Faithful Expression of Imprinted Genes in Cloned Mice

Inoue, Kimiko; Kohda, Takashi; Lee, Ji-Young; Ogonuki, Narumi; Mochida, Keiichi; Noguchi, Yoko; Tanemura, Kentaro; Kaneko-Ishino, Tomoko; Ishino, Fumitoshi; Ogura, Atsuo

doi:10.1126/science.295.5553.297

Cited by 260 publications

(169 citation statements)

References 6 publications

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“…Defects in the trans-acting machinery that regulates imprinting, such as DNA methyltransferase deficiency (Lei et al, 1996;Bourc'his et al, 2001;Hata et al, 2002;Kaneda et al, 2004;Arima et al, 2006) or mutations causing familial hydatidiform moles (Judson et al, 2002;Murdoch et al, 2006) result in abnormal placentation. Finally, interspecific hybrids (Vrana et al, 1998;Vrana et al, 2000), somatic cell nuclear transfer embryos (Dindot et al, 2004;Inoue et al, 2002) and uniparental embryos (Surani et al, 1986;Varmuza et al, 1993;Mann 2005) all suffer from dysmorphic trophoblast, in part or in whole because of abnormal expression of imprinted genes.…”

Section: Sfmbt2 and Yy1 Interact In Mammalian Cellsmentioning

confidence: 99%

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

Kuzmin

Han

Golding

et al. 2008

Gene Expression Patterns

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Genomic imprinting has dramatic effects on placental development, as has been clearly observed in interspecific hybrid, somatic cell nuclear transfer, and uniparental embryos. In fact, the earliest defects in uniparental embryos are evident first in the extraembryonic trophoblast. We performed a microarray comparison of gynogenetic and androgenetic mouse blastocysts, which are predisposed to placental pathologies, to identify imprinted genes. In addition to identifying a large number of known imprinted genes, we discovered that the Polycomb group (PcG) gene Sfmbt2 is imprinted. Sfmbt2 is expressed preferentially from the paternal allele in early embryos, and in later stage extraembryonic tissues. A CpG island spanning the transcriptional start site is differentially methylated on the maternal allele in e14.5 placenta. Sfmbt2 is located on proximal chromosome 2, in a region known to be imprinted, but for which no genes had been identified until now. This possibly identifies a new imprinted domain within the murine genome. We further demonstrate that murine SFMBT2 protein interacts with the transcription factor YY1, similar to the Drosophila PHO-RC. KeywordsGenomic Imprinting; Sfmbt2; PcG gene; Extraembryonic tissues; placenta; MMU2; YY1; microarrays; uniparental embryos Results and DiscusssionThe role played by imprinted genes in placental development is gaining wider attention as the impact of imprinting disruptions on placental pathology is explored. Both hyper-and hypoplastic placentation are linked to imprinted gene function (Kanayama et al., 2002;Murdoch et al., 2006; reviewed in Kaneko-Ishino et al., 2003). The most dramatic example of this is diploid, uniparental embryos. Gynogenetic embryos (two maternal/no paternal genomes) and androgenetic embryos (two paternal/no maternal genomes) both exhibit defects in the earliest differentiated tissue in mammals, the extraembryonic trophoblast (Barton et al., 1984;McGrath and Solter, 1984;Mann, 2005). At mid-gestation, gynogenetic embryos possess only a few residual trophoblast giant cells while androgenetic embryos are characterized by a mass of hypertrophic trophoblast. These observations indicate that a suite of genes required * Corresponding author. s.varmuza@utoronto.ca; tel. 1-416-978-2759; FAX 1-416-978-8532. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. NIH Public Access Author ManuscriptGene Expr Patterns. Author manuscript; available in PMC 2009 January 1. Published in final edited form as:Gene Expr Patterns. 2008 January ; 8(2): 107-116. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manu...

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Section: Sfmbt2 and Yy1 Interact In Mammalian Cellsmentioning

confidence: 99%

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

Kuzmin

Han

Golding

et al. 2008

Gene Expression Patterns

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“…Transcription in transplanted nucleus ceases during the process [4,13] and resumes several hours after PPN formation [14]. There is accumulating evidence that reprogramming in transcription profile [15] and epigenetic marks [7][8][9][10][11][12] is incomplete in the majority of cloned embryos. A large proportion of them display ectopic gene expression and aberrant covalent modifications that are correlated with the donor cell type [7][8][9][10][11][12]15].…”

Section: Introductionmentioning

confidence: 99%

“…In cloned embryos and animals, X-chromosome inactivation is reversed [5] and telomeres are extended [6]. Patterns in DNA methylation and histone modification are also reprogrammed, although such reprogramming is not efficient [7][8][9][10][11][12]. Transcription in transplanted nucleus ceases during the process [4,13] and resumes several hours after PPN formation [14].…”

Section: Introductionmentioning

confidence: 99%

“…There is accumulating evidence that reprogramming in transcription profile [15] and epigenetic marks [7][8][9][10][11][12] is incomplete in the majority of cloned embryos. A large proportion of them display ectopic gene expression and aberrant covalent modifications that are correlated with the donor cell type [7][8][9][10][11][12]15]. The primary mechanism responsible for reprogramming the somatic cell gene expression profile to that of the embryo is not yet defined [16][17][18].…”

Section: Introductionmentioning

confidence: 99%

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Nuclear reprogramming: the strategy used in normal development is also used in somatic cell nuclear transfer and parthenogenesis

et al. 2007

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Somatic cell nuclear transfer (SCNT) and parthenogenesis are alternative forms of reproduction and development, building new life cycles on differentiated somatic cell nuclei and duplicated maternal chromatin, respectively. In the preceding paper (Sun F, et al., Cell Res 2007; 17:117-134.), we showed that an "erase-and-rebuild" strategy is used in normal development to transform the maternal gene expression profile to a zygotic one. Here, we investigate if the same strategy also applies to SCNT and parthenogenesis. The relationship between chromatin and chromatin factors (CFs) during SCNT and parthenogenesis was examined using immunochemical and GFP-fusion protein assays. Results from these studies indicated that soon after nuclear transfer, a majority of CFs dissociated from somatic nuclei and were redistributed to the cytoplasm of the egg. The erasure process in oogenesis is recaptured during the initial phase in SCNT. Most CFs entered pseudo-pronuclei shortly after their formation. In parthenogenesis, all parthenogenotes underwent normal oogenesis, and thus had removed most CFs from chromosomes before the initiation of development. The CFs were subsequently re-associated with female pronuclei in time and sequence similar to that in fertilized embryos. Based on these data, we conclude that the "erase-and-rebuild" process observed in normal development also occurs in SCNT and in parthenogenesis, albeit in altered fashions. The process is responsible for transcription reprogramming in these procedures. The "erase" process in SCNT is compressed and the efficiency is compromised, which likely contribute to the developmental defects often observed in nuclear transfer (nt) embryos. Furthermore, results from this study indicated that the cytoplasm of an egg contains most, if not all, essential components for assembling the zygotic program and can assemble them onto appropriate diploid chromatin of distinct origins.

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“…Epigenetic studies revealed mostly normal X-chromosome inactivation Wrenzycki et al 2002) but showed methylation instability at specific CpG islands in cloned mouse embryos obtained from somatic (Ohgane et al 2001) and embryonic stem (ES) cells (Humpherys et al 2001). Studies on epigenetic changes have also been conducted on the small proportion of clones that become fetuses or develop to term, indicating that imprinting is largely normal or that mammalian development is tolerant of epigenetic aberrations (Humpherys et al 2001;Inoue et al 2002).…”

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confidence: 99%

Oct4 distribution and level in mouse clones: consequences for pluripotency

Boiani¹,

Eckardt²,

Schöler³

et al. 2002

Genes Dev.

482

332

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Somatic cell clones often fail at a developmental stage coincident with commencement of differentiation. The transcription factor Oct4 is expressed during cleavage stages and is essential for the differentiation of the blastocyst. Oct4 expression becomes restricted to the inner cell mass and epiblast. After gastrulation Oct4 is active only in germ cells and is silent in somatic cells. Here, Oct4 and an Oct4-GFP transgene were used as markers for which gene reprogramming could be directly related to the developmental potential of somatic cell clones. Cumulus cell clones initiated Oct4 expression at the correct stage but showed an incorrect spatial expression in the majority of blastocysts. The ability of clones to form outgrowths was reduced, and the outgrowths had low or even undetectable levels of Oct4 RNA or GFP. The quality of GFP signals in blastocysts correlated with the ability to generate outgrowths that maintain GFP expression and the frequency of embryonic stem (ES) cell derivation. Abnormal Oct4 expression in clones is either directly or indirectly caused by reprogramming errors and is indicative of a general failure to reset the genetic program. The abnormal Oct4 expression may be associated with aberrant expression of other crucial developmental genes, leading to abnormalities at various embryonic stages. Regardless of other genes, the variations observed in Oct4 levels alone account for the majority of failures currently observed for somatic cell cloning.

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Faithful Expression of Imprinted Genes in Cloned Mice

Cited by 260 publications

References 6 publications

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

The PcG gene Sfmbt2 is paternally expressed in extraembryonic tissues

Nuclear reprogramming: the strategy used in normal development is also used in somatic cell nuclear transfer and parthenogenesis

Oct4 distribution and level in mouse clones: consequences for pluripotency

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