Transient co-expression of engineered transcriptional repressors (ETRs) allows for
stable and highly specific epigenetic silencing of endogenous genes, which is amenable
to multiplexing and can be reverted by targeted DNA demethylation.
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Here, the scientists repurpose the endogenous retroviruses’ silencing machinery of embryonic stem cells to stably silence three highly expressed genes in somatic cells by epigenetics. This was achieved by transiently expressing combinations of engineered transcriptional repressors that bind to and synergize at the target locus to instruct repressive histone marks and de novo DNA methylation, thus ensuring long-term memory of the repressive epigenetic state. They demonstrate the portability of this technology by multiplex gene silencing, adopting different DNA binding platforms and interrogating thousands of genomic loci in different cell types, including primary T lymphocytes. Targeted epigenome editing might have broad application in research and medicine.