimation method to compare the fraction of cells with the FCO signature in tumor tissues and their corresponding nontumor normal tissues.]]> 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 Transcriptional Control and Transcriptomic Analysis of Lipid Metabolism in Skin barrier formation and Atopic Dermatitis (AD). Bhattacharya N, Ganguli-Indra G, Indra AK
Expert Rev Proteomics (Jul 2019)

Atopic dermatitis (AD) is a multifactorial ailment associated with barrier breach and intense systemic inflammation. Several studies over the years have shown the complex interplay of a large number of factors in governing the progression and outcome of AD. In addition to the diverse types of AD resulting due to variation in the intrinsic mechanisms giving rise to AD such as single nucleotide polymorphisms (SNPs), epigenetic alterations or transcriptional changes, extrinsic factors such as age, ancestry, ethnicity, immunological background of the subject, the interactions of the subject with environmental stimuli and existing microbiome in the periphery surrounding the subject account for further heterogeneity in the clinical manifestations of the disease. Here we have selectively discussed transcriptional regulation of genes associated with skin lipid metabolism in the context of AD. Transcriptional control and transcriptomic changes are just one face of this multifaceted disease known to affect humans and a detailed study concerning those will enable us to develop targeted therapies to deal with the disease. Large-scale integration of different omics approaches (genomics, epigenomics, transcriptomics, lipidomics, proteomics, metabolomics, effect of exposome) will help identify the potential candidate gene(s) associated with the development of various endotypes of AD.]]> Wed, 31 Dec 1969 19:00:00 EST Tracing the origin and evolution history of methylation-related genes in plants. Pei L, Zhang L, Li J, Shen C, Qiu P, Tu L, Zhang X, Wang M
BMC Plant Biol (Jul 2019)

DNA methylation is a crucial epigenetic modification, which is involved in many biological processes, including gene expression regulation, embryonic development, cell differentiation and genomic imprinting etc. And it also involves many key regulatory genes in eukaryotes. By tracing the evolutionary history of methylation-related genes, we can understand the origin and expansion time of these genes, which helps to understand the evolutionary history of plants, and we can also understand the changes of DNA methylation patterns in different species. However, most studies on the evolution of methylation-related genes failed to be carried out for the whole DNA methylation pathway.]]> Wed, 31 Dec 1969 19:00:00 EST Impact of genetic subtypes of Prader-Willi syndrome with growth hormone therapy on intelligence and body mass index. Butler MG, Matthews NA, Patel N, Surampalli A, Gold JA, Khare M, Thompson T, Cassidy SB, Kimonis VE
Am J Med Genet A (Jul 2019)

Prader-Willi syndrome (PWS) is a genomic imprinting disorder characterized by infantile hypotonia with a poor suck and failure to thrive, hypogenitalism/hypogonadism, behavior and cognitive problems, hormone deficiencies, hyperphagia, and obesity. The Stanford Binet and Wechsler (WAIS-R; WISC-III) intelligence (IQ) tests were administered on 103 individuals with PWS from two separate cohorts [University of California, Irvine (UCI) (N = 56) and Vanderbilt University (N = 47)] and clinical information obtained including growth hormone (GH) treatment, PWS molecular classes, weight and height. Significantly higher IQ scores (p < .02) were found representing the vocabulary section of the Stanford Binet test in the growth hormone (GH) treated group when compared with non-GH treatment in the pediatric-based UCI PWS cohort with a trend for stabilization of vocabulary IQ scores with age in the GH treated maternal disomy (UPD) 15 subject group. Significant differences (p = .05) were also found in the adult-based Vanderbilt PWS cohort with 15q11-q13 deletion subjects having lower Verbal IQ scores compared with UPD 15. No difference in body mass index was identified based on the PWS molecular class or genetic subtype. Medical care and response to treatment with growth hormone may influence intelligence impacted by PWS genetic subtypes and possibly age, but more studies are needed.]]> Wed, 31 Dec 1969 19:00:00 EST Meg3-DMR, not the Meg3 gene, regulates imprinting of the Dlk1-Dio3 locus. Zhu W, Botticelli EK, Kery RE, Mao Y, Wang X, Yang A, Wang X, Zhou J, Zhang X, Soberman RJ, Klibanski A, Zhou Y
Dev Biol (Jul 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 Transcriptional regulation of normal human mammary cell heterogeneity and its perturbation in breast cancer. Pellacani D, Tan S, Lefort S, Eaves CJ
EMBO J (Jul 2019)

The mammary gland in adult women consists of biologically distinct cell types that differ in their surface phenotypes. Isolation and molecular characterization of these subpopulations of mammary cells have provided extensive insights into their different transcriptional programs and regulation. This information is now serving as a baseline for interpreting the heterogeneous features of human breast cancers. Examination of breast cancer mutational profiles further indicates that most have undergone a complex evolutionary process even before being detected. The consequent intra-tumoral as well as inter-tumoral heterogeneity of these cancers thus poses major challenges to deriving information from early and hence likely pervasive changes in potential therapeutic interest. Recently described reproducible and efficient methods for generating human breast cancers de novo in immunodeficient mice transplanted with genetically altered primary cells now offer a promising alternative to investigate initial stages of human breast cancer development. In this review, we summarize current knowledge about key transcriptional regulatory processes operative in these partially characterized subpopulations of normal human mammary cells and effects of disrupting these processes in experimentally produced human breast cancers.]]> Wed, 31 Dec 1969 19:00:00 EST Network-Based Integrative Analysis of Genomics, Epigenomics and Transcriptomics in Autism Spectrum Disorders. Di Nanni N, Bersanelli M, Cupaioli FA, Milanesi L, Mezzelani A, Mosca E
Int J Mol Sci (Jul 2019)

Current studies suggest that autism spectrum disorders (ASDs) may be caused by many genetic factors. In fact, collectively considering multiple studies aimed at characterizing the basic pathophysiology of ASDs, a large number of genes has been proposed. Addressing the problem of molecular data interpretation using gene networks helps to explain genetic heterogeneity in terms of shared pathways. Besides, the integrative analysis of multiple omics has emerged as an approach to provide a more comprehensive view of a disease. In this work, we carry out a network-based meta-analysis of the genes reported as associated with ASDs by studies that involved genomics, epigenomics, and transcriptomics. Collectively, our analysis provides a prioritization of the large number of genes proposed to be associated with ASDs, based on genes' relevance within the intracellular circuits, the strength of the supporting evidence of association with ASDs, and the number of different molecular alterations affecting genes. We discuss the presence of the prioritized genes in the SFARI (Simons Foundation Autism Research Initiative) database and in gene networks associated with ASDs by other investigations. Lastly, we provide the full results of our analyses to encourage further studies on common targets amenable to therapy.]]> Wed, 31 Dec 1969 19:00:00 EST miR-412-5p targets Xpo1 to regulate angiogenesis in hemorrhoid tissue. Wang C, Lu H, Luo C, Song C, Wang Q, Peng Y, Xin Y, Liu T, Yang W
Gene (Jul 2019)

Hemorrhoid is a common and recurrent proctological disease, which is often accompanied by angiogenesis and edema. MicroRNAs in the DLK1-DIO3 imprinted clusters are involved in the development and pathogenesis of mammalian hemorrhoids. Results of the present study indicated multiple, differential expression of DLK1-DIO3 imprinted cluster microRNA between hemorrhoid and normal tissues, where miR-412-5p expression in hemorrhoid tissue was significantly decreased. Fluorescein reporter assays showed that miR-412-5p silenced Xpo1 mRNA expression by targeting its 3'-UTR. Overexpression of miR-412-5p in human umbilical vein endothelial cells (HUVECs) indicated that proliferation, migration and formation of vascular structures in HUVECs were inhibited in vitro. In addition, overexpression of miR-412-5p significantly inhibited Xpo1 expression and promoted upregulation of the p53 protein and its retention in the nucleus. Simultaneously, expression of p66 and p16 proteins was activated. In summary, downregulation of endogenous miR-412-5p expression in hemorrhoid vascular endothelial cells leads to high expression of the target gene Xpo1 and translocation of the p53 protein out of the nucleus, rendering it unable to activate p66 and p16. This ultimately weakens regulation of the vascular endothelial cell cycle, thereby accelerating the division of hemorrhoid vascular endothelial cells, leading to angiogenesis.]]> Wed, 31 Dec 1969 19:00:00 EST Genome imprinting in stem cells: A mini-review. Godini R, Karami K, Fallahi H
Gene Expr Patterns (Jul 2019)

Genomic imprinting is an epigenetic process result in silencing of one of the two alleles (maternal or paternal) based on the parent of origin. Dysregulation of imprinted genes results in detectable developmental and differential abnormalities. Epigenetics erasure is required for resetting the cell identity to a ground state during the production of induced pluripotent stem (iPS) cells from somatic cells. There are some contradictory reports regarding the status of the imprinting marks in the genome of iPS cells. Additionally, many studies highlighted the existence of subtle differences in the imprinting loci between different types of iPS cells and embryonic stem (ES) cells. These observations could ultimately undermine the use of patient-derived iPS cells for regenerative medicine.]]> Wed, 31 Dec 1969 19:00:00 EST Regulation of cytochrome P450 expression by microRNAs and long non coding RNAs: Epigenetic mechanisms in environmental toxicology and carcinogenesis. Li D, Tolleson WH, Yu D, Chen S, Guo L, Xiao W, Tong W, Ning B
J Environ Sci Health C Environ Carcinog Ecotoxicol Rev (Jul 2019)

Environmental exposures to hazardous chemicals are associated with a variety of human diseases and disorders, including cancers. Phase I metabolic activation and detoxification reactions catalyzed by cytochrome P450 enzymes (CYPs) affect the toxicities of many xenobiotic compounds. Proper regulation of CYP expression influences their biological effects. Noncoding RNAs (ncRNAs) are involved in regulating CYP expression, and ncRNA expression is regulated in response to environmental chemicals. The mechanistic interactions between ncRNAs and CYPs associated with the toxicity and carcinogenicity of environmental chemicals are described in this review, focusing on microRNA-dependent CYP regulation. The role of long noncoding RNAs in regulating CYP expression is also presented and new avenues of research concerning this regulatory mechanism are described.]]> Wed, 31 Dec 1969 19:00:00 EST NUCLIZE for quantifying epigenome: generating histone modification data at single-nucleosome resolution using genuine nucleosome positions. Zheng D, Trynda J, Sun Z, Li Z
BMC Genomics (Jul 2019)

Defining histone modification at single-nucleosome resolution provides accurate epigenomic information in individual nucleosomes. However, most of histone modification data deposited in current databases, such as ENCODE and Roadmap, have low resolution with peaks of several kilo-base pairs (kb), which due to the technical defects of regular ChIP-Seq technology.]]> Wed, 31 Dec 1969 19:00:00 EST