'; ?> 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, 22 Jul 2018 21:46:01 EDT Sun, 22 Jul 2018 21:46:01 EDT jirtle@radonc.duke.edu james001@jirtle.com Evolutionary Changes in Transcriptional Regulation: Insights into Human Behavior and Neurological Conditions. Doan RN, Shin T, Walsh CA
Annu Rev Neurosci (Jul 2018)

Understanding the biological basis for human-specific cognitive traits presents both immense challenges and unique opportunities. Although the question of what makes us human has been investigated with several different methods, the rise of comparative genomics, epigenomics, and medical genetics has provided tools to help narrow down and functionally assess the regions of the genome that seem evolutionarily relevant along the human lineage. In this review, we focus on how medical genetic cases have provided compelling functional evidence for genes and loci that appear to have interesting evolutionary signatures in humans. Furthermore, we examine a special class of noncoding regions, human accelerated regions (HARs), that have been suggested to show human-lineage-specific divergence, and how the use of clinical and population data has started to provide functional information to examine these regions. Finally, we outline methods that provide new insights into functional noncoding sequences in evolution.]]>
Wed, 31 Dec 1969 19:00:00 EST
Aberrant imprinting may underlie evolution of parthenogenesis. Kirioukhova O, Shah JN, Larsen DS, Tayyab M, Mueller NE, Govind G, Baroux C, Federer M, Gheyselinck J, Barrell PJ, Ma H, Sprunck S, Huettel B, Wallace H, Grossniklaus U, Johnston AJ
Sci Rep (Jul 2018)

Genomic imprinting confers parent-of-origin-specific gene expression, thus non-equivalent and complementary function of parental genomes. As a consequence, genomic imprinting poses an epigenetic barrier to parthenogenesis in sexual organisms. We report aberrant imprinting in Boechera, a genus in which apomicts evolved from sexuals multiple times. Maternal activation of a MADS-box gene, a homolog of which is imprinted and paternally expressed in the sexual relative Arabidopsis, is accompanied by locus-specific DNA methylation changes in apomicts where parental imprinting seems to be relaxed.]]>
Wed, 31 Dec 1969 19:00:00 EST
'Omic' technologies as a helpful tool in radioecological research. Volkova PY, Geras'kin SA
J Environ Radioact (Sep 2018)

This article presents a brief review of the modern 'omic' technologies, namely genomics, epigenomics, transcriptomics, proteomics, and metabolomics, as well as the examples of their possible use in radioecology. For each technology, a short description of advances, limitations, and instrumental applications is given. In addition, the review contains examples of successful use of 'omic' technologies in the assessment of biological effects of pollutants in the field conditions.]]>
Wed, 31 Dec 1969 19:00:00 EST
The effects of DNA methylation on human psychology. Kader F, Ghai M, Maharaj L
Behav Brain Res (07 2018)

DNA methylation is a fundamental epigenetic modification in the human genome; pivotal in development, genomic imprinting, X inactivation, chromosome stability, gene expression and methylation aberrations are involved in an array of human diseases. Methylation at promoters is associated with transcriptional repression, whereas gene body methylation is generally associated with gene expression. Extrinsic factors such as age, diets and lifestyle affect DNA methylation which consequently alters gene expression. Stress, anxiety, depression, life satisfaction, emotion among numerous other psychological factors also modify DNA methylation patterns. This correlation is frequently investigated in four candidate genes; NR3C1, SLC6A4, BDNF and OXTR, since regulation of these genes directly impact responses to social situations, stress, threats, behaviour and neural functions. Such studies underpin the hypothesis that DNA methylation is involved in deviant human behaviour, psychological and psychiatric conditions. These candidate genes may be targeted in future to assess the correlation between methylation, social experiences and long-term behavioural phenotypes in humans; and may potentially serve as biomarkers for therapeutic intervention.]]>
Wed, 31 Dec 1969 19:00:00 EST
Biospecimens and the ABCD study: Rationale, methods of collection, measurement and early data. Uban KA, Horton MK, Jacobus J, Heyser C, Thompson WK, Tapert SF, Madden PAF, Sowell ER,  
Dev Cogn Neurosci (Aug 2018)

Biospecimen collection in the Adolescent Brain Cognitive Development (ABCD) study - of hair samples, shed deciduous (baby) teeth, and body fluids - will serve dual functions of screening for study eligibility, and providing measures of biological processes thought to predict or correlate with key study outcomes on brain and cognitive development. Biosamples are being collected annually to screen for recency of drug use prior to the neuroimaging or cognitive testing visit, and to store for the following future studies: (1) on the effects of exposure to illicit and recreational drugs (including alcohol and nicotine); (2) of pubertal hormones on brain and cognitive developmental trajectories; (3) on the contribution of genomics and epigenomics to child and adolescent development and behavioral outcomes; and (4) with pre- and post-natal exposure to environmental neurotoxicants and drugs of abuse measured from novel tooth analyses. The present manuscript describes the rationales for inclusion and selection of the specific biospecimens, methodological considerations for each measure, future plans for assessment of biospecimens during follow-up visits, and preliminary ABCD data to illustrate methodological considerations.]]>
Wed, 31 Dec 1969 19:00:00 EST
Multi-omics analyses reveal epigenomics basis for cotton somatic embryogenesis through successive regeneration acclimation (SRA) process. Li J, Wang M, Li Y, Zhang Q, Lindsey K, Daniell H, Jin S, Zhang X
Plant Biotechnol J (Jul 2018)

Plant regeneration via somatic embryogenesis is time-consuming and highly genotype-dependent. The plant somatic embryogenesis process provokes many epigenetics changes including DNA methylation and histone modification. Recently, an elite cotton Jin668, with an extremely high regeneration ability, was developed from its maternal inbred Y668 cultivar using a Successive Regeneration Acclimation (SRA) strategy. To reveal the underlying mechanism of SRA, we carried out a genome-wide single-base resolution methylation analysis for non-embryogenic calluses (NECs), ECs, somatic embryos (SEs) during the somatic embryogenesis procedure and the leaves of regenerated offspring plants. Jin668 (R4) regenerated plants were CHH hypomethylated compared with the R0 regenerated plants of SRA process. The increase of CHH methylation from NEC to EC were demonstrated to be associated with the RNA-dependent DNA methylation (RdDM) and the H3K9me2-dependent pathway. Intriguingly, the hypomethylated CHH differentially methylated regions (DMRs) of promoter activated some hormone-related and WUSCHEL-related homeobox genes during the somatic embryogenesis process. Inhibiting DNA methylation using zebularine treatment in NEC increased the number of embryos. Our multi-omics data provide new insights into the dynamics of DNA methylation during the plant tissue culture and regenerated offspring plants. This study also reveals that induced hypomethylation (SRA) may faciliate the higher plant regeneration ability and optimize maternal genetic cultivar. This article is protected by copyright. All rights reserved.]]>
Wed, 31 Dec 1969 19:00:00 EST
Fibrosis: Lessons from OMICS analyses of the human lung. Yu G, Ibarra GH, Kaminski N
Matrix Biol (Aug 2018)

In recent decades there has been a significant shift in our understanding of idiopathic pulmonary fibrosis (IPF), a progressive and lethal disorder. While initially much of the mechanistic understanding was derived from hypotheses generated from animal models of disease, in recent decades new insights derived from humans with IPF have taken precedence. This is mainly because of the establishment of large collections of IPF lung tissues and patient cohorts, and the emergence of high throughput profiling technologies collectively termed 'omics' technologies based on their shared suffix. In this review we describe impacts of 'omics' analyses of human IPF samples on our understanding of the disease. In particular, we discuss the results of genomics and transcriptomics studies, as well as proteomics, epigenomics and metabolomics. We then describe how these findings can be integrated in a modified paradigm of human idiopathic pulmonary fibrosis, that introduces the 'hallmarks of aging' as a central theme in the IPF lung. This allows resolution of all the disparate cellular and molecular features in IPF, from the central role of epithelial cells, through the dramatic phenotypic alterations observed in fibroblasts and the numerous aberrations that inflammatory cells exhibit. We end with reiterating a call for renewed efforts to collect and analyze carefully characterized human tissues, in ways that would facilitate implementation of novel technologies for high resolution single cell omics profiling.]]>
Wed, 31 Dec 1969 19:00:00 EST
Epigenetic Control of Interleukin-9 in Asthma. Lloyd CM, Harker JA
N Engl J Med (07 2018)

Wed, 31 Dec 1969 19:00:00 EST
Placental Defects: An Epigenetic Perspective. Deshpande SS, Balasinor NH
Reprod Sci (Aug 2018)

Placenta, the first organ to be formed during gestation, plays a crucial role in intrauterine regulation of fetal growth and is involved in several functions during fetal development such as exchange of nutrients, wastes, and gases; protection against maternal immune rejection; and various metabolic and endocrine functions. Several studies have shown the regulation of epigenetic factors and the phenomenon of genomic imprinting in placentation and embryogenesis. Any gain or loss of imprint marks in the placenta has been shown to associate with severe placental defects which in turn affect both the mother and the growing fetus and can have long-term effects during adulthood. Using candidate and genome-wide high throughput approaches, several studies have shown association between aberrant epigenetic factors in the form of DNA methylation, histone modifications, and non-coding RNAs and placental defects in both human and animal models as well as using in vitro studies. In the current review, we discuss several placenta-related pathophysiologies and their association with various aberrant epigenetic factors and gene expression patterns in both in vivo and in vitro systems. This review will help the researchers gain insight into the recent evidences in the area of placentation and epigenetics and to design novel strategies to study and prevent the defects in this underestimated organ.]]>
Wed, 31 Dec 1969 19:00:00 EST
OBscure but not OBsolete: Perturbations of the frontal cortex in common between rodent olfactory bulbectomy model and major depression. Rajkumar R, Dawe GS
J Chem Neuroanat (Sep 2018)

Olfactory bulbectomy (OBX) has been used as a model of depression over several decades. This model presupposes a mechanism that is still not proven in clinical depression. A wealth of clinical literature has focused on the derangements in frontal cortex (prefrontal, orbitofrontal and anterior cingulate cortices) associated with depression. In this comprehensive review, anatomical, electrophysiological and molecular sequelae of bulbectomy in the rodent frontal cortex are explored and compared with findings on brains of humans with major depression. Certain commonalities in neurobiological features of the perturbed frontal cortex in the bulbectomised rodent and the depressed human brain are evident. Also, meta-analysis reports on clinical studies on depressed patients provide prima facie evidence that perturbations in the frontal cortex are associated with major depression. Analysing the pattern of perturbations in the chemical neuroanatomy of the frontal cortex will contribute to understanding of the neurobiology of depression. Revisiting the OBX model of depression to examine these neurobiological changes in frontal cortex with contemporary imaging, proteomics, lipidomics, metabolomics and epigenomics technologies is proposed as an approach to enhance the translational value of this animal model to facilitate identification of targets and biomarkers for clinical depression.]]>
Wed, 31 Dec 1969 19:00:00 EST
Epigenomic profiling of non-small cell lung cancer xenografts uncover LRP12 DNA methylation as predictive biomarker for carboplatin resistance. Grasse S, Lienhard M, Frese S, Kerick M, Steinbach A, Grimm C, Hussong M, Rolff J, Becker M, Dreher F, Schirmer U, Boerno S, Ramisch A, Leschber G, Timmermann B, Grohé C, Lüders H, Vingron M, Fichtner I, Klein S, Odenthal M, Büttner R, Lehrach H, Sültmann H, Herwig R, Schweiger MR
Genome Med (Jul 2018)

Non-small cell lung cancer (NSCLC) is the most common cause of cancer-related deaths worldwide and is primarily treated with radiation, surgery, and platinum-based drugs like cisplatin and carboplatin. The major challenge in the treatment of NSCLC patients is intrinsic or acquired resistance to chemotherapy. Molecular markers predicting the outcome of the patients are urgently needed.]]>
Wed, 31 Dec 1969 19:00:00 EST
Incomplete methylation of a germ cell tumor (Seminoma) in a Prader-Willi male. Eldar-Geva T, Gross-Tsur V, Hirsch HJ, Altarescu G, Segal R, Zeligson S, Golomb E, Epsztejn-Litman S, Eiges R
Mol Genet Genomic Med (Jul 2018)

Prader-Willi syndrome (PWS) is a multisystem genetic disorder characterized by lack of satiety leading to morbid obesity, variable degrees of mental retardation, behavior disorders, short stature, and hypogonadism. The underlying genetic cause for PWS is an imprinting defect resulting from a lack of expression of several paternally inherited genes embedded within the 15q11.2-q13 region. Although the clinical expression of hypogonadism in PWS is variable, there are no known cases of fertility in PWS men. In this paper, we described a pure, nearly diploid seminoma in an apparently 32 year-old infertile man with PWS due to maternal uniparental disomy (UPD) on chromosome 15. The development of a germ cell tumor in this subject was an unanticipated result. The aim of this study was to explore the origin of the germ cell tumor in this PWS male patient.]]>
Wed, 31 Dec 1969 19:00:00 EST
Nucleoporin 107, 62 and 153 mediate Kcnq1ot1 imprinted domain regulation in extraembryonic endoderm stem cells. Sachani SS, Landschoot LS, Zhang L, White CR, MacDonald WA, Golding MC, Mann MRW
Nat Commun (Jul 2018)

Genomic imprinting is a phenomenon that restricts transcription to predominantly one parental allele. How this transcriptional duality is regulated is poorly understood. Here we perform an RNA interference screen for epigenetic factors involved in paternal allelic silencing at the Kcnq1ot1 imprinted domain in mouse extraembryonic endoderm stem cells. Multiple factors are identified, including nucleoporin 107 (NUP107). To determine NUP107's role and specificity in Kcnq1ot1 imprinted domain regulation, we deplete Nup107, as well as Nup62, Nup98/96 and Nup153. Nup107, Nup62 and Nup153, but not Nup98/96 depletion, reduce Kcnq1ot1 noncoding RNA volume, displace the Kcnq1ot1 domain from the nuclear periphery, reactivate a subset of normally silent paternal alleles in the domain, alter histone modifications with concomitant changes in KMT2A, EZH2 and EHMT2 occupancy, as well as reduce cohesin interactions at the Kcnq1ot1 imprinting control region. Our results establish an important role for specific nucleoporins in mediating Kcnq1ot1 imprinted domain regulation.]]>
Wed, 31 Dec 1969 19:00:00 EST
Molecular biomarkers in gastro-esophageal cancer: recent developments, current trends and future directions. Battaglin F, Naseem M, Puccini A, Lenz HJ
Cancer Cell Int (2018)

Gastro-esophageal adenocarcinomas (GEA) represent a severe global health burden and despite improvements in the multimodality treatment of these malignancies the prognosis of patients remains poor. HER2 overexpression/amplification has been the first predictive biomarker approved in clinical practice to guide patient selection for targeted treatment with trastuzumab in advanced gastric and gastro-esophageal junction cancers. More recently, immunotherapy has been approved for the treatment of GEA and PD-L1 expression is now a biomarker required for the administration of pembrolizumab in these diseases. Significant progress has been made in recent years in dissecting the genomic makeup of GEA in order to identify distinct molecular subtypes linked to distinct patterns of molecular alterations. GEA have been found to be highly heterogeneous malignances, representing a challenge for biomarkers discovery and targeted treatment development. The current review focuses on an overview of established and novel promising biomarkers in GEA, covering recent molecular classifications from TCGA and ACRG. Main elements of molecular heterogeneity are discussed, as well as emerging mechanisms of primary and secondary resistance to HER2 targeted treatment and recent biomarker-driven trials. Future perspectives on the role of epigenetics, miRNA/lncRNA and liquid biopsy, and patient-derived xenograft models as a new platform for molecular-targeted drug discovery in GEA are presented. Our knowledge on the genomic landscape of GEA continues to evolve, uncovering the high heterogeneity and deep complexity of these tumors. The availability of new technologies and the identification of promising novel biomarker will be critical to optimize targeted treatment development in a setting where therapeutic options are currently lacking. Nevertheless, clinical validation of novel biomarkers and treatment strategies still represents an issue.]]>
Wed, 31 Dec 1969 19:00:00 EST
Roles of CTCF in conformation and functions of chromosome. Liu F, Wu D, Wang X
Semin Cell Dev Biol (Jul 2018)

CCCTC-binding factor (CTCF) plays indispensable roles in transcriptional inhibition/activation, insulation, gene imprinting, and regulation of 3Dchromatin structure. CTCF contributes to formation of genome multi-dimensions, regulation of dimensional changes, or control of central signals to transcriptional networks. A large number of factors affect CTCF binding, methylation/demethylation, base mutation, or poly(adp-ribosyl)ation. CTCF is one of the most important elements in the regulation of chromatin folding by combining with CBSs in TADs in a positive-reverse or reverse-positive orders. CTCF acts as a versatile nuclear factor, a transcriptional activator or repressor, an insulator binding factor, or a regulator of genomic imprinting as required for various biological procedures. Although molecular regulatory mechanisms of CTCF in cell differentiation and disease development remains unclear, roles of CTCF in carcinogenesis have been intensively explored. There is little understanding about regulatory roles of CTCF in inflammation-associated transcriptional signaling, cell injury, organ dysfunction, and systemic responses. It is also highly expected that further in-depth studies of CTCF control mechanisms can provide better understanding of disease development and potential disease-specific biomarkers and therapeutic targets.]]>
Wed, 31 Dec 1969 19:00:00 EST
Analysis of the Paternally-Imprinted DLK1-MEG3 and IGF2-H19 Tandem Gene Loci in NT2 Embryonal Carcinoma Cells Identifies DLK1 as a Potential Therapeutic Target. Sellers ZP, Schneider G, Maj M, Ratajczak MZ
Stem Cell Rev (Jul 2018)

The paternally-imprinted genes insulin-like growth factor 2 (IGF2), H19, delta-like homologue 1 (DLK1), and maternally-expressed gene 3 (MEG3) are expressed from the tandem gene loci IGF2-H19 and DLK1-MEG3, which play crucial roles in initiating embryogenesis and development. The erasure of imprinting (EOI) at differentially methylated regions (DMRs) which regulate the expression of these genes maintains the developmental quiescence of primordial germ cells (PGCs) migrating through the embryo proper during embryogenesis and prevents them from forming teratomas. To address the potential involvement of the IGF2-H19 and DLK1-MEG3 loci in the pathogenesis of embryonal carcinoma (EC), we investigated their genomic imprinting at DMRs in the human PGC-derived EC cell line NTera-2 (NT2). We observed EOI at the IGF2-H19 locus and, somewhat to our surprise, a loss of imprinting (LOI) at the DLK1-MEG3 locus. As a result, NT2 cells express imprinted gene ratios from these loci such that there are i) low levels of the proliferation-promoting IGF2 relative to ii) high levels of the proliferation-inhibiting long noncoding RNA (lncRNA) H19 and iii) high levels of proliferation-promoting DLK1 relative to iv) low levels of the proliferation-inhibiting lncRNA MEG3. Consistent with this pattern of expression, the knockdown of DLK1 mRNA by shRNA resulted in decreased in vitro cell proliferation and in vivo tumor growth as well as decreased in vivo organ seeding by NT2 cells. Furthermore, treatment of NT2 cells with the DNA methyltransferase inhibitor 5-aza-2'-deoxycytidine (5-azaD) inhibited their proliferation. This inhibition was accompanied by changes in expression of both tandem gene sets: a decrease in the expression of DLK1 and upregulation of the proliferation-inhibiting lncRNA MEG3, and at the same time upregulation of IGF2 and downregulation of the lncRNA H19. These results suggest that the DLK1-MEG3 locus, and not the IGF2-H19 locus, drives the tumorigenicity of NT2 cells. Based on these results, we identified DLK1 as a novel treatment target for EC that could be downregulated by 5-azaD.]]>
Wed, 31 Dec 1969 19:00:00 EST
Distinct methylation profile of mucinous ovarian carcinoma reveals susceptibility to proteasome inhibitors. Liew PL, Huang RL, Weng YC, Fang CL, Hui-Ming Huang T, Lai HC
Int J Cancer (Jul 2018)

Mucinous type of epithelial ovarian cancer (MuOC) is a unique subtype with a poor survival outcome in recurrent and advanced stages. The role of type-specific epigenomics and its clinical significance remains uncertain. We analyzed the methylomic profiles of 6 benign mucinous adenomas, 24 MuOCs, 103 serous type of epithelial ovarian cancers (SeOCs) and 337 nonepithelial ovarian cancers. MuOC and SeOC exhibited distinct DNA methylation profiles comprising 101 genes, 81 of which exhibited low methylation in MuOC and were associated with the response to glucocorticoid, ATP hydrolysis-coupled proton transport, proteolysis involved in the cellular protein catabolic process and ion transmembrane transport. Hierarchical clustering analysis showed that the profiles of MuOC were similar to colorectal adenocarcinoma and stomach adenocarcinoma. Genetic interaction network analysis of differentially methylated genes in MuOC showed a dominant network module is the proteasome subunit beta (PSMB) family. Combined functional module and methylation analysis identified PSMB8 as a candidate marker for MuOC. Immunohistochemical staining of PSMB8 used to validate in 94 samples of ovarian tumors (mucinous adenoma, MuOC or SeOC) and 62 samples of gastrointestinal cancer. PSMB8 was commonly expressed in MuOC and gastrointestinal cancer samples, predominantly as strong cytoplasmic and occasionally weak nuclei staining, but was not expressed in SeOC samples. Carfilzomib, a second-generation proteasome inhibitor, suppressed MuOC cell growth in vitro. This study unveiled a mucinous-type-specific methylation profile and suggests the potential use of a proteasome inhibitor to treat MuOC.]]>
Wed, 31 Dec 1969 19:00:00 EST
Prospective Isolation of Poised iPSC Intermediates Reveals Principles of Cellular Reprogramming. Schwarz BA, Cetinbas M, Clement K, Walsh RM, Cheloufi S, Gu H, Langkabel J, Kamiya A, Schorle H, Meissner A, Sadreyev RI, Hochedlinger K
Cell Stem Cell (Jul 2018)

Cellular reprogramming converts differentiated cells into induced pluripotent stem cells (iPSCs). However, this process is typically very inefficient, complicating mechanistic studies. We identified and molecularly characterized rare, early intermediates poised to reprogram with up to 95% efficiency, without perturbing additional genes or pathways, during iPSC generation from mouse embryonic fibroblasts. Analysis of these cells uncovered transcription factors (e.g., Tfap2c and Bex2) that are important for reprogramming but dispensable for pluripotency maintenance. Additionally, we observed striking patterns of chromatin hyperaccessibility at pluripotency loci, which preceded gene expression in poised intermediates. Finally, inspection of these hyperaccessible regions revealed an early wave of DNA demethylation that is uncoupled from de novo methylation of somatic regions late in reprogramming. Our study underscores the importance of investigating rare intermediates poised to produce iPSCs, provides insights into reprogramming mechanisms, and offers a valuable resource for the dissection of transcriptional and epigenetic dynamics intrinsic to cell fate change.]]>
Wed, 31 Dec 1969 19:00:00 EST
The stimulatory G protein Gα is required in melanocortin 4 receptor-expressing cells for normal energy balance, thermogenesis, and glucose metabolism. Podyma B, Sun H, Wilson EA, Carlson B, Pritikin E, Gavrilova O, Weinstein LS, Chen M
J Biol Chem (Jul 2018)

Central melanocortin 4 receptors (MC4Rs) stimulate energy expenditure and inhibit food intake. MC4Rs activate the G protein Gα, but whether Gα mediates all MC4R actions has not been established. Individuals with Albright hereditary osteodystrophy (AHO), who have heterozygous Gα-inactivating mutations, only develop obesity when the Gα mutation is present on the maternal allele because of tissue-specific genomic imprinting. Furthermore, evidence in mice implicates Gα imprinting within the central nervous system (CNS) in this disorder. In this study, we examined the effects of Gα in MC4R-expressing cells on metabolic regulation. Mice with homozygous Gα deficiency in MC4R-expressing cells (MC4RGsKO) developed significant obesity with increased food intake and decreased energy expenditure, along with impaired insulin sensitivity and cold-induced thermogenesis. Moreover, the ability of the MC4R agonist melanotan-II (MTII) to stimulate energy expenditure and to inhibit food intake was impaired in MC4RGsKO mice. MTII failed to stimulate the secretion of the anorexigenic hormone peptide YY (PYY) from enteroendocrine L cells, a physiological response mediated by MC4R-Gα signaling, even though baseline PYY levels were elevated in these mice. In Gα heterozygotes, mild obesity and reduced energy expenditure were present only in mice with a Gα deletion on the maternal allele in MC4R-expressing cells, whereas food intake was unaffected. These results demonstrate that Gα signaling in MC4R-expressing cells is required for controlling energy balance, thermogenesis, and peripheral glucose metabolism. They further indicate that Gα imprinting in MC4R-expressing cells contributes to obesity in Gα knockout mice and probably in individuals with Albright hereditary osteodystrophy as well.]]>
Wed, 31 Dec 1969 19:00:00 EST
GWAS4D: multidimensional analysis of context-specific regulatory variant for human complex diseases and traits. Huang D, Yi X, Zhang S, Zheng Z, Wang P, Xuan C, Sham PC, Wang J, Li MJ
Nucleic Acids Res (Jul 2018)

Genome-wide association studies have generated over thousands of susceptibility loci for many human complex traits, and yet for most of these associations the true causal variants remain unknown. Tissue/cell type-specific prediction and prioritization of non-coding regulatory variants will facilitate the identification of causal variants and underlying pathogenic mechanisms for particular complex diseases and traits. By leveraging recent large-scale functional genomics/epigenomics data, we develop an intuitive web server, GWAS4D (http://mulinlab.tmu.edu.cn/gwas4d or http://mulinlab.org/gwas4d), that systematically evaluates GWAS signals and identifies context-specific regulatory variants. The updated web server includes six major features: (i) updates the regulatory variant prioritization method with our new algorithm; (ii) incorporates 127 tissue/cell type-specific epigenomes data; (iii) integrates motifs of 1480 transcriptional regulators from 13 public resources; (iv) uniformly processes Hi-C data and generates significant interactions at 5 kb resolution across 60 tissues/cell types; (v) adds comprehensive non-coding variant functional annotations; (vi) equips a highly interactive visualization function for SNP-target interaction. Using a GWAS fine-mapped set for 161 coronary artery disease risk loci, we demonstrate that GWAS4D is able to efficiently prioritize disease-causal regulatory variants.]]>
Wed, 31 Dec 1969 19:00:00 EST