Abstract
Imprinting diseases (IDs) are rare congenital disorders caused by aberrant dosages of imprinted genes. Rare IDs are comprised by a group of several distinct disorders that share a great deal of homology in terms of genetic etiologies and symptoms. Disruption of genetic or epigenetic mechanisms can cause issues with regulating the expression of imprinted genes, thus leading to disease. Genetic mutations affect the imprinted genes, duplications, deletions, and uniparental disomy (UPD) are reoccurring phenomena causing imprinting diseases. Epigenetic alterations on methylation marks in imprinting control centers (ICRs) also alters the expression patterns and the majority of patients with rare IDs carries intact but either silenced or overexpressed imprinted genes. Canonical CRISPR/Cas9 editing relying on double-stranded DNA break repair has little to offer in terms of therapeutics for rare IDs. Instead CRISPR/Cas9 can be used in a more sophisticated way by targeting the epigenome. Catalytically dead Cas9 (dCas9) tethered with effector enzymes such as DNA de- and methyltransferases and histone code editors in addition to systems such as CRISPRa and CRISPRi have been shown to have high epigenome editing efficiency in eukaryotic cells. This new era of CRISPR epigenome editors could arguably be a game-changer for curing and treating rare IDs by refined activation and silencing of disturbed imprinted gene expression. This review describes major CRISPR-based epigenome editors and points out their potential use in research and therapy of rare imprinting diseases.
Highlights
Nuclease activity is executed by two Cas9 cleavage domains, RuvC and HNH, which together mediate a double-strand
Dead Cas9 fused or bound to an ‘epi- effector’ domain can modulate gene expression in most conceivable ways able to ameliorate or treat rare Imprinting diseases (IDs) caused by aberrant gene expression of imprinted genes
The epigenome editors based on CRISPR/Cas system represents new ways of activating existing but silenced alleles on the other parent-of-origin chromosome or ways to decrease the expression of genes, which are improperly biallelically expressed
Summary
The current course of genome engineering is set by tools derived from the bacterial immune system referred to as CRISPR/Cas DNA methylation is an epigenetic modification playing a crucial role in many regulatory processes It is involved in regulation of transcriptional gene expression, genomic imprinting, X inactivation, silencing of mobile elements, and maintenance of genome integrity [12]. Epi-editors with DNMT catalytic domains modify CpG-rich loci in the manner described above, leading to silencing of gene expression and chromatin rearrangements [15,16]. After treatment of affected mice, researchers observed elevated expression of targeted genes, together with decreased promoter methylation and reduced fibrogenesis in kidneys [70] These studies imply that CRISPR epi-editor systems with TET catalytic domains are capable of effective demethylation in a locus-specific manner
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
