Molecular mechanisms of genomic imprinting and clinical implications for cancer

2011 ◽  
Vol 13 ◽  
Author(s):  
Santiago Uribe-Lewis ◽  
Kathryn Woodfine ◽  
Lovorka Stojic ◽  
Adele Murrell
Keyword(s):  
Gene Expression ◽  
Genomic Imprinting ◽  
Noncoding Rna ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Early Event ◽  
Imprinted Genes ◽  
Epigenetic Changes ◽  
Imprinted Gene ◽  
Growth Loss

Genomic imprinting is an epigenetic marking of genes in the parental germline that ensures the stable transmission of monoallelic gene expression patterns in a parent-of-origin-specific manner. Epigenetic marking systems are thus able to regulate gene activity independently of the underlying DNA sequence. Several imprinted gene products regulate cell proliferation and fetal growth; loss of their imprinted state, which effectively alters their dosage, might promote or suppress tumourigenic processes. Conversely, global epigenetic changes that underlie tumourigenesis might affect imprinted gene expression. Here, we review imprinted genes with regard to their roles in epigenetic predisposition to cancer, and discuss acquired epigenetic changes (DNA methylation, histone modifications and chromatin conformation) either as a result of cancer or as an early event in neoplasia. We also address recent work showing the potential role of noncoding RNA in modifying chromatin and affecting imprinted gene expression, and summarise the effects of loss of imprinting in cancer with regard to the roles that imprinted genes play in regulating growth signalling cascades. Finally, we speculate on the clinical applications of epigenetic drugs in cancer.

187 IMPRINTED GENE EXPRESSION IN IN VIVO-AND IN VITRO-PRODUCED BOVINE FETUSES AND PLACENTAS

2008 ◽  
Vol 20 (1) ◽  
pp. 173
Author(s):  
F. Perecin ◽  
S. C. Méo ◽  
W. Yamazaki ◽  
C. R. Ferreira ◽  
F. H. Biase ◽  
...  
Keyword(s):  
Gene Expression ◽  
Expression Patterns ◽  
Rna Extraction ◽  
Imprinted Genes ◽  
Total Rna ◽  
Imprinted Gene ◽  
Bovine Fetuses ◽  
Low Efficiency

Some gestational alterations associated with bovine somatic cell nuclear transfer (SCNT) are presumably consequences of abnormal imprinted gene expression. This work aimed to evaluate the expression patterns of imprinted genes IGF2 and IGF2R in bovine fetuses and chorioallantoic membranes derived from in vivo- and in vitro-produced embryos. Fetuses were produced by AI (in vivo group, n = 3), IVF (n = 3), parthenogenesis (n = 3), or SCNT (n = 2). Cows with positive pregnancy diagnosis after ultrasonographic examination were slaughtered between Days 33 and 36 of gestation. The reproductive tract was transported on ice to the laboratory, where fetuses and chorioallantoic fragments were collected and stored in liquid nitrogen. Total RNA extraction was performed using TRIzol, according to manufacturer's instructions, and the reverse transcription reaction was carried out with 1 µg of total RNA, 6.75 µm oligo pd(T)12–18, and 50 U of reverse transcriptase (Improm-II, Promega, Madison, WI, USA). The relative quantification of IGF2 and IGF2R transcripts was done using real-time PCR with SYBR Green dye. The average efficiency of PCR amplifications was estimated for each gene using a linear regression on the logarithm of fluorescence per cycle (Ramakers et al. 2003 Neurosci. Lett. 339, 62–66), and the expression ratios were calculated according to the method described previously by Livak and Schmittgen (2001 Methods 25, 402–408). To verify statistical differences, a pair-wise fixed reallocation randomization test (Pfaffl et al. 2002 Nucl. Acids Res. 30, e36) was used. All expression ratios were normalized by glyceraldehyde 3-phosphate dehydrogenase expression and calibrated by the in vivo group (expression assumed as 1.00 for all genes and tissues). The analysis of relative differences on transcript levels of imprinted genes in fetuses revealed IGF2 down-regulation (P < 0.05) in the SCNT (0.19) and parthenogenetic (0.02) groups when compared to the in vivo group and IVF fetuses (2.02). In chorioallantois, IGF2 was down-regulated (P < 0.001) in parthenotes (0.001) when compared to the in vivo, IVF (3.13), and SCNT (0.98) groups. IGF2R was down-regulated (P < 0.001) in SCNT chorioallantois (0.25) when compared to the in vivo group. Low expression of IGF2 in parthenogenetic fetuses and chorioallantois confirms its imprinted status in bovine. Alterations in the relative frequency of IGF2 and IGF2R transcripts were observed in bovine SCNT-derived fetuses and chorioallantoic membranes, respectively, supporting the hypothesis that abnormalities in the expression of imprinted genes are causes for the low efficiency of SCNT procedures in this species. Such alterations suggest modifications in DNA methylation patterns at IGF2 and IGF2R imprinting centers.

Genomic imprinting and human disease

2010 ◽  
Vol 48 ◽  
pp. 187-200 ◽  
Author(s):  
Ryutaro Hirasawa ◽  
Robert Feil
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genomic Imprinting ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Germ Line ◽  
Imprinted Genes ◽  
Foetal Growth ◽  
Sequence Elements ◽  
Covalent Modifications

In many epigenetic phenomena, covalent modifications on DNA and chromatin mediate somatically heritable patterns of gene expression. Genomic imprinting is a classical example of epigenetic regulation in mammals. To date, more than 100 imprinted genes have been identified in humans and mice. Many of these are involved in foetal growth and deve lopment, others control behaviour. Mono-allelic expression of imprinted genes depends on whether the gene is inherited from the mother or the father. This remarkable pattern of expression is controlled by specialized sequence elements called ICRs (imprinting control regions). ICRs are marked by DNA methylation on one of the two parental alleles. These allelic marks originate from either the maternal or the paternal germ line. Perturbation of the allelic DNA methylation at ICRs is causally involved in several human diseases, including the Beckwith–Wiedemann and Silver–Russell syndromes, associated with aberrant foetal growth. Perturbed imprinted gene expression is also implicated in the neuro-developmental disorders Prader–Willi syndrome and Angelman syndrome. Embryo culture and human-assisted reproduction procedures can increase the occurrence of imprinting-related disorders. Recent research shows that, besides DNA methylation, covalent histone modifications and non-histone proteins also contribute to imprinting regulation. The involvement of imprinting in specific human pathologies (and in cancer) emphasizes the need to further explore the underlying molecular mechanisms.

scholarly journals Associations between imprinted gene expression in the placenta, human fetal growth and preeclampsia

2017 ◽  
Vol 13 (11) ◽  
pp. 20170643 ◽  
Author(s):  
Julian K. Christians ◽  
Katherine Leavey ◽  
Brian J. Cox
Keyword(s):  
Gene Expression ◽  
Genomic Imprinting ◽  
Fetal Growth ◽  
Placental Insufficiency ◽  
Imprinted Genes ◽  
Nutrient Allocation ◽  
Imprinted Gene ◽  
Expression Levels ◽  
Kinship Theory ◽  
Coordinated Regulation

Genomic imprinting is essential for normal placental and fetal growth. One theory to explain the evolution of imprinting is the kinship theory (KT), which predicts that genes that are paternally expressed will promote fetal growth, whereas maternally expressed genes will suppress growth. We investigated the expression of imprinted genes using microarray measurements of expression in term placentae. Correlations between birthweight and the expression levels of imprinted genes were more significant than for non-imprinted genes, but did not tend to be positive for paternally expressed genes and negative for maternally expressed genes. Imprinted genes were more dysregulated in preeclampsia (a disorder associated with placental insufficiency) than randomly selected genes, and we observed an excess of patterns of dysregulation in preeclampsia that would be expected to reduce nutrient allocation to the fetus, given the predictions of the KT. However, we found no evidence of coordinated regulation among these imprinted genes. A few imprinted genes have previously been shown to be associated with fetal growth and preeclampsia, and our results indicate that this is true for a broader set of imprinted genes.

scholarly journals 26ABERRANT REPROGRAMMING OF IMPRINTED GENE EXPRESSION IN ENLARGED PLACENTAS OF MICE CLONED FROM ES CELLS TREATED WITH TSA OR 5AZAC

2004 ◽  
Vol 16 (2) ◽  
pp. 135
Author(s):  
S.G. Baqir ◽  
Q. Zhou ◽  
A. Jouneau ◽  
J.-P. Renard ◽  
D.H. Betts ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Histone Acetylation ◽  
Nuclear Transfer ◽  
Es Cells ◽  
Expression Patterns ◽  
Gene Expression Patterns ◽  
Imprinted Genes ◽  
Imprinted Gene ◽  
Donor Cells

The success rate of producing cloned animals is very low, and in many cases is associated with the formation of enlarged placentas. Increasing evidence has pointed towards epigenetic deregulation of imprinted genes due to incomplete or abnormal resetting of DNA methylation and/or histone acetylation patterns during development. It has previously been shown that drugs that alter DNA methylation (5AzaC) and histone acetylation (TSA) over-express imprinted genes in mouse ES cells (Baqir and Smith, 2001, Theriogenology 55, 410). Our objective in this study was to determine whether nuclear transfer is able to reprogram imprinted gene expression patterns in the placenta of mice cloned from ES donor nuclei exposed to 5AzaC and TSA. ES donor cells were treated with either TSA or 5AzaC prior to injection into enucleated oocytes. Total RNA was extracted from placentas of day 14–15 fetus clones, and reversed transcribed; the expression pattern of imprinted genes (Ipl, Mash2, Igf2, H19, Igf2r, p57, Peg1), non-imprinted placental-specific genes (Esx1, Dlx3, Tpbp) and a housekeeping gene (Gapdh) was examined by Real Time PCR. Samples were standardized with an exogenous control (Globin) and expressed as fold changes in relation to placentas of cloned fetus derived from non-treated donor cells. Data were analyzed by ANOVA and mean gene expression values were compared using the Tukey-Kramer test. Our results show that several imprinted genes (Mash2, H19, Ipl) and placenta-specific genes (Esx1 and Dlx1) were properly reprogrammed in non-enlarged (71mg) placentas of fetus clones derived from the TSA and 5AzaC treated ES donor cells. Although Gapdh expression did not differ among normal and enlarged 210mg) placenta groups, the expression level of Igf2 and Mash2 was higher in enlarged placentas from fetus clones produced from TSA-treated ES donor cells (4.6 and 3.5 fold) compared to non-enlarged placentas from non-treated ES cells (1 fold). Conversely, oversized placentas from cloned fetuses derived from TSA-treated donor ES cells under-expressed Peg1, H19 and Ipl (0.5, 0.2 and 0.2 fold, respectively) compared to control placentas (1 fold). In addition, enlarged placentas from the TSA- and 5AzaC-treated group displayed down-regulation of placenta specific genes Esx1 and Dlx3 and up-regulation of Tpbp, suggesting the presence of abnormal distribution of placental layers. These results indicate that while several imprinted and non-imprinted placenta specific genes were correctly expressed in normal size placentas of fetus clones derived from TSA and 5AzaC treated donor ES cells, enlarged placentas displayed aberrant gene expression patterns, suggesting that improper resetting of the epigenetic program after nuclear transfer is directly related to altered DNA methylation and histone acetylation patterns. Funded by NSERC &amp; CIHR.

scholarly journals Genomic Imprinting of Dopa decarboxylase in Heart and Reciprocal Allelic Expression with Neighboring Grb10

2007 ◽  
Vol 28 (1) ◽  
pp. 386-396 ◽  
Author(s):  
Trevelyan R. Menheniott ◽  
Kathryn Woodfine ◽  
Reiner Schulz ◽  
Andrew J. Wood ◽  
David Monk ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
Promoter Region ◽  
Germ Line ◽  
Differential Methylation ◽  
Dopa Decarboxylase ◽  
Imprinted Genes ◽  
Chromosome 11 ◽  
Imprinted Gene ◽  
Line Methylation ◽  
Intron 1

ABSTRACT By combining a tissue-specific microarray screen with mouse uniparental duplications, we have identified a novel imprinted gene, Dopa decarboxylase (Ddc), on chromosome 11. Ddc_exon1a is a 2-kb transcript variant that initiates from an alternative first exon in intron 1 of the canonical Ddc transcript and is paternally expressed in trabecular cardiomyocytes of the embryonic and neonatal heart. Ddc displays tight conserved linkage with the maternally expressed and methylated Grb10 gene, suggesting that these reciprocally imprinted genes may be coordinately regulated. In Dnmt3L mutant embryos that lack maternal germ line methylation imprints, we show that Ddc is overexpressed and Grb10 is silenced. Their imprinting is therefore dependent on maternal germ line methylation, but the mechanism at Ddc does not appear to involve differential methylation of the Ddc_exon1a promoter region and may instead be provided by the oocyte mark at Grb10. Our analysis of Ddc redefines the imprinted Grb10 domain on mouse proximal chromosome 11 and identifies Ddc_exon1a as the first example of a heart-specific imprinted gene.

scholarly journals Genomic imprinting and its role in ethiology of human hereditary diseases

2004 ◽  
Vol 3 (3) ◽  
pp. 8-17
Author(s):  
S. A. Nazarenko
Keyword(s):  
Gene Expression ◽  
Genomic Imprinting ◽  
Special Class ◽  
Growth And Development ◽  
Epigenetic Inheritance ◽  
Hereditary Diseases ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Methylation Of Dna ◽  
Differential Gene

Genomic imprinting is a form of non-Mendelian epigenetic inheritance that is defined by differential gene expression depending on its parental origin — maternal or paternal. It is known about 60 imprinted genes many of which effect significantly on the fetus growth and development. Methylation of DNA cytosine bases that defines the interaction of DNA and proteins identifying the modified bases and controls the gene expression through chromatin compacting-decompacting mechanism, is a main epigenetic genom modifier. Disturbances in monoallelic gene expression lead to the development of a special class of human hereditary diseases — genomic imprinting diseases.

scholarly journals DNA demethylase ROS1 negatively regulates the imprinting of DOGL4 and seed dormancy in Arabidopsis thaliana

2018 ◽  
Vol 115 (42) ◽  
pp. E9962-E9970 ◽  
Author(s):  
Haifeng Zhu ◽  
Wenxiang Xie ◽  
Dachao Xu ◽  
Daisuke Miki ◽  
Kai Tang ◽  
...  
Keyword(s):  
Gene Expression ◽  
Seed Dormancy ◽  
Genomic Imprinting ◽  
Dna Demethylation ◽  
Paternal Allele ◽  
Maternal Allele ◽  
Imprinted Gene ◽  
Differential Gene ◽  
Parent Of Origin ◽  
Dna Demethylase

Genomic imprinting is a form of epigenetic regulation resulting in differential gene expression that reflects the parent of origin. In plants, imprinted gene expression predominantly occurs in the seed endosperm. Maternal-specific DNA demethylation by the DNA demethylase DME frequently underlies genomic imprinting in endosperm. Whether other more ubiquitously expressed DNA demethylases regulate imprinting is unknown. Here, we found that the DNA demethylase ROS1 regulates the imprinting of DOGL4. DOGL4 is expressed from the maternal allele in endosperm and displays preferential methylation and suppression of the paternal allele. We found that ROS1 negatively regulates imprinting by demethylating the paternal allele, preventing its hypermethylation and complete silencing. Furthermore, we found that DOGL4 negatively affects seed dormancy and response to the phytohormone abscisic acid and that ROS1 controls these processes by regulating DOGL4. Our results reveal roles for ROS1 in mitigating imprinted gene expression and regulating seed dormancy.

scholarly journals Integrative Transcriptomics Reveals Activation of Innate Immune Responses and Inhibition of Inflammation During Oral Immunotherapy for Egg Allergy in Children

2021 ◽  
Vol 12 ◽  
Author(s):  
Piia Karisola ◽  
Kati Palosuo ◽  
Victoria Hinkkanen ◽  
Lukas Wisgrill ◽  
Terhi Savinko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Clinical Outcome ◽  
Immune Responses ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Oral Immunotherapy ◽  
Innate Immune ◽  
Egg Allergy ◽  
Innate Immune Responses ◽  
Open Label

We previously reported the results of a randomized, open-label trial of egg oral immunotherapy (OIT) in 50 children where 44% were desensitized and 46% were partially desensitized after 8 months of treatment. Here we focus on cell-mediated molecular mechanisms driving desensitization during egg OIT. We sought to determine whether changes in genome-wide gene expression in blood cells during egg OIT correlate with humoral responses and the clinical outcome. The blood cell transcriptome of 50 children receiving egg OIT was profiled using peripheral blood mononuclear cell (PBMC) samples obtained at baseline and after 3 and 8 months of OIT. We identified 467 differentially expressed genes (DEGs) after 3 or 8 months of egg OIT. At 8 months, 86% of the DEGs were downregulated and played a role in the signaling of TREM1, IL-6, and IL-17. In correlation analyses, Gal d 1–4-specific IgG4 antibodies associated positively with DEGs playing a role in pathogen recognition and antigen presentation and negatively with DEGs playing a role in the signaling of IL-10, IL-6, and IL-17. Desensitized and partially desensitized patients had differences in their antibody responses, and although most of the transcriptomic changes were shared, both groups had also specific patterns, which suggest slower changes in partially desensitized and activation of NK cells in the desensitized group. OIT for egg allergy in children inhibits inflammation and activates innate immune responses regardless of the clinical outcome at 8 months. Changes in gene expression patterns first appear as posttranslational protein modifications, followed by more sustained epigenetic gene regulatory functions related to successful desensitization.

scholarly journals An animal model study on the gene expression profile of meniscal degeneration

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Yehan Fang ◽  
Hui Huang ◽  
Gang Zhou ◽  
Qinghua Wang ◽  
Feng Gao ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pathway Analysis ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Control Group ◽  
Ion Binding ◽  
Endoplasmic Reticulum Membrane ◽  
Rt Pcr ◽  
Go Analysis ◽  
Meniscal Degeneration

AbstractMeniscal degeneration is a very common condition in elderly individuals, but the underlying mechanisms of its occurrence are not completely clear. This study examines the molecular mechanisms of meniscal degeneration. The anterior cruciate ligament (ACL) and lateral collateral ligament (LCL) of the right rear limbs of seven Wuzhishan mini-pigs were resected (meniscal degeneration group), and the left rear legs were sham-operated (control group). After 6 months, samples were taken for gene chip analysis, including differentially expressed gene (DEG) analysis, gene ontology (GO) analysis, clustering analysis, and pathway analysis. The selected 12 DEGs were validated by real time reverse transcription-polymerase chain reaction (RT-PCR). The two groups showed specific and highly clustered DEGs. A total of 893 DEGs were found, in which 537 are upregulated, and 356 are downregulated. The GO analysis showed that the significantly affected biological processes include nitric oxide metabolic process, male sex differentiation, and mesenchymal morphogenesis, the significantly affected cellular components include the endoplasmic reticulum membrane, and the significantly affected molecular functions include transition metal ion binding and iron ion binding. The pathway analysis showed that the significantly affected pathways include type II diabetes mellitus, inflammatory mediator regulation of TRP channels, and AMPK signaling pathway. The results of RT-PCR indicate that the microarray data accurately reflects the gene expression patterns. These findings indicate that several molecular mechanisms are involved in the development of meniscal degeneration, thus improving our understanding of meniscal degeneration and provide molecular therapeutic targets in the future.

scholarly journals Gene Expression Patterns Underlying the Reinstatement of Plasticity in the Adult Visual System

2013 ◽  
Vol 2013 ◽  
pp. 1-8 ◽  
Author(s):  
Ettore Tiraboschi ◽  
Ramon Guirado ◽  
Dario Greco ◽  
Petri Auvinen ◽  
Jose Fernando Maya-Vetencourt ◽  
...  
Keyword(s):  
Gene Expression ◽  
Visual Cortex ◽  
Large Scale ◽  
Molecular Mechanisms ◽  
Expression Patterns ◽  
Monocular Deprivation ◽  
Adult Brain ◽  
Gene Expression Patterns ◽  
Postnatal Life ◽  
Critical Periods

The nervous system is highly sensitive to experience during early postnatal life, but this phase of heightened plasticity decreases with age. Recent studies have demonstrated that developmental-like plasticity can be reactivated in the visual cortex of adult animals through environmental or pharmacological manipulations. These findings provide a unique opportunity to study the cellular and molecular mechanisms of adult plasticity. Here we used the monocular deprivation paradigm to investigate large-scale gene expression patterns underlying the reinstatement of plasticity produced by fluoxetine in the adult rat visual cortex. We found changes, confirmed with RT-PCRs, in gene expression in different biological themes, such as chromatin structure remodelling, transcription factors, molecules involved in synaptic plasticity, extracellular matrix, and excitatory and inhibitory neurotransmission. Our findings reveal a key role for several molecules such as the metalloproteases Mmp2 and Mmp9 or the glycoprotein Reelin and open up new insights into the mechanisms underlying the reopening of the critical periods in the adult brain.

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