Inheritable silencing of endogenous genes by hit-and-run targeted epigenetic editing
Open accessAbstract
Gene silencing is instrumental to interrogate gene function and holds promise for therapeutic applications. Here, we 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. Silencing was highly specific, as shown by genome-wide analyses, sharply confined to the targeted locus without spreading to nearby genes, resistant to activation induced by cytokine stimulation, and relieved only by targeted DNA demethylation. We 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.
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Targeted de-methylation with a dCas9-TET fusion protein has been demonstrated.
“Similarly, targeted de-methylation with a dCas9-TET fusion protein has been demonstrated (Amabile et al., 2016; Liu et al., 2016), and this strategy could be used to restore an insulated neighborhood whose anchor site is disrupted by aberrant DNA methylation (Figure 8B).”
From Insulated Neighborhoods: Structural and Functional Units of Mammalian Gene Control (2016) · cites this paper as Amabile et al., 2016
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- Authors
- Amabile, A., Migliara, A., Capasso, P., Biffi, M., Cittaro, D., Naldini, L., & Lombardo, A.
- Affiliations
- Vita-Salute San Raffaele University (IT)
- The San Raffaele Telethon Institute for Gene Therapy (IT)
- IRCCS Ospedale San Raffaele (IT)
- Corresponding author
- Naldini, Luigi
- Lombardo, Angelo
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2016-09
- Volume
- 167
- Issue
- 1
- Pages
- 219-232.e14
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5039111
- OpenAlex
- W2522031854
- Cited by
- 516
- References
- 52
- Citations by year
- 2026: 45 · 2025: 51 · 2024: 62 · 2023: 52 · 2022: 57 · 2021: 56 · 2020: 43 · 2019: 48 · 2018: 48 · 2017: 46 · 2016: 5
- FWCI
- 25.46
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Archivio Istituzionale della Ricerca - Università Vita-Salute San Raffaele (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Keywords
- gene silencing, endogenous retroviruses, embryonic stem cells, de novo methylation, epigenetic memory, T cells, cytokine induction, DNA demethylation
- MeSH terms
- Gene Editing, DNA Methyltransferase 3A, DNA (Cytosine-5-)-Methyltransferases, Genetic Engineering, Humans, Repressor Proteins, T-Lymphocytes, Gene Targeting, DNA Methylation, Catalytic Domain, Gene Silencing, Kruppel-Like Transcription Factors, Embryonic Stem Cells
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