Khdc3 Regulates Metabolism Across Generations in a DNA-Independent Manner [small RNA-seq]

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. Comparison of small RNAs from oocytes of wild type, Khdc3-null, and wild type mice generated from Khdc3-null grandfathers and wild type grandmothers (WT**(P)).遗传变异可改变精子与卵母细胞内诸如小分子RNA（small RNAs）这类可遗传分子的表达谱，以此方式，即便自身未被遗传，祖先携带的遗传变异仍可对子代表型产生显著影响。本研究显示，源自携带哺乳动物生殖细胞基因Khdc3突变的祖先的野生型雌性小鼠，会出现可跨多代延续的肝脏代谢缺陷。我们发现，源自Khdc3突变体的遗传型野生型雌性小鼠，其关键肝脏代谢基因存在转录失调现象，该失调可跨多代延续，并可通过雌性与雄性谱系传递。该现象与携带突变祖先的野生型小鼠血液中经肝脏代谢的分子失调存在关联。Khdc3基因敲除雌性小鼠及其野生型后代的卵母细胞中，均存在多种小分子RNA的失调现象，这表明配子中的这些表观遗传变化可在代际间传递表型。我们的研究结果证实，Khdc3基因的祖先突变可产生潜在可永久延续的跨代遗传表型。本研究将对野生型、Khdc3基因敲除型，以及由Khdc3基因敲除祖父与野生型祖母繁育得到的野生型小鼠（WT**(P)）的卵母细胞小分子RNA进行比对分析。