Epigenetics Podcast

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

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Polycomb and Three-Dimensional Genome Organisation (Oliver Bell)

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In this episode of the Epigenetics Podcast, we talked with Onder Albayram from the Medical University of South Carolina about the role of the endocannabinoid system in brain aging and neuroprotection.

A major part of the conversation focuses on the endocannabinoid system. We talk about CB1 receptors, the endogenous ligands anandamide and 2-AG, and the enzymes involved in making and breaking them down. Dr. Albayram explains that this signaling system is widespread in the brain and is important for neuroimmune regulation and neuronal communication.

We then cover his aging studies in the hippocampus. He reports that endocannabinoid tone declines with age, with reduced 2-AG and related biosynthetic machinery in old hippocampus, without a compensatory increase in receptor expression. He also describes experiments showing that deleting CB1 receptors improves learning in young animals but impairs performance in old animals.

Another key topic is low-dose THC treatment in old mice. He reports that prolonged low-dose THC improved learning and memory in old animals, while reducing performance in young animals. After washout, the older animals still showed improved behavior, along with changes in synaptic proteins and gene expression patterns that shifted toward a younger profile.

We also discuss the epigenetic findings. He says THC increased histone acetylation at promoters of anti-aging genes such as BDNF and Klotho after treatment had ended, suggesting longer-lasting regulation. He is now focusing on GABAergic neurons in the hippocampus to identify the specific epigenetic mechanisms involved and how they may relate to age-dependent neurodegenerative disorders.

References

Albayram, O., Alferink, J., Pitsch, J., Piyanova, A., Neitzert, K., Poppensieker, K., Mauer, D., Michel, K., Legler, A., Becker, A., Monory, K., Lutz, B., Zimmer, A., & Bilkei-Gorzo, A. (2011). Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging. Proceedings of the National Academy of Sciences of the United States of America, 108(27), 11256–11261. https://doi.org/10.1073/pnas.1016442108

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In this episode of the Epigenetics Podcast, we talked with Kunal Rai from MD Anderson Cancer Center about his work on chromatin state reprogramming in cancer progression.

A major part of the conversation covers his postdoctoral work on active DNA demethylation. He describes how he identified an AID-MBD4-based mechanism, later supported by GAD45, and how this work showed a role for DNA demethylation in early neuronal differentiation and in colon cancer initiation.

We then discuss his move into his own lab and his work on melanoma progression. He explains how he used broad epigenomic profiling, chromatin state analysis, and 3D chromatin methods to study enhancers and chromatin organization, and how these approaches helped reveal changes linked to cancer progression.

Another topic is his work on epigenetic regulators such as RNF2 and KMT2D. He describes findings on polycomb and trithorax-related factors, including tumor-suppressive roles for KMT2D in melanoma and lung cancer, and how KMT2D loss affects cell phenotype and metabolism.

Finally, we talk about lab organization, collaboration, and newer technologies. He says his group works across multiple cancer types and increasingly includes immunology, single-cell methods, spatial epigenomics, and clinical translation, while still using ChIP-seq, CUT&RUN, and CUT&Tag where appropriate.

References

Fiziev, P., Akdemir, K. C., Miller, J. P., Keung, E. Z., Samant, N. S., Sharma, S., Natale, C. A., Terranova, C. J., Maitituoheti, M., Amin, S. B., Martinez-Ledesma, E., Dhamdhere, M., Axelrad, J. B., Shah, A., Cheng, C. S., Mahadeshwar, H., Seth, S., Barton, M. C., Protopopov, A., Tsai, K. Y., … Rai, K. (2017). Systematic Epigenomic Analysis Reveals Chromatin States Associated with Melanoma Progression. Cell reports, 19(4), 875–889. https://doi.org/10.1016/j.celrep.2017.03.078

Terranova, C. J., Tang, M., Maitituoheti, M., Raman, A. T., Ghosh, A. K., Schulz, J., Amin, S. B., Orouji, E., Tomczak, K., Sarkar, S., Oba, J., Creasy, C., Wu, C. J., Khan, S., Lazcano, R., Wani, K., Singh, A., Barrodia, P., Zhao, D., Chen, K., … Rai, K. (2021). Reprogramming of bivalent chromatin states in NRAS mutant melanoma suggests PRC2 inhibition as a therapeutic strategy. Cell reports, 36(3), 109410. https://doi.org/10.1016/j.celrep.2021.109410

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In this episode of the Epigenetics Podcast, we talked with Steffen Rulands from the Ludwig Maximilian University of Munich about how methods from statistical physics can be used to study collective phenomena in biology. We discuss his path from physics into stem cell biology and epigenetics, and how this background shapes the questions he asks in his work.

We talk about his lab’s focus on quantitative and mechanistic modeling rather than wet lab experiments. He explains that he uses single-cell genomics and other datasets to understand how cells make decisions, with interests ranging from development and regeneration to aging and rejuvenation.

A major topic is DNA methylation during embryonic development. We discuss how he and his collaborators found surprisingly simple, self-similar patterns in methylation over time and along the genome, and how they explained these patterns with a feedback loop between chromatin conformation and methylation deposition.

We also cover his collaboration on social insect colonies, where he examines how DNA methylation and gene regulation help explain stable social roles and flexibility when the queen is removed. In that system, interactions across the whole nest shape the regulation of queen- and worker-associated genes.

Later in the conversation, we turn to aging. We discuss his recent work on temporal hierarchies in epigenetic aging and on collective dynamics of DNA methylation, where we ask how molecular-scale events can combine to produce the long timescale of organismal aging. We close by talking about rejuvenation, general principles in aging, and the role of physics in identifying what is generic versus what is specifically regulated in biology.

References

Rulands, S., Lee, H. J., Clark, S. J., Angermueller, C., Smallwood, S. A., Krueger, F., Mohammed, H., Dean, W., Nichols, J., Rugg-Gunn, P., Kelsey, G., Stegle, O., Simons, B. D., & Reik, W. (2018). Genome-Scale Oscillations in DNA Methylation during Exit from Pluripotency. Cell systems, 7(1), 63–76.e12. https://doi.org/10.1016/j.cels.2018.06.012

Olmeda, F., Lohoff, T., Kafetzopoulos, I. et al. Scaling and self-similarity in the formation of the embryonic epigenome. Nat. Phys. 22, 931–940 (2026). https://doi.org/10.1038/s41567-026-03263-x

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In this episode, we speak with Andrea Brand, Chair of the Department of Cell Biology at NYU Grossman School of Medicine and Director of the Regenerative Medicine Institute. We discuss her scientific path from yeast gene regulation to Drosophila neurobiology, and how early interests in DNA and microscopy shaped her career.

We talk about the development of the GAL4 system with Norbert Perrimon and how it enabled targeted gene expression in specific tissues and cells. Andrea explains why this approach has remained useful across decades, including its applications in Drosophila and beyond, while noting that no experimental system is perfect and results should be cross-checked with other methods.

We also discuss targeted DAM-ID and chromatin DAM-ID, methods developed in her lab to study protein-DNA interactions and chromatin marks in vivo without removing cells from their normal tissue environment. Andrea describes how these tools helped her lab analyze neural stem cells in their niche and investigate changes in chromatin during quiescence and reactivation.

A major theme of the conversation is neural stem cell quiescence. We cover how her lab found that quiescent stem cells can show unexpectedly open chromatin, express neuronal genes, and adopt neuron-like features, including long projections and interactions with neurons. We also discuss the link to metabolism, including feeding signals, the fat body, blood-brain barrier glia, insulin-like peptides, and TGF-beta signaling.

Finally, we talk about Andrea’s recent move toward human brain organoids and the goal of connecting model organism work to human biology and patient data. We discuss ongoing work on quiescent cells, TRIB family genes, and cancer–neuron interactions, as well as the need to better distinguish quiescence from senescence in vivo.

References

Brand, A. H., & Perrimon, N. (1993). Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development (Cambridge, England), 118(2), 401–415. https://doi.org/10.1242/dev.118.2.401

Southall, T. D., Gold, K. S., Egger, B., Davidson, C. M., Caygill, E. E., Marshall, O. J., & Brand, A. H. (2013). Cell-type-specific profiling of gene expression and chromatin binding without cell isolation: assaying RNA Pol II occupancy in neural stem cells. Developmental cell, 26(1), 101–112. https://doi.org/10.1016/j.devcel.2013.05.020

Tang, J. L. Y., Hakes, A. E., Krautz, R., Suzuki, T., Contreras, E. G., Fox, P. M., & Brand, A. H. (2022). NanoDam identifies Homeobrain (ARX) and Scarecrow (NKX2.1) as conserved temporal factors in the Drosophila central brain and visual system. Developmental cell, 57(9), 1193–1207.e7. https://doi.org/10.1016/j.devcel.2022.04.008

Cheetham, S. W., & Brand, A. H. (2018). RNA-DamID reveals cell-type-specific binding of roX RNAs at chromatin-entry sites. Nature structural & molecular biology, 25(1), 109–114. https://doi.org/10.1038/s41594-017-0006-4

Cheetham, S. W., Gruhn, W. H., van den Ameele, J., Krautz, R., Southall, T. D., Kobayashi, T., Surani, M. A., & Brand, A. H. (2018). Targeted DamID reveals differential binding of mammalian pluripotency factors. Development (Cambridge, England), 145(20), dev170209. https://doi.org/10.1242/dev.170209

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