Maternal obesity imprints methylation marks in oocytes to drive intergenerational metabolic dysfunction

In the present study, genome-wide profiling revealed that maternal obesity induces locus-specific DNA methylation changes in oocytes. Of them, a subset of metabolic genes, particularly Hnf1α, Thra, and Pdk4, exhibited persistent transcriptional dysregulation across two successive generations.

Notably, aberrant methylation at these loci was erased during embryogenesis but re-established postnatally in both germline and somatic tissues, supporting the concept of “methylation memory”. At single-CpG resolution, we identified methylation landmarks at three metabolic loci that strongly correlated with gene expression. Furthermore, by employing methylation-edited mouse model, we demonstrated that targeted oocyte hypermethylation at Hnf1α enhanced hepatic gluconeogenesis in the offspring, whereas Pdk4 hypermethylation impaired muscle glucose tolerance, both in a female-specific manner.