The role of DNA demethylation in liver to pancreas transdifferentiation

Abstract

Background Insulin producing cells generated by liver cell transdifferentiation, could serve as an attractive source for regenerative medicine. The present study assesses the relationship between DNA methylation pTFs induced liver to pancreas transdifferentiation. Results The transdifferentiation process is associated with DNA demethylation, mainly at gene regulatory sites, and with increased expression of these genes. Active inhibition of DNA methylation promotes the pancreatic transcription factor-induced transdifferentiation process, supporting a causal role for DNA demethylation in this process. Conclusions Transdifferentiation is associated with global DNA hypomethylation, and with increased expression of specific demethylated genes. A combination of epigenetic modulators may be used to increase chromatin accessibility of the pancreatic transcription factors, thus promoting the efficiency of the developmental process.

Increasing Specificity of Targeted DNA Methylation Editing by Non-Enzymatic CRISPR/dCas9-Based Steric Hindrance

“…DNA modifications are base specific and can provide higher sequence-specific resolution than histone modifications, which can cover a wider region. There is a significant body of evidence that demonstrates DNA methylation alterations in various diseases, such as cancer [19][20][21][22], autoimmune disease [23,24], cardiovascular disease [25][26][27][28], and metabolic disease [24,29]. If it is indeed demonstrated that specific alterations are causal, targeted epigenetic editing could potentially reverse the disease-associated DNA methylation profiles in vivo; in other words, targeted epigenetic editing is well suited to address both causality and correction.…”

“…If it is indeed demonstrated that specific alterations are causal, targeted epigenetic editing could potentially reverse the disease-associated DNA methylation profiles in vivo; in other words, targeted epigenetic editing is well suited to address both causality and correction. Targeted epigenetic programming may also have applications in cell therapy and immune therapy, as in, for instance, trans-differentiation of liver cells to produce insulin through demethylation of the insulin gene and pancreatic-specific transcription factors [28,30] or silencing of checkpoint inhibitors in patient T cells [31,32] to enhance immunotherapy. However, there are still numerous barriers to overcome.…”