Transgenerational inheritance of epigenetic marks: Fact or Fiction

Ehsan Pourkarimi

Molecular Biology Program, Memorial Sloan-Kettering Cancer Center

Epigenetic marks are important for the regulation of DNA replication and for the maintenance of transcriptional states. We and others have recently shown that histone modifications that demarcate genetic enhancers, such as histone H3K27 acetylation (ac) and H3K4 di/tri methylation (2/3 me) are correlated with origins of DNA replication (1). At present we know very little as to how such marks are maintained during DNA replication, across many cell divisions within the development of an organism, or in extreme cases, from one generation to the next. The notion of the transgenerational inheritance of epigenetic marks has been a subject of heated discussion for centuries. While there is growing evidence for the occurrence of such inheritance, we have yet to fully understand its underlying mechanism.

By taking advantage of nuclease deficient CRISPR/Cas9 (dCas9) technology, we have recently developed an epigenome editing tool kit in C. elegans and generated ectopic H3K27ac at a defined locus to investigate the transgenerational inheritance of such epigenetic marks. We have shown that directing dCas9::HAT to a region 5 kb upstream of the transcriptional start site leads to ectopic H3K27ac and, consequently, to the ectopic expression of downstream genes. Using an inducible promoter, we are able to express dCas9::HAT during larval development and track its effects into adulthood. Surprisingly, this ectopic H3K27 ac was maintained throughout development and led to the sustained expression of the targeted genes in adult worms. More importantly, we have strong evidence that the ectopic H3K27ac in the germline of the parental generation is transgenerationally inherited to the following generations. To our knowledge, this is the first evidence of the inheritance of activating histone modifications, such as those that define genetic enhancers.

1. E. Pourkarimi, J. M. Bellush, I. Whitehouse, Spatiotemporal coupling and decoupling of gene transcription with DNA replication origins during embryogenesis in C. elegans. Elife 5, (2016).