Heritability of DNA Methylation Editing in Hematopoiesis

In a study appearing in the Proceedings of the National Academy of Sciences, researchers from Queen Mary University of London investigated the effect of cancer-specific DNA methylation changes on cell physiology. Building off the CRISPR/Cas9 gene editing approach, the investigators developed a method to perform epigenetic editing, which they applied to hematopoietic stem and progenitor cells. In particular, they used dCas9-3A3L to target DNA methylation and edit methylation at the CDKN2B (p15) and ARF (p14) promoters. From this, they found the ectopic DNA methylation is maintained as cells differentiate, both in vitro and in vivo. Moreover, they found that hypermethylation of p15 derails differentiation of HSPCs in vivo. As p15 methylation is heritable in both myeloid and lymphoid lineages, the authors say this demonstrates their method's usability for generating disease-relevant mouse models of human hematopoietic malignancy. "Our study shows CRISPR/dCas9 DNAm editing in primary human HSPCs is possible and gives insights into the maintenance of de novo methylation during hematopoiesis in vitro and in vivo," they conclude.