Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 111, Issue 33, Pages E3415-E3421Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1400672111
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Funding
- Novartis Research Foundation
- European Union [FP7- HEALTH-2010-257082, FP7-282510]
- European Research Council (EpiGePlas)
- Swiss National Science Foundation Sinergia program
- Swiss Initiative in Systems Biology (RTD Cell Plasticity)
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Trimethylation of histone H3 at lysine 27 H3K27me3) is a chromatin mark associated with Polycomb-mediated gene repression. Despite its critical role in development, it remains largely unclear how this mark is targeted to defined loci in mammalian cells. Here, we use iterative genome editing to identify small DNA sequences capable of autonomously recruiting Polycomb. We inserted 28 DNA elements at a defined chromosomal position in mouse embryonic stem cells and assessed their ability to promote H3K27me3 deposition. Combined with deletion analysis, we identified DNA elements as short as 220 nucleotides that correctly recapitulate endogenous H3K27me3 patterns. Functional Polycomb recruiter sequences are invariably CpG-rich but require protection against DNA methylation. Alternatively, their activity can be blocked by placement of an active promoter-enhancer pair in cis. Taken together, these data support the model whereby PRC2 recruitment at specific targets in mammals is positively regulated by local CpG density yet obstructed by transcriptional activity or DNA methylation.
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