Erasing genomic imprinting memory in mouse clone embryos produced from day 11.5 primordial germ cells

Development ◽  
2002 ◽  
Vol 129 (8) ◽  
pp. 1807-1817 ◽  
Author(s):  
Jiyoung Lee ◽  
Kimiko Inoue ◽  
Ryuichi Ono ◽  
Narumi Ogonuki ◽  
Takashi Kohda ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Nuclear Transfer ◽  
Monoallelic Expression ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Specific Expression ◽  
Male And Female ◽  
Imprinted Gene ◽  
Methylation Patterns

Genomic imprinting is an epigenetic mechanism that causes functional differences between paternal and maternal genomes, and plays an essential role in mammalian development. Stage-specific changes in the DNA methylation patterns of imprinted genes suggest that their imprints are erased some time during the primordial germ cell (PGC) stage, before their gametic patterns are re-established during gametogenesis according to the sex of individuals. To define the exact timing and pattern of the erasure process, we have analyzed parental-origin-specific expression of imprinted genes and DNA methylation patterns of differentially methylated regions (DMRs) in embryos, each derived from a single day 11.5 to day 13.5 PGC by nuclear transfer. Cloned embryos produced from day 12.5 to day 13.5 PGCs showed growth retardation and early embryonic lethality around day 9.5. Imprinted genes lost their parental-origin-specific expression patterns completely and became biallelic or silenced. We confirmed that clones derived from both male and female PGCs gave the same result, demonstrating the existence of a common default state of genomic imprinting to male and female germlines. When we produced clone embryos from day 11.5 PGCs, their development was significantly improved, allowing them to survive until at least the day 11.5 embryonic stage. Interestingly, several intermediate states of genomic imprinting between somatic cell states and the default states were seen in these embryos. Loss of the monoallelic expression of imprinted genes proceeded in a step-wise manner coordinated specifically for each imprinted gene. DNA demethylation of the DMRs of the imprinted genes in exact accordance with the loss of their imprinted monoallelic expression was also observed. Analysis of DNA methylation in day 10.5 to day 12.5 PGCs demonstrated that PGC clones represented the DNA methylation status of donor PGCs well. These findings provide strong evidence that the erasure process of genomic imprinting memory proceeds in the day 10.5 to day 11.5 PGCs, with the timing precisely controlled for each imprinted gene. The nuclear transfer technique enabled us to analyze the imprinting status of each PGC and clearly demonstrated a close relationship between expression and DNA methylation patterns and the ability of imprinted genes to support development.

scholarly journals Multiple Imprinted Genes Associated with Prader-Willi Syndrome and Location of an Imprinting Control Element

1996 ◽  
Vol 45 (1-2) ◽  
pp. 87-89
Author(s):  
R.D. Nicholls ◽  
M.T.C. Jong ◽  
C.C. Glenn ◽  
J. Gabriel ◽  
P.K. Rogan ◽  
...  
Keyword(s):  
Genomic Imprinting ◽  
Epigenetic Modification ◽  
Uniparental Disomy ◽  
Paternal Allele ◽  
Control Element ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Mammalian Development ◽  
Specific Expression ◽  
Large Deletions

Our studies aim to identify the mechanisms and genes involved in genomic imprinting in mammalian development and human disease. Imprinting refers to an epigenetic modification of DNA that results in parent-of-origin specific expression during embryogenesis and in the adult. This imprint is reset at each generation, depending on the sex of the parental gametogenesis. Prader-Willi (PWS) and Angelman (AS) syndromes are excellent models for the study of genomic imprinting in humans, since these distinct neurobehavioural disorders are both associated with genetic abnormalities (large deletions, uniparental disomy, and imprinting mutations) of inheritance in chromosome 15q11-q13, dependent on the parental origin (reviewed in ref. 1). Some AS patients have biparental inheritance, consistent with a single imprinted gene (active on the maternal chromosome), whereas similar PWS patients are not found suggesting that at least two imprinted genes (active on the paternal allele) may be necessary for classical PWS. We have previously shown that the small ribonucleoprotein associated protein SmN gene (SNRPN), located in the PWS critical region [2], is only expressed from the paternal allele and is differentially methylated on parental alleles [3]. Therefore, SNRPN may have a role in PWS. Methylation imprints have also been found at two other loci in 15q11-q13, PW71 [4] and D15S9 [5], which map 120 kb and 1.5 Mb proximal to SNRPN, respectively. We have now characterized in detail the gene structure and expression from two imprinted loci within 15q11-q13, SNRPN and D15S9, which suggests that both loci are surprisingly complex, with important implications for the pathogenesis of PWS.

scholarly journals New insights into establishment and maintenance of DNA methylation imprints in mammals

2013 ◽  
Vol 368 (1609) ◽  
pp. 20110336 ◽  
Author(s):  
Gavin Kelsey ◽  
Robert Feil
Keyword(s):  
Dna Methylation ◽  
Recent Work ◽  
Genomic Imprinting ◽  
Histone Modifications ◽  
Germ Cells ◽  
Differential Methylation ◽  
Imprinted Genes ◽  
Male And Female ◽  
Rational Models ◽  
The Times

Fundamental to genomic imprinting in mammals is the acquisition of epigenetic marks that differ in male and female gametes at ‘imprinting control regions’ (ICRs). These marks mediate the allelic expression of imprinted genes in the offspring. Much has been learnt about the nature of imprint marks, the times during gametogenesis at which they are laid down and some of the factors responsible especially for DNA methylation. Recent work has revealed that transcription and histone modifications are critically involved in DNA methylation acquisition, and these findings allow us to propose rational models for methylation establishment. A completely novel perspective on gametic DNA methylation has emerged from epigenomic profiling. Far more differentially methylated loci have been identified in gametes than known imprinted genes, which leads us to revise the notion that methylation of ICRs is a specifically targeted process. Instead, it seems to obey default processes in germ cells, giving rise to distinct patterns of DNA methylation in sperm and oocytes. This new insight, together with the identification of proteins that preserve DNA methylation after fertilization, emphasizes the key role played by mechanisms that selectively retain differential methylation at imprinted loci during early development. Addressing these mechanisms will be essential to understanding the specificity and evolution of genomic imprinting.

scholarly journals Gamete imprinting: setting epigenetic patterns for the next generation

2006 ◽  
Vol 18 (2) ◽  
pp. 63 ◽  
Author(s):  
Jacquetta M. Trasler
Keyword(s):  
Dna Methylation ◽  
Genomic Dna ◽  
Germ Line ◽  
Imprinted Genes ◽  
Specific Expression ◽  
Placental Function ◽  
Early Embryos ◽  
Parent Of Origin ◽  
Methylation Patterns ◽  
Epigenetic Patterns

The acquisition of genomic DNA methylation patterns, including those important for development, begins in the germ line. In particular, imprinted genes are differentially marked in the developing male and female germ cells to ensure parent-of-origin-specific expression in the offspring. Abnormalities in imprints are associated with perturbations in growth, placental function, neurobehavioural processes and carcinogenesis. Based, for the most part, on data from the well-characterised mouse model, the present review will describe recent studies on the timing and mechanisms underlying the acquisition and maintenance of DNA methylation patterns in gametes and early embryos, as well as the consequences of altering these patterns.

scholarly journals Genomic imprinting and cancer: Remembering the parental origin

2010 ◽  
Vol 32 (5) ◽  
pp. 26-29
Author(s):  
Adele Murrell ◽  
Santiago Uribe-Lewis
Keyword(s):  
Dna Methylation ◽  
Genomic Imprinting ◽  
Histone Modifications ◽  
Germ Cells ◽  
Parental Origin ◽  
Imprinted Genes ◽  
Parental Allele ◽  
Paternal Line ◽  
Specific Manner ◽  
Parental Copy

Genomic imprinting results in only one copy of a diploid pair of alleles being expressed in a parentof-origin-specific manner. The ‘imprint’ encodes a memory of whether a gene came through the maternal or paternal line and contains the information that decides which parental copy will be active or silent. Imprints are established in the developing gametes, passed on to the next generation after fertilization where they are read and maintained in the somatic cells or erased and reset in the germ cells. The components of the ‘memory’ are a combination of epigenetic features such as DNA methylation, post-translational histone modifications and protein/RNA factors that can bind to DNA and label the genes such that a cell's transcription machinery can distinguish between maternal and paternal alleles. Most imprinted genes are associated with sequences that are methylated on only one parental allele, known as differentially methylated regions (DMRs).

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.

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 & CIHR.

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 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 ZFP57 dictates allelic expression switch of target imprinted genes

2021 ◽  
Vol 118 (5) ◽  
pp. e2005377118
Author(s):  
Weijun Jiang ◽  
Jiajia Shi ◽  
Jingjie Zhao ◽  
Qiu Wang ◽  
Dan Cong ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Notch Signaling ◽  
Notch Pathway ◽  
Notch Signaling Pathway ◽  
Mouse Embryos ◽  
The Other ◽  
Allelic Expression ◽  
Monoallelic Expression ◽  
Imprinted Genes ◽  
Parent Of Origin

ZFP57 is a master regulator of genomic imprinting. It has both maternal and zygotic functions that are partially redundant in maintaining DNA methylation at some imprinting control regions (ICRs). In this study, we found that DNA methylation was lost at most known ICRs in Zfp57 mutant embryos. Furthermore, loss of ZFP57 caused loss of parent-of-origin–dependent monoallelic expression of the target imprinted genes. The allelic expression switch occurred in the ZFP57 target imprinted genes upon loss of differential DNA methylation at the ICRs in Zfp57 mutant embryos. Specifically, upon loss of ZFP57, the alleles of the imprinted genes located on the same chromosome with the originally methylated ICR switched their expression to mimic their counterparts on the other chromosome with unmethylated ICR. Consistent with our previous study, ZFP57 could regulate the NOTCH signaling pathway in mouse embryos by impacting allelic expression of a few regulators in the NOTCH pathway. In addition, the imprinted Dlk1 gene that has been implicated in the NOTCH pathway was significantly down-regulated in Zfp57 mutant embryos. Our allelic expression switch models apply to the examined target imprinted genes controlled by either maternally or paternally methylated ICRs. Our results support the view that ZFP57 controls imprinted expression of its target imprinted genes primarily through maintaining differential DNA methylation at the ICRs.

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