CpG Islands, Polycomb, and the Regulation of Transcription (Rob Klose)

In this episode we speak with Rob Klose, Professor of Genetics at the University of Oxford, about how CpG islands help control gene expression and chromatin regulation during development.

We discuss how his lab connected CpG islands to histone modifications and chromatin regulation. He describes how KDM2A and KDM2B were found to recognize CpG islands, how this led to the study of H3K36 methylation at promoters, and how BioCAP was developed to isolate non-methylated DNA. He also explains how this work showed that CpG islands are conserved across vertebrates.

We also talk about the unexpected link between CpG islands, PRC1, and PRC2. He outlines how PRC1-dependent H2A ubiquitylation can recruit PRC2 and promote H3K27 trimethylation, and how his lab tested these pathways with ectopic tethering experiments. He further discusses what is known about H2A ubiquitylation, how it may affect access of the pre-initiation complex, and why the exact mechanism is still not fully understood.

Another major theme is how CpG islands may help maintain gene expression states. We cover how SET1 at CpG islands helps prevent premature transcription termination at a subset of genes, especially those that are lowly transcribed, and how Polycomb can help lock genes in an off state. He also explains how the plus-one nucleosome and other early elongation barriers fit into this framework.

Finally, we discuss the value of combining bulk genomics with live-cell imaging. He describes how single-cell approaches reveal stochastic, burst-like transcription that is hidden by ensemble measurements, and why his lab is now building synthetic systems and mathematical models to test how CpG islands, enhancers, and core promoters work together to shape transcription.

References

• Blackledge NP, Zhou JC, Tolstorukov MY, Farcas AM, Park PJ, Klose RJ. CpG islands recruit a histone H3 lysine 36 demethylase. Mol Cell. 2010 Apr 23;38(2):179-90. doi: 10.1016/j.molcel.2010.04.009. PMID: 20417597; PMCID: PMC3098377.

• Blackledge NP, Farcas AM, Kondo T, King HW, McGouran JF, Hanssen LLP, Ito S, Cooper S, Kondo K, Koseki Y, Ishikura T, Long HK, Sheahan TW, Brockdorff N, Kessler BM, Koseki H, Klose RJ. Variant PRC1 complex-dependent H2A ubiquitylation drives PRC2 recruitment and polycomb domain formation. Cell. 2014 Jun 5;157(6):1445-1459. doi: 10.1016/j.cell.2014.05.004. Epub 2014 May 22. PMID: 24856970; PMCID: PMC4048464.

• Long HK, King HW, Patient RK, Odom DT, Klose RJ. Protection of CpG islands from DNA methylation is DNA-encoded and evolutionarily conserved. Nucleic Acids Res. 2016 Aug 19;44(14):6693-706. doi: 10.1093/nar/gkw258. Epub 2016 Apr 15. PMID: 27084945; PMCID: PMC5001583.

• Huseyin, M.K., Klose, R.J. Live-cell single particle tracking of PRC1 reveals a highly dynamic system with low target site occupancy. Nat Commun 12, 887 (2021). https://doi.org/10.1038/s41467-021-21130-6

Related Episodes

• Polycomb and Three-Dimensional Genome Organisation (Oliver Bell)

• Polycomb Proteins, Gene Regulation, and Genome Organization in Drosophila (Giacomo Cavalli)

• CpG Islands, DNA Methylation, and Disease (Sir Adrian Bird)

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