Genomic Imprinting.pdf

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Peer Reviewer Comments

Two peer reviewers provided comments on the study by Weinberg-Shukron et al. on genomic imprinting at the Dlk1/Dio3 locus in mice.

Reviewer #1

The study examines genotype/epigenotype correlations with measured phenotypes at the imprinted Dlk1/Dio3 locus.
The data suggest that balanced gene dosage control, rather than parental origin, is crucial for normal development.
The authors used a series of detailed deletions of the control region at the Dlk1/Dio3 locus and careful phenotypic measurements.
The results show that normal development depends on keeping a balanced expression between genes in the Dlk1/Dio3 locus, rather than absolute expression levels.

Reviewer #2

The study investigated the consequences of deleting a CpG island (CGI) within an intergenic differentially methylated region (DMR) at the Dlk1-Dio3 locus.
The authors generated mice with deletions on the maternal or paternal chromosome or on both and determined transcript levels, DNA methylation, and phenotypic outcomes.
The main conclusions are:
1. A dependency between regulatory elements of the Dlk1-Dio3 locus controls parent-specific gene expression.
2. Flipping imprinting patterns on parental chromosomes rescues the lethality of each deletion on its own.
The reviewer raised several concerns, including:
+ The terms "balanced expression" and "absolute levels" are misleading.
+ The results do not allow conclusions about the relevance of absolute levels.
+ The lethality of animals with certain deletions may be due to direct consequences of the loss of expression of specific genes.
+ The authors should provide more information on the tissues used for DNA and RNA isolation and the exact ages of postnatal animals.