Ensuring the sustainability of our environment is a noble goal, and when it comes to the chromatin microenvironments epigenome editing is no exception. While we’ve seen a range of epigenome editing applications, the long-term (mitotically stable) nature of these modifications has remained a challenge.
In 2002, epigenome editing demonstrated that when it comes to the regulation of gene expression, some histone modifications aren’t just a consequence of transcription and are capable of initiating it. Now, the pioneering epigenetic editing lab of Marianne Rots at the University of Groningen has stepped up to the challenge of sustainable epigenetic editing.
In their research, the team utilized two DNA-binding domains, Zinc Fingers (ZFs) and deactivated Cas9 (dCas9) for some precision epigenome editing. They also experimented with two histone methyltransferases that deposit activating marks: PRDM9, which brings forth H3K4me, and DOT1L, the provider of H3K79me.
And if that wasn’t enough options for you, the experiments ranged across a number of cell lines, which include: HEK293T human embryonic kidney cells, A549 lung cancer cells, A2780 ovarian cancer cells, as well as HeLa and C33a cervical cancer cells.
Here’s what they discovered about editing different chromatin microenvironments:
- PRDM9 can target activating H3K4me to a locus that isn’t DNA hypermethylated and stably re-activate silenced genes
- DNA hypermethylation of a CpG island at a target locus only allows for transient, and not stable, reactivation by PRDM9
- Co-targeting PRDM9 and DOT1L effectors allows for sustained activation in regions of DNA hypermethylation
Thus, it appears that histone crosstalk is critical for re-activating the expression of genes regulated by CpGs islands with DNA hypermethylation. Rots concludes, “By epigenetic editing, we induced H3K4me on silenced genes and observed gene re-expression. More importantly, we also addressed sustainability and demonstrated the role of H3K79 in sustained expression.”
Go learn how to use epigenome editing to sustain your expression over at Nature Communications, August 2016