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 Divergence among rice cultivars reveals roles for transposition and epimutation in ongoing evolution of genomic imprinting

2021 ◽  
Vol 118 (29) ◽  
pp. e2104445118
Author(s):  
Jessica A. Rodrigues ◽  
Ping-Hung Hsieh ◽  
Deling Ruan ◽  
Toshiro Nishimura ◽  
Manoj K. Sharma ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Genomic Imprinting ◽  
Small Rnas ◽  
Imprinted Genes ◽  
Dna Hypomethylation ◽  
Transcription Start ◽  
Specific Expression ◽  
Parent Of Origin

Parent-of-origin–dependent gene expression in mammals and flowering plants results from differing chromatin imprints (genomic imprinting) between maternally and paternally inherited alleles. Imprinted gene expression in the endosperm of seeds is associated with localized hypomethylation of maternally but not paternally inherited DNA, with certain small RNAs also displaying parent-of-origin–specific expression. To understand the evolution of imprinting mechanisms in Oryza sativa (rice), we analyzed imprinting divergence among four cultivars that span both japonica and indica subspecies: Nipponbare, Kitaake, 93-11, and IR64. Most imprinted genes are imprinted across cultivars and enriched for functions in chromatin and transcriptional regulation, development, and signaling. However, 4 to 11% of imprinted genes display divergent imprinting. Analyses of DNA methylation and small RNAs revealed that endosperm-specific 24-nt small RNA–producing loci show weak RNA-directed DNA methylation, frequently overlap genes, and are imprinted four times more often than genes. However, imprinting divergence most often correlated with local DNA methylation epimutations (9 of 17 assessable loci), which were largely stable within subspecies. Small insertion/deletion events and transposable element insertions accompanied 4 of the 9 locally epimutated loci and associated with imprinting divergence at another 4 of the remaining 8 loci. Correlating epigenetic and genetic variation occurred at key regulatory regions—the promoter and transcription start site of maternally biased genes, and the promoter and gene body of paternally biased genes. Our results reinforce models for the role of maternal-specific DNA hypomethylation in imprinting of both maternally and paternally biased genes, and highlight the role of transposition and epimutation in rice imprinting evolution.

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.

scholarly journals Cell–cell coupling and DNA methylation abnormal phenotypes in the after-hours mice

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Federico Tinarelli ◽  
Elena Ivanova ◽  
Ilaria Colombi ◽  
Erica Barini ◽  
Edoardo Balzani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Neuronal Networks ◽  
Molecular Mechanisms ◽  
Ex Vivo ◽  
Neuronal Cultures ◽  
Functional Impairments ◽  
After Hours ◽  
The Impact

Abstract Background DNA methylation has emerged as an important epigenetic regulator of brain processes, including circadian rhythms. However, how DNA methylation intervenes between environmental signals, such as light entrainment, and the transcriptional and translational molecular mechanisms of the cellular clock is currently unknown. Here, we studied the after-hours mice, which have a point mutation in the Fbxl3 gene and a lengthened circadian period. Methods In this study, we used a combination of in vivo, ex vivo and in vitro approaches. We measured retinal responses in Afh animals and we have run reduced representation bisulphite sequencing (RRBS), pyrosequencing and gene expression analysis in a variety of brain tissues ex vivo. In vitro, we used primary neuronal cultures combined to micro electrode array (MEA) technology and gene expression. Results We observed functional impairments in mutant neuronal networks, and a reduction in the retinal responses to light-dependent stimuli. We detected abnormalities in the expression of photoreceptive melanopsin (OPN4). Furthermore, we identified alterations in the DNA methylation pathways throughout the retinohypothalamic tract terminals and links between the transcription factor Rev-Erbα and Fbxl3. Conclusions The results of this study, primarily represent a contribution towards an understanding of electrophysiological and molecular phenotypic responses to external stimuli in the Afh model. Moreover, as DNA methylation has recently emerged as a new regulator of neuronal networks with important consequences for circadian behaviour, we discuss the impact of the Afh mutation on the epigenetic landscape of circadian biology.

scholarly journals Genomic imprinting in germ cells: imprints are under control

Reproduction ◽  
2010 ◽  
Vol 140 (3) ◽  
pp. 411-423 ◽  
Author(s):  
Philippe Arnaud
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Germ Cells ◽  
Imprinted Genes ◽  
Regulatory Sequences ◽  
Sequence Specificity ◽  
Maternal Allele ◽  
Primary Sequence ◽  
Chromatin Configuration

The cis-acting regulatory sequences of imprinted gene loci, called imprinting control regions (ICRs), acquire specific imprint marks in germ cells, including DNA methylation. These epigenetic imprints ensure that imprinted genes are expressed exclusively from either the paternal or the maternal allele in offspring. The last few years have witnessed a rapid increase in studies on how and when ICRs become marked by and subsequently maintain such epigenetic modifications. These novel findings are summarised in this review, which focuses on the germline acquisition of DNA methylation imprints and particularly on the combined role of primary sequence specificity, chromatin configuration, non-histone proteins and transcriptional events.

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 Mutant p63 affects epidermal cell identity through rewiring the enhancer landscape

2018 ◽  
Author(s):  
Jieqiong Qu ◽  
Sabine Tanis ◽  
Jos P.H. Smits ◽  
Evelyn N. Kouwenhoven ◽  
Martin Oti ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Binding ◽  
Epidermal Cell ◽  
Developmental Disorders ◽  
Molecular Mechanisms ◽  
Epidermal Keratinocytes ◽  
Cell Identity ◽  
Keratinocyte Proliferation ◽  
Eec Syndrome ◽  
Proliferation And Differentiation

AbstractTranscription factor p63 is a key regulator of epidermal keratinocyte proliferation and differentiation. In humans mutations in p63 cause several developmental disorders with defects of ectoderm-derived structures including the epidermis. The underlying molecular mechanisms of these mutations however remain unclear. Here we characterized the transcriptome and epigenome from EEC syndrome patients carrying mutations in the p63 DNA-binding domain. The transcriptome of p63 mutant keratinocytes deviated from the normal epidermal cell identity. Epigenomic analyses showed that the deregulated gene expression in p63 mutant keratinocytes resulted from an altered enhancer landscape contributed by loss of p63-bound active enhancers and by unexpected gain of enhancers. The gained enhancers in mutant keratinocytes were frequently bound by deregulated transcription factors such as RUNX1. Reversing RUNX1 overexpression partially rescued deregulated gene expression as well as the enhancer distribution. Our findings support the pivotal role of p63 in controlling the enhancer landscape of epidermal keratinocytes and identify a novel mechanism whereby p63 DNA-binding mutations associated with EEC syndrome rewire the enhancer landscape and affect epidermal cell identity.

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 The H19 Differentially Methylated Region Marks the Parental Origin of a Heterologous Locus without Gametic DNA Methylation

2004 ◽  
Vol 24 (9) ◽  
pp. 3588-3595 ◽  
Author(s):  
Kye-Yoon Park ◽  
Elizabeth A. Sellars ◽  
Alexander Grinberg ◽  
Sing-Ping Huang ◽  
Karl Pfeifer
Keyword(s):  
Dna Methylation ◽  
Mouse Chromosome ◽  
Germ Line ◽  
Transcriptional Silencing ◽  
Chromosome 7 ◽  
Differentially Methylated Region ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Chromosome 5 ◽  
The Third

ABSTRACT Igf2 and H19 are coordinately regulated imprinted genes physically linked on the distal end of mouse chromosome 7. Genetic analyses demonstrate that the differentially methylated region (DMR) upstream of the H19 gene is necessary for three distinct functions: transcriptional insulation of the maternal Igf2 allele, transcriptional silencing of paternal H19 allele, and marking of the parental origin of the two chromosomes. To test the sufficiency of the DMR for the third function, we inserted DMR at two heterologous positions in the genome, downstream of H19 and at the alpha-fetoprotein locus on chromosome 5. Our results demonstrate that the DMR alone is sufficient to act as a mark of parental origin. Moreover, this activity is not dependent on germ line differences in DMR methylation. Thus, the DMR can mark its parental origin by a mechanism independent of its own DNA methylation.

scholarly journals Methylation pattern polymorphism of cyp19a in Nile tilapia and hybrids

2018 ◽  
Vol 13 (1) ◽  
pp. 327-334 ◽  
Author(s):  
Xiaowu Chen ◽  
Yonghua Zhao ◽  
Yudong He ◽  
Jinliang Zhao
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Methylation Level ◽  
Molecular Mechanisms ◽  
Methylation Pattern ◽  
Male Ratio ◽  
Sex Development ◽  
Pattern Polymorphism ◽  
Fish Hybrids

AbstractSkewed sex development is prevalent in fish hybrids. However, the histological observation and molecular mechanisms remain elusive. In this study, we showed that the interspecific hybrids of the two fish species, Oreochromis niloticus and Oreochromis aureus, had a male ratio of 98.02%. Microscopic examination revealed that the gonads of both male and female hybrids were developmentally retarded. Compared with the ovaries, the testes of both O. niloticus and hybrids showed higher DNA methylation level in two selected regions in the promoter of cyp19a, the gonadal aromatase gene that converts androgens into estrogens, cyp19a showed higher level gene expression in the ovary than in the testis in both O. niloticus and hybrid tilapia. Methylation and gene expression level of cyp19a were negative correlation between the testis and ovary. Gene transcription was suppressed by the methylation of the cyp19a promoter in vitro. While there is no obvious difference of the methylation level in testis or ovary between O. niloticus and hybrids. Thus, the DNA methylation of the promoter of cyp19a may be an essential component of the sex maintenance, but not a determinant of high male ratio and developmental retardation of gonads in tilapia hybrids.

scholarly journals Smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic traits

2020 ◽  
Vol 12 (1) ◽  
Author(s):  
Silvana C. E. Maas ◽  
Michelle M. J. Mens ◽  
Brigitte Kühnel ◽  
Joyce B. J. van Meurs ◽  
André G. Uitterlinden ◽  
...  
Keyword(s):  
Gene Expression ◽  
Dna Methylation ◽  
Association Study ◽  
Multiple Testing ◽  
Molecular Mechanisms ◽  
Mediation Effect ◽  
Rotterdam Study ◽  
Versus Gene ◽  
Metabolic Trait ◽  
Metabolic Traits

Abstract Background Tobacco smoking is a well-known modifiable risk factor for many chronic diseases, including cardiovascular disease (CVD). One of the proposed underlying mechanism linking smoking to disease is via epigenetic modifications, which could affect the expression of disease-associated genes. Here, we conducted a three-way association study to identify the relationship between smoking-related changes in DNA methylation and gene expression and their associations with cardio-metabolic traits. Results We selected 2549 CpG sites and 443 gene expression probes associated with current versus never smokers, from the largest epigenome-wide association study and transcriptome-wide association study to date. We examined three-way associations, including CpG versus gene expression, cardio-metabolic trait versus CpG, and cardio-metabolic trait versus gene expression, in the Rotterdam study. Subsequently, we replicated our findings in The Cooperative Health Research in the Region of Augsburg (KORA) study. After correction for multiple testing, we identified both cis- and trans-expression quantitative trait methylation (eQTM) associations in blood. Specifically, we found 1224 smoking-related CpGs associated with at least one of the 443 gene expression probes, and 200 smoking-related gene expression probes to be associated with at least one of the 2549 CpGs. Out of these, 109 CpGs and 27 genes were associated with at least one cardio-metabolic trait in the Rotterdam Study. We were able to replicate the associations with cardio-metabolic traits of 26 CpGs and 19 genes in the KORA study. Furthermore, we identified a three-way association of triglycerides with two CpGs and two genes (GZMA; CLDND1), and BMI with six CpGs and two genes (PID1; LRRN3). Finally, our results revealed the mediation effect of cg03636183 (F2RL3), cg06096336 (PSMD1), cg13708645 (KDM2B), and cg17287155 (AHRR) within the association between smoking and LRRN3 expression. Conclusions Our study indicates that smoking-related changes in DNA methylation and gene expression are associated with cardio-metabolic risk factors. These findings may provide additional insights into the molecular mechanisms linking smoking to the development of CVD.

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