Hierarchical Phenotypic and Epigenetic Variation in Cloned Swine1

Archer, Gregory S.; Dindot, Scott V.; Friend, T.H.; Walker, S.; Zaunbrecher, Gretchen M.; Lawhorn, Bruce; Piedrahita, Jorge A.

doi:10.1095/biolreprod.103.016147

Cited by 89 publications

(58 citation statements)

References 20 publications

(25 reference statements)

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“…In fact, the expression of all but one gene (ARAF1) in organs of individual deceased clones was found to exceed this threshold and was likely abnormal (Table 2). Similar expression abnormalities were found in DNA methylation in cloned pigs and deceased cloned bovine calves (Archer et al 2003;Li et al, 2004;Yang et al, 2005). The same 2SD comparisons in the surviving clones revealed much less dysregulation (Table 2).…”

Section: Discussionsupporting

confidence: 62%

“…Faulty or incomplete epigenetic reprogramming has been observed in different stages of development (Cezar et al 2003;Kang et al 2001b;Mann et al 2003). Even in cloned animals that survive to term, different aspects of epigenetic abnormalities are evident, although the majority of these animals appear to be healthy and normal (Archer et al 2003;Li et al 2004;Xue et al 2002).…”

Section: Introductionmentioning

confidence: 99%

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Expression of X‐linked genes in deceased neonates and surviving cloned female piglets

Jiang

Lai

Samuel

et al. 2007

Molecular Reproduction Devel

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Animal cloning through somatic cell nuclear transfer is very inefficient, probably due to insufficient reprogramming of the donor nuclei, which in turn would cause the dysregulation of gene expression. X-Chromosome inactivation (XCI) is a multi-step epigenetic process utilized by mammals to achieve dosage compensation in females. Our aim was to determine if any dysregulation of X-linked genes, which would be indicative of unfaithful reprogramming of donor nuclei, was present in cloned pigs. Real time reverse transcription polymerase chain reaction (RT-PCR) was performed to quantify the transcript levels of five X-linked genes, XIST, TSIX, HPRT1, G6PD, ARAF1 and one autosomal gene, COL4A1 in major organs of neonatal deceased and surviving female cloned pigs and age-matched control pigs from conventional breeding. Aberrant expression level of these genes was prevalent in the neonatal deceased clones, while it was only moderate in cloned pigs that survived after birth. These results suggest a correlation between the viability of the clones and the normality of their gene expression and provide a possible explanation for the death of a large portion of cloned animals around birth.

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Section: Discussionsupporting

confidence: 62%

Section: Introductionmentioning

confidence: 99%

Expression of X‐linked genes in deceased neonates and surviving cloned female piglets

Jiang

Lai

Samuel

et al. 2007

Molecular Reproduction Devel

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“…The demethylation of these sequences was also shown to be similar to the in vivo produced blastocysts. Pre-1 and centromeric satellite sequences were found to have similar methylation levels in healthy cloned pigs and control pigs (Archer et al, 2003). However, even normal appearing pigs can have aberrant expression of imprinted genes (Jiang et al, 2007).…”

Section: Introductionmentioning

confidence: 87%

Aberrant DNA methylation in porcine in vitro‐, parthenogenetic‐, and somatic cell nuclear transfer‐produced blastocysts

Bonk

Lai

et al. 2007

Molecular Reproduction Devel

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Early embryonic development in the pig requires DNA methylation remodeling of the maternal and paternal genomes. Aberrant remodeling, which can be exasperated by in vitro technologies, is detrimental to development and can result in physiological and anatomic abnormalities in the developing fetus and offspring. Here, we developed and validated a microarray based approach to characterize on a global scale the CpG methylation profiles of porcine gametes and blastocyst stage embryos. The relative methylation in the gamete and blastocyst samples showed that 18.5% (921/4,992) of the DNA clones were found to be significantly different (P < 0.01) in at least one of the samples. Furthermore, for the different blastocyst groups, the methylation profile of the in vitro-produced blastocysts was less similar to the in vivo-produced blastocysts as compared to the parthenogenetic-and somatic cell nuclear transfer (SCNT)-produced blastocysts. The microarray results were validated by using bisulfite sequencing for 12 of the genomic regions in liver, sperm, and in vivoproduced blastocysts. These results suggest that a generalized change in global methylation is not responsible for the low developmental potential of blastocysts produced by using in vitro techniques. Instead, the appropriate methylation of a relatively small number of genomic regions in the early embryo may enable early development to occur. Mol. Reprod.

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“…Although it is normally assumed that the use of cloned animals will exhibit less interindividual phenotypic variation and allow for a reduction of the number of animals needed to obtain statistically sound data, this assumption has been found not always to be warranted. For example, the variability in blood parameters and metabolites (Archer et al, 2003;Clausen et al, 2011) as well as the gene expression of fetal growth-related genes ( Jiang et al, 2007) was found to be similar in cloned as in normal pigs. It has been proposed that some of this variation may stem from maternal mitochondrial DNA from the donor cell (St. John et al, 2005).…”

Section: Introductionmentioning

confidence: 97%

Expression of Innate Immune Response Genes in Liver and Three Types of Adipose Tissue in Cloned Pigs

Rødgaard

Skovgaard

Stagsted

et al. 2012

Cellular Reprogramming

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The pig has been proposed as a relevant model for human obesity-induced inflammation, and cloning may improve the applicability of this model. We tested the assumptions that cloning would reduce interindividual variation in gene expression of innate immune factors and that their expression would remain unaffected by the cloning process. We investigated the expression of 40 innate immune factors by high-throughput quantitative real-time PCR in samples from liver, abdominal subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), and neck SAT in cloned pigs compared to normal outbred pigs.The variation in gene expression was found to be similar for the two groups, and the expression of a small number of genes was significantly affected by cloning. In the VAT and abdominal SAT, six out of seven significantly differentially expressed genes were downregulated in the clones. In contrast, most differently expressed genes in both liver and neck SAT were upregulated (seven out of eight). Remarkably, acute phase proteins (APPs) dominated the upregulated genes in the liver, whereas APP expression was either unchanged or downregulated in abdominal SAT and VAT. The general conclusion from this work is that cloning leads to subtle changes in specific subsets of innate immune genes. Such changes, even if minor, may have phenotypic effects over time, e.g., in models of long-term inflammation related to obesity.

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Hierarchical Phenotypic and Epigenetic Variation in Cloned Swine1

Cited by 89 publications

References 20 publications

Expression of X‐linked genes in deceased neonates and surviving cloned female piglets

Expression of X‐linked genes in deceased neonates and surviving cloned female piglets

Aberrant DNA methylation in porcine in vitro‐, parthenogenetic‐, and somatic cell nuclear transfer‐produced blastocysts

Expression of Innate Immune Response Genes in Liver and Three Types of Adipose Tissue in Cloned Pigs

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