Epigenome engineering: new technologies for precision medicine

Abstract

Chromatin adopts different configurations that are regulated by reversible covalent modifications, referred to as epigenetic marks. Epigenetic inhibitors have been approved for clinical use to restore epigenetic aberrations that result in silencing of tumor-suppressor genes, oncogene addictions, and enhancement of immune responses. However, these drugs suffer from major limitations, such as a lack of locus selectivity and potential toxicities. Technological advances have opened a new era of precision molecular medicine to reprogram cellular physiology. The locus-specificity of CRISPR/dCas9/12a to manipulate the epigenome is rapidly becoming a highly promising strategy for personalized medicine. This review focuses on new state-of-the-art epigenome editing approaches to modify the epigenome of neoplasms and other disease models towards a more ‘normal-like state’, having characteristics of normal tissue counterparts. We highlight biomolecular engineering methodologies to assemble, regulate, and deliver multiple epigenetic effectors that maximize the longevity of the therapeutic effect, and we discuss limitations of the platforms such as targeting efficiency and intracellular delivery for future clinical applications.

Epigenetics, microRNA and Metabolic Syndrome: A Comprehensive Review

“…The use of epigenetic editing tools for MetS is still in its infancy, although there is growing interest in using these tools for other related metabolic diseases, such as T2DM [ 162 ]. Since the loss of insulin-secreting β-cells is characteristic of the diabetes pathophysiology and because these cells do not proliferate readily, expanding the source of these cells remains a challenge.…”

Reprogramming the anti-tumor immune response via CRISPR genetic and epigenetic editing

“…For further details on the concerns surrounding use of CRISPR-based therapeutics in a general sense, we refer to excellent previously published reviews. 74 , 158 , 159 , 160 , 161 In this section, however, we focus specifically on the concerns associated with CRISPR use in cancer immunotherapy.…”

“…For the most studied domains, such as VP64 and KRAB, off targets have been shown to be either zero or have negligible effects on non-cognate gene transcription. 74 Finally, whereas Cas9 genome engineering unavoidably results in permanent changes, epigenetic approaches are reversible, circumventing the risk of inducing sequence changes in the target DNA, 71,75 a key factor in the targeting of tumors harboring high degrees of genetic instability. Moreover, the durability of the epigenetic and If no donor-corrected template is available, non-homologous end joining (NHEJ) occurs whereby random insertions and/or deletions are incorporated, rendering the gene non-functional or disrupted.…”

Silencing hepatitis B virus covalently closed circular DNA: The potential of an epigenetic therapy approach

“…Epigenome engineering has become a popular targeted gene therapy approach to promote locus-specific epigenetic changes to treat genetic diseases[ 24 ]. Effector domains based on a variety of transcriptional activators, repressors, and chromatin remodeling enzymes including the typical writers, readers and erasers (Table 1 ) have been fused to DNA binding domains (DBD) to promote site-specific modifications.…”

“…CRISPR/Cas base editors comprising an APOBEC1 deaminase, Cas9 nickase, and uracil glycosylase inhibitor introduced point mutations in cccDNA as well as integrated viral DNA[ 23 ]. A number of new epigenome engineering platforms have also been developed, which could be used to generate targeted epigenetic changes to control gene expression[ 24 ]. Such an approach may be well suited to treating CHB, as epigenetic modifications regulate cccDNA minichromosome organization and can either promote or repress viral transcription[ 25 - 27 ].…”