Ancestral Mutation in Khdc3 Leads to Transgenerational Metabolic Defects in Genetically Wild Type Mice

Core Concepts

Ancestral mutation in the mammalian germ cell gene Khdc3 leads to persistent metabolic defects in the liver of genetically wild type female descendants over multiple generations, potentially through the inheritance of dysregulated small RNAs in the oocytes.

Abstract

The study investigates the transgenerational effects of a mutation in the mammalian germ cell gene Khdc3. Key findings:

Genetically wild type female mice descended from Khdc3-null ancestors (WT* mice) exhibit persistent dysregulation of critical hepatic metabolic genes, including upregulation of Cyp17a1, a central regulator of lipid metabolism.

The metabolic defects in WT* mice are transmitted through both male and female mutant ancestors and persist over at least 6 generations, even after reintroduction of the wild type Khdc3 allele.

WT* mice have abnormal serum levels of multiple hepatically-metabolized molecules, including bile acids, xenobiotics, and metabolic cofactors. These defects are exacerbated when the mice are challenged with a high-fat diet.

Oocytes from Khdc3-null females and their wild type descendants (WT**) show dysregulation of multiple miRNAs and tRNA fragments, some of which are commonly dysregulated between the two genotypes. This suggests the inheritance of altered small RNAs may contribute to the transgenerational metabolic phenotypes.

An outcrossing experiment demonstrates the maternal transmission of the metabolic defects, ruling out mechanisms involving inherited DNA variants, DNA methylation, or histone modifications.

Overall, the study reveals a DNA-independent, transgenerational inheritance of metabolic phenotypes driven by ancestral mutation in the germ cell gene Khdc3, potentially mediated by altered small RNA profiles in the oocytes.

Stats

Cyp17a1 mRNA expression is significantly increased in the livers of KOKO, KO*, and WT* female mice compared to WT females.
Serum of WT**(P), WT****(P), and KOKO mice show abnormal levels of multiple bile acids, xenobiotics, and metabolic cofactors compared to WT mice.
WT****(P) female mice exposed to a high-fat diet show further dysregulation of serum lipid molecules and decreased levels of other hepatic metabolites compared to WT mice on a high-fat diet.

Quotes

"Wild type females descended from Khdc3-null mice have dysfunctional expression of critical hepatic metabolic genes that persists over multiple generations, and that this effect is transmitted from both male and female mutant ancestors."
"The persistence of these abnormalities in genetically wild type mice suggests that altered epigenetic information in the germ cells is transmitting the inherited metabolic phenotypes."
"Accordingly, we observed that the oocytes of Khdc3-null females and their wild type descendants have multiple dysregulated miRNAs and tsRNAs, suggesting a mechanism of inheritance."

Key Insights Distilled From

Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner

by Senaldi,L., ... at www.biorxiv.org 03-01-2024

https://www.biorxiv.org/content/10.1101/2024.02.27.582278v1

Deeper Inquiries

How do the transgenerational metabolic defects observed in this study impact other physiological processes and disease susceptibility in the wild type descendants?

The transgenerational metabolic defects observed in this study, resulting from ancestral Khdc3 mutation, can have far-reaching impacts on various physiological processes and disease susceptibility in the wild type descendants. Firstly, the dysregulation of hepatic metabolic genes can lead to disruptions in energy metabolism, affecting processes such as glucose and lipid metabolism. This can result in metabolic disorders such as obesity, insulin resistance, and dyslipidemia in the descendants. Additionally, since the liver plays a crucial role in detoxification and metabolism of xenobiotics, the observed defects may also impact the body's ability to process and eliminate toxins, potentially increasing susceptibility to environmental toxins and chemical exposures. Furthermore, the abnormal levels of bile acids and other metabolites in the serum of the affected mice suggest potential disruptions in liver function, which can have cascading effects on overall health and disease susceptibility. These metabolic defects may also contribute to the development of liver diseases such as non-alcoholic fatty liver disease (NAFLD) and liver fibrosis, further exacerbating the health outcomes of the descendants.

How do the potential mechanisms by which the dysregulated small RNAs in the oocytes of Khdc3 mutant mice are able to persistently alter hepatic gene expression and metabolism across multiple generations?

The dysregulated small RNAs in the oocytes of Khdc3 mutant mice can persistently alter hepatic gene expression and metabolism across multiple generations through several potential mechanisms. Firstly, these small RNAs, such as miRNAs and tRNA fragments, can directly target and regulate the expression of genes involved in hepatic metabolism, leading to sustained dysregulation of metabolic pathways in the liver. The altered expression of small RNA-processing genes in the liver of the descendants suggests a disruption in the processing and function of small RNAs, further contributing to the persistent metabolic defects. Additionally, the inheritance of these dysregulated small RNAs from the germ cells of Khdc3 mutant ancestors to subsequent generations can establish an epigenetic memory that perpetuates the abnormal gene expression patterns in the liver. This epigenetic inheritance may involve modifications to chromatin structure, DNA methylation patterns, or histone modifications that maintain the altered gene expression profiles over generations. Furthermore, the interplay between small RNAs and other regulatory molecules in the oocytes, such as RNA-binding proteins and epigenetic modifiers, may create a feedback loop that sustains the transmission of metabolic phenotypes across generations.

Could the transgenerational inheritance of metabolic phenotypes mediated by ancestral Khdc3 mutation have implications for understanding the role of germ cell epigenetics in the transmission of complex traits and disease risk in humans?

The transgenerational inheritance of metabolic phenotypes mediated by ancestral Khdc3 mutation has significant implications for understanding the role of germ cell epigenetics in the transmission of complex traits and disease risk in humans. Firstly, this study highlights the potential for non-DNA molecules, such as small RNAs, to serve as carriers of epigenetic information that can influence offspring phenotypes across generations. Understanding the mechanisms by which these small RNAs are inherited and impact gene expression in target tissues, such as the liver, can provide insights into the broader role of germ cell epigenetics in shaping complex traits and disease susceptibility in humans. Additionally, the persistence of metabolic defects over multiple generations in the absence of the causal genetic mutation underscores the importance of considering non-genetic factors in the transmission of traits and disease risk. This study suggests that ancestral mutations in germ cell genes can have lasting effects on metabolic health and disease susceptibility in descendants, highlighting the need to explore similar mechanisms in human populations to better understand the interplay between genetics, epigenetics, and environmental factors in shaping health outcomes. By elucidating the molecular pathways involved in transgenerational inheritance of metabolic phenotypes, researchers can gain valuable insights into the potential mechanisms underlying intergenerational transmission of complex traits and diseases in humans.