In these GEITP pages, we have often discussed that any phenotype (trait) can be Mendelian or multifactorial. Mendelian inheritance involves the contribution from one or a relatively small number of genes –– and manifestations can occur at birth or later in life. Multifactorial traits include contributions from genetics (differences in DNA sequence), plus epigenetics (differences in the chromosome other than DNA variants), plus environmental effects (adverse insults that can alter either DNA sequence or epigenetic factors), plus even transgenerational effects (still poorly understood, a stimulus in the grandparent that affects the parent and can even affect the grandchild). Epigenetics classically has included DNA-methylation, RNA-interference, histone modifications, and chromatin remodeling.
The topic of the attached publication represents epigenetic effects, which can cause certain disorders also has been used as therapy to treat certain complex diseases –– such as cancer, type-2 diabetes, autoimmunity, and some Mendelian disorders. Most of these approaches have relied on drugs that ubiquitously alter epigenetic marks (e.g. DNA-methylation or histone modifications). These “epi-drugs” cause many side-effects, because ”off-target genes” can also be affected. Therefore, it is important to establish new methods for generating targeted epigenetic modifications that alter only the expression of specific genes.
Also discussed on these pages numerous times, CRISPR/Cas9 methodology has led to the development of tools for rapid and efficient RNA-based, sequence-specific genome editing. In addition to enabling the engineering of genomes, recent alterations to the CRISPR/Cas9 system have provided opportunities for regulating gene expression and for creating epigenetic alterations –– without introducing DNA double-strand breaks (this circumvents concerns of creating undesirable permanent mutations in target genomes).
Authors [see attached] describe a robust system for in vivo activation of endogenous target genes through trans-epigenetic remodeling. The system relies on recruitment of Cas9 and transcriptional activation complexes to target loci by modified single-guide RNAs. As proof-of-principle, authors used this technology to treat mouse models of type-2 diabetes, muscular dystrophy, and acute kidney disease. Their data show that CRISPR/Cas9-mediated target gene activation can be achieved in the intact animal, leading to quantifiable phenotypes and amelioration of disease symptoms. This breakthrough should establish new avenues for developing targeted epigenetic therapies against human diseases.
Cell 14 Dec 2017; 171, 1495–1507