Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 119, Issue 22, Pages -Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2201883119
Keywords
3D genome; heterochromatin; epigenetic silencing; Polycomb-group proteins; RNA-mediated Polycomb loops
Categories
Funding
- NIH [S10OD018220, RM1-HG007735, R35-CA209919]
- Deutsche Forschungsgemeinschaft (DFG) [KR 5172/1]
- NSF Graduate Research Fellowship Program [NSF DGE-1656518]
- Stanford Graduate Fellowship
- DFG [MU 880/16-1]
Ask authors/readers for more resources
Polycomb-group proteins are involved in gene silencing through H3K27me3 deposition and chromatin compaction. This study investigates the distribution of long-range Polycomb-associated DNA loops in mouse ESCs and human induced pluripotent stem cells, and finds that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes. Furthermore, the study demonstrates that RNA binding is crucial for PRC2 occupancy and Polycomb-associated DNA looping. These findings reveal the importance of developmental gene loci in Polycomb spreading and provide insights into the regulation of gene silencing.
Polycomb-group proteins play critical roles in gene silencing through the deposition of histone H3 lysine 27 trimethylation (H3K27me3) and chromatin compaction. This process is essential for embryonic stem cell (ESC) pluripotency, differentiation, and development. Polycomb repressive complex 2 (PRC2) can both read and write H3K27me3, enabling progressive spreading of H3K27me3 on the linear genome. Long-range Polycomb-associated DNA contacts have also been described, but their regulation and role in gene silencing remain unclear. Here, we apply H3K27me3 HiChIP, a protein-directed chromosome conformation method, and optical reconstruction of chromatin architecture to profile long-range Polycomb-associated DNA loops that span tens to hundreds of megabases across multiple topological associated domains in mouse ESCs and human induced pluripotent stem cells. We find that H3K27me3 loop anchors are enriched for Polycomb nucleation points and coincide with key developmental genes. Genetic deletion of H3K27me3 loop anchors results in disruption of spatial contact between distant loci and altered H3K27me3 in cis, both locally and megabases away on the same chromosome. In mouse embryos, loop anchor deletion leads to ectopic activation of the partner gene, suggesting that Polycomb-associated loops control gene silencing during development. Further, we find that alterations in PRC2 occupancy resulting from an RNA binding-deficient EZH2 mutant are accompanied by loss of Polycomb-associated DNA looping. Together, these results suggest PRC2 uses RNA binding to enhance long-range chromosome folding and H3K27me3 spreading. Developmental gene loci have unique roles in Polycomb spreading, emerging as important architectural elements of the epigenome.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available