Abnormal postnatal maintenance of elevated DLK1 transcript levels in callipyge sheep

Abstract

The underlying mechanism of the callipyge muscular hypertrophy phenotype in sheep (Ovis aries) is not presently understood. This phenotype, characterized by increased glycolytic type II muscle proportion and cell size accompanied by decreased adiposity, is not visibly detectable until approximately three to eight weeks after birth. The muscular hypertrophy results from a single nucleotide change located at the telomeric end of ovine Chromosome 18, in the region between the imprinted MATERNALLY EXPRESSED GENE 3 (MEG3) and DELTA, DROSOPHILA, HOMOLOG-LIKE 1 (DLK1) genes. The callipyge phenotype is evident only when the mutation is paternally inherited by a heterozygous individual. We have examined the pre-and postnatal expression of MEG3 and DLK1 in sheep of all four possible genotypes in affected and unaffected muscles as well as in liver. Here we show that the callipyge phenotype correlates with abnormally high DLK1 expression during the postnatal period in the affected sheep and that this elevation is specific to the hypertrophy-responsive fast-twitch muscles. These results are the first to show anomalous gene expression that coincides with both the temporal and spatial distribution of the callipyge phenotype. They suggest that the effect of the callipyge mutation is to interfere with the normal postnatal downregulation of DLK1 expression.

Regulation of DLK1 by the maternally expressed miR-379/miR-544 cluster may underlie callipyge polar overdominance inheritance

“…This phenotypic difference may be due to different expression patterns of DLK1. In CLPG sheep, elevated paternal expression of DLK1 caused by a CLPG point mutation persists over the lifespan of the animal (4,5), whereas in miR-379/miR-544 cluster KO mice, DLK1 is expressed in a physiological manner, showing predominant expression at the neonatal stage and almost no expression during adulthood. Such a transient increase in DLK1 may also be the primary reason why the muscle hypertrophy is relatively small in comparison with CLPG sheep.…”

“…This hypertrophy occurs primarily in the muscles of the pelvic limbs and loin and some muscles in the shoulder, which are enriched with a high proportion of type IIB fast-twitch glycolytic fibers (4). Although the molecular regulation of these hypertrophic processes is yet to be determined, Delta-like 1 homolog (DLK1) is found to be the causative protein (5)(6)(7)(8)(9)(10). The unique mode of inheritance of the CLPG phenotype has attracted a great deal of attention within the scientific community.…”

Frequent IGF2/H19 Domain Epigenetic Alterations and Elevated IGF2 Expression in Epithelial Ovarian Cancer

“…A role for noncoding RNAs is implicated in the regulation of imprinted genes due to the preponderance of these transcribed sequences located in imprinted domains and empirical data suggesting their importance (26,27,(31)(32)(33)(34)(35)(36)(37)(38)(39)(40)(41)(42). For example, the genes Delta, Drosophila homologue-like 1 (DLK1) and maternally expressed gene 3 (MEG3) in the imprinted domain on human chromosome 14 bear remarkable similarity to the IGF2/H19 domain in terms of the genomic organization and putative regulatory features (43)(44)(45).…”

“…A regulatory role has been postulated for MEG3 RNA in modulating the expression of the paternally expressed DLK1. This is based on analysis of these two genes in sheep (Ovis aries) that exhibit a muscular hypertrophy phenotype characterized by enhanced DLK1 expression and maintenance of normal imprinting (31). In this case, the ratio of expression of the protein coding to the RNA encoding gene seems to be an important factor in the development of the hypertrophic phenotype.…”

Environmental epigenomics in human health and disease

“…The homologous regions on human chromosome 14 and mouse chromosome 12 have been intensively studied because the genes DLK1 and MEG3, which are present in this region, are reciprocally imprinted and expressed from the paternal and maternal alleles, respectively [Schmidt et al, 2000;Takada et al, 2000;Wylie et al, 2000]. Mutation detection in a ram of callipyge phenotype revealed a single A/ G polymorphism in the CLPG1 gene that causes muscle hypertrophy in sheep [Murphy et al, 2005].…”