Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner
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Curated by eLife
eLife assessment
This important mouse study shows that wild-type female progeny of Khdc3 mutants have abnormal gene expression relating to hepatic metabolism, which persists over multiple generations and passes through both female and male lineages. Information about litter size and a full phenotypic description of the phenotype of each progeny should be included to evaluate the impact of KHDC3 mutation on the progeny; in its current state, the evidence for the authors' claims is incomplete. A role for small RNAs on this phenomenon is proposed but has not been functionally validated. The work will be of interest to researchers in the field of DNA-independent mechanism of inheritance. Mentioning the experimental organism in title and abstract would ensure that it targets the appropriate audience.
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Abstract
Genetic variants can alter the profile of heritable molecules such as small RNAs in sperm and oocytes, and in this manner ancestral genetic variants can have a significant effect on offspring phenotypes even if they are not themselves inherited. Here we show that wild type female mice descended from ancestors with a mutation in the mammalian germ cell gene Khdc3 have hepatic metabolic defects that persist over multiple generations. We find that genetically wild type females descended from Khdc3 mutants have transcriptional dysregulation of critical hepatic metabolic genes, which persist over multiple generations and pass through both female and male lineages. This was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with mutational ancestry. The oocytes of Khdc3 -null females, as well as their wild type descendants, had dysregulation of multiple small RNAs, suggesting that these epigenetic changes in the gametes transmit the phenotype between generations. Our results demonstrate that ancestral mutation in Khdc3 can produce transgenerational inherited phenotypes, potentially indefinitely.
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eLife assessment
This important mouse study shows that wild-type female progeny of Khdc3 mutants have abnormal gene expression relating to hepatic metabolism, which persists over multiple generations and passes through both female and male lineages. Information about litter size and a full phenotypic description of the phenotype of each progeny should be included to evaluate the impact of KHDC3 mutation on the progeny; in its current state, the evidence for the authors' claims is incomplete. A role for small RNAs on this phenomenon is proposed but has not been functionally validated. The work will be of interest to researchers in the field of DNA-independent mechanism of inheritance. Mentioning the experimental organism in title and abstract would ensure that it targets the appropriate audience.
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Reviewer #1 (Public review):
The key discovery of the manuscript is that the authors found that genetically wild type females descended from Khdc3 mutants shows abnormal gene expression relating to hepatic metabolism, which persist over multiple generations and pass through both female and male lineages. They also find dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with Khdc3 mutant ancestry. These data provide solid evidence further support that phenotype can be transmitted to multiple generations without altering DNA sequence, supporting the involvement of epigenetic mechanisms. The authors further performed exploratory studies on the small RNA profiles in the oocytes of Khdc3-null females, and their wild type descendants, suggesting that altered small RNA expression could be a contributor of …
Reviewer #1 (Public review):
The key discovery of the manuscript is that the authors found that genetically wild type females descended from Khdc3 mutants shows abnormal gene expression relating to hepatic metabolism, which persist over multiple generations and pass through both female and male lineages. They also find dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with Khdc3 mutant ancestry. These data provide solid evidence further support that phenotype can be transmitted to multiple generations without altering DNA sequence, supporting the involvement of epigenetic mechanisms. The authors further performed exploratory studies on the small RNA profiles in the oocytes of Khdc3-null females, and their wild type descendants, suggesting that altered small RNA expression could be a contributor of the observed phenotype transmission, although this has not been functionally validated.
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Reviewer #2 (Public review):
Summary:
This manuscript aimed to investigate the non-genetic impact of KHDC3 mutation on the liver metabolism. To do that they analyzed the female liver transcriptome of genetically wild type mice descended from female ancestors with a mutation in the Khdc3 gene. They found that genetically wild type females descended from Khdc3 mutants have hepatic transcriptional dysregulation which persist over multiple generations in the progenies descended from female ancestors with a mutation in the Khdc3 gene. This transcriptomic deregulation was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with female mutational ancestry. Furthermore, to determine whether small non-coding RNA could be involved in the maternal non-genetic transmission of the hepatic …
Reviewer #2 (Public review):
Summary:
This manuscript aimed to investigate the non-genetic impact of KHDC3 mutation on the liver metabolism. To do that they analyzed the female liver transcriptome of genetically wild type mice descended from female ancestors with a mutation in the Khdc3 gene. They found that genetically wild type females descended from Khdc3 mutants have hepatic transcriptional dysregulation which persist over multiple generations in the progenies descended from female ancestors with a mutation in the Khdc3 gene. This transcriptomic deregulation was associated with dysregulation of hepatically-metabolized molecules in the blood of these wild type mice with female mutational ancestry. Furthermore, to determine whether small non-coding RNA could be involved in the maternal non-genetic transmission of the hepatic transcriptomic deregulation, they performed small RNA-seq of oocytes from Khdc3-/- mice and genetically wild type female mice descended from female ancestors with a Khdc3 mutation and claimed that oocytes of wild type female offspring from Khdc3-null females has dysregulation of multiple small RNAs.
Finally, they claimed that their data demonstrates that ancestral mutation in Khdc3 can produce transgenerational inherited phenotypes.
However, at this stage and considering the information provided in the paper, I think that these conclusions are too preliminary. Indeed, several controls/experiments need to be added to reach those conclusions.
Additional context you think would help readers interpret or understand the significance of the work
• Line 25: this first sentence is very strong and needs to be documented in the introduction.
• Line 48: Reference 5 is not appropriate since the paper shows the remodeling of small RNA during post-testicular maturation of mammalian sperm and their sensibility to environment. Please, change it
• Line 51: "implies" is too strong and should be replaced by « suggests »
• Line 67: reference is missing
Database, the accession numbers are lacking.
• References showing the maternal transmission of non-genetically inherited phenotypes in mice via small RNA need to be added
• Line 378: All RNA-Seq and small RNA-Seq data are available in the NCBI GEO -
