Understanding the mechanisms that drive the in-6heritance of acquired DNA-modifying marks from female mouse eggs is critical for ensuring healthy embryo and placenta development.When French zoologist Jean-Baptiste Lamarck first pro-posed that acquired traits could be inherited in 1809, his idea was met with scepticism. This doubt endured and the theory was largely brushed aside for nearly two centuries. Today, insights from epigenetics are reviving the concept of acquired inheritance, showing that our behaviours and environment can prompt physical modifications to our DNA-some of which can in fact be passed on.Changes to the genetic code primarily involve the ad-dition of chemical groups either directly to the DNA or to proteins called histones around which the sequence wraps. These “marks” affect how nearby genes are expressed with-out altering the underlying code.For example, a histone modification called H3K27me3 plays a key role in imprinting, a phenomenon in which ex-pression of a gene differs depending on its parent of origin. By acting to suppress copies of genes obtained from the mother, H3K27me3-mediated imprinting leads to expres-sion of only the paternally-derived allele.“We previously showed that acquired H3K27me3 marks can be passed on in mammals,” said Azusa Inoue, Young Chief Investigator of the Laboratory for Metabolic Epi-genetics at IMS. In their new study published in Nature Genetics, Inoue and colleagues investigated how this hap-pens and what role it plays in embryo development.Based on previous evidence that H3K27me3 interacts with a modification called H2AK119ub1, the researchers hypothesized that the latter may be involved in the forma-tion of the former. To test this theory, they used a tech-nique called low-input CUT&RUN to find the locations at which the marks bind.Looking first in egg cells, the team noted that the two modifications overlapped with one another. They saw similar patterns in fertilised eggs and at several stages across embryo development, with any addition or loss of H2AK119ub1 preceding that of H3K27me3.Suspecting that H2AK119ub1 may act as an instruc-tion telling H3K27me3 where and when to form, the researchers next deleted two proteins needed to make H2AK119ub1. Indeed, egg cells missing H2AK119ub1 also lacked H3K27me3 at select genes. These genes were conse-quently more highly expressed than in control situations, an indication that normal H3K27me3-mediated imprint-ing of maternally-derived genes had been impacted.Surprisingly, the team found that the loss of H3K27me3 was irreversibly inherited by the next generation, an ef-fect that had several adverse repercussions. In addition to loss of H3K27me3-related imprinting, the missing mark increased the risk of prenatal death and placenta enlarge-ment.“These findings have important clinical implications because they suggest that changes to histone modifications in egg cells that arise before pregnancy cannot be undone once the eggs are fertilized,” Inoue explained.In follow-up studies, Inoue wants to find out how defects in histone-based inheritance compromise late de-velopment and what impact environmental changes and disease have on inheritable histone modifications.Figure: Inheritance of H3K27me3 marks in egg cells has important implications for embryo and placenta developmentA region-specific loss of H3K27me3 in egg cells, induced by knocking out (KO) two proteins (Polycomb group ring finger 1 and 6 (Pcgf1/6)), is irreversibly inherited by em-bryos and causes loss of H3K27me3-mediated imprinting, partial prenatal lethality, and placental enlargement.Original paper:Mei H, Kozuka C, Hayashi R, Kumon M, Koseki H, Inoue A. H2AK119ub1 guides maternal inheritance and zygotic deposition of H3K27me3 in mouse embryos. Nat Genet 53, 539-550 (2021)Azusa InoueHow acquired DNA marks are inherited
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