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2015 ; 112
(15
): 4618-23
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Characterization of global loss of imprinting in fetal overgrowth syndrome
induced by assisted reproduction
#MMPMID25825726
Chen Z
; Hagen DE
; Elsik CG
; Ji T
; Morris CJ
; Moon LE
; Rivera RM
Proc Natl Acad Sci U S A
2015[Apr]; 112
(15
): 4618-23
PMID25825726
show ga
Embryos generated with the use of assisted reproductive technologies (ART) can
develop overgrowth syndromes. In ruminants, the condition is referred to as large
offspring syndrome (LOS) and exhibits variable phenotypic abnormalities including
overgrowth, enlarged tongue, and abdominal wall defects. These characteristics
recapitulate those observed in the human loss-of-imprinting (LOI) overgrowth
syndrome Beckwith-Wiedemann (BWS). We have recently shown LOI at the KCNQ1 locus
in LOS, the most common epimutation in BWS. Although the first case of
ART-induced LOS was reported in 1995, studies have not yet determined the extent
of LOI in this condition. Here, we determined allele-specific expression of
imprinted genes previously identified in human and/or mouse in day ?105 Bos
taurus indicus × Bos taurus taurus F1 hybrid control and LOS fetuses using
RNAseq. Our analysis allowed us to determine the monoallelic expression of 20
genes in tissues of control fetuses. LOS fetuses displayed variable LOI compared
with controls. Biallelic expression of imprinted genes in LOS was associated with
tissue-specific hypomethylation of the normally methylated parental allele. In
addition, a positive correlation was observed between body weight and the number
of biallelically expressed imprinted genes in LOS fetuses. Furthermore, not only
was there loss of allele-specific expression of imprinted genes in LOS, but also
differential transcript amounts of these genes between control and overgrown
fetuses. In summary, we characterized previously unidentified imprinted genes in
bovines and identified misregulation of imprinting at multiple loci in LOS. We
concluded that LOS is a multilocus LOI syndrome, as is BWS.