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  An epigenetic phenomenon involves heritable changes in the structure and function of the genome over and above the DNA sequence. This layer of information is also referred to as Epigenome. Epigenetic information is encoded in the reversible chemical modifications of histone proteins and DNA, in particular. These epigenetic modifications act as the main drivers of the cellular differentiation and de-differentiation, establishing an “epigenetic memory” that robustly maintains cell identity and can represent a formidable barrier to cellular reprogramming. Similarly, losses of cell identity can result from aberrations in nature’s tightly engineered circuits of protein-protein and protein-DNA interactions that maintain the stable inheritance of the modified chromatin states. This epigenetic layer of genome regulation is increasingly linked to the human disease. A few recent reports have demonstrated the engineering of the transcriptional effectors that allow the targeted manipulation of the epigenetic landscape also known as epigenome engineering and/or epigenome editing. This innovative Epigenome engineering framework has opened a window of opportunity towards controlled switching of the epigenetic states as discovery and application tools (including therapeutics) within a wider synthetic biology framework.

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Targeting epigenomic modifications

One of the main principles of epigenomic editing is the targeting of enzymes to specific regions of DNA. For example, targeting a histone methylase enzyme to a specific DNA sequence could increase histone methylation in that region. There have been several different ways of achieving specific targeting, including transcription activator-like effector proteins (TALEs) or zinc finger proteins. The most commonly used method now is using a modified CRISPR-Cas9 system. Whilst the classic use of CRISPR involves using the Cas9 enzyme to introduce targeted double stranded breaks, epigenomic modifications can be introduced using an inactivated or 'dead' Cas9 (dCas9). Different enzymes can be conjugated to dCas9 and will then be specifically localised to the DNA sequence specified by the CRISPR system. In 2015, researchers conjugated CRISPR-dCas9 to the catalytic core of p300, an acetyltransferase enzymes. This allowed them to induce localised acetylation of histone proteins and subsequent transcriptional activation.

 

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