ArticleScientific reports2021
Epigenetic silencing directs expression heterogeneity of stably integrated multi-transcript unit genetic circuits.
Article in Scientific reports, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- IQGAP Family Proteins in Colorectal Cancer: Molecular Mechanisms and Prognostic Implications.Diagnostics (Basel, Switzerland) · 2026Review
- Development of a BM7G(TKO/hCD46/hCD55/hTHBD/hEPCR) donor pig with endogenous promoter-driven transgenes for xenotransplantation.Frontiers in immunology · 2026Article
- Reversing transgene silencing via targeted chromatin editing.bioRxiv : the preprint server for biology · 2025Article
- Expression of UCOE and HSP27 Molecular Elements to Improve the Stable Protein Production on HEK293 Cells.BioMed research international · 2025Article
- SHIELD: a platform for high-throughput screening of barrier-type DNA elements in human cells.Nature communications · 2023Article
- The sound of silence: Transgene silencing in mammalian cell engineering.Cell systems · 2022Review
- Epigenetic cell memory: The gene's inner chromatin modification circuit.PLoS computational biology · 2022Article
- Review
- Novel synthetic biology approaches for developmental systems.Stem cell reports · 2021Review
Corrections and comments
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Authors and funding
8 authors.
Funding
Abstract
We report that epigenetic silencing causes the loss of function of multi-transcript unit constructs that are integrated using CRISPR-Cas9. Using a modular two color reporter system flanked by selection markers, we demonstrate that expression heterogeneity does not correlate with sequence alteration but instead correlates with chromosomal accessibility. We partially reverse this epigenetic silencing via small-molecule inhibitors of methylation and histone deacetylation. We then correlate each heterogeneously-expressing phenotype with its expected epigenetic state by employing ATAC-seq. The stability of each expression phenotype is reinforced by selective pressure, which indicates that ongoing epigenetic remodeling can occur for over one month after integration. Collectively, our data suggests that epigenetic silencing limits the utility of multi-transcript unit constructs that are integrated via double-strand repair pathways. Our research implies that mammalian synthetic biologists should consider localized epigenetic outcomes when designing complex genetic circuits.
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Registered trials
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