Epigenetics Podcast

In this episode of the Epigenetics Podcast, we talked with Melanie Eckersley-Maslin from the Peter McCallum Cancer Center about her work on DPPA2 and DPPA4 as Chromatin Priming Factors.

During her PhD in David Spector’s lab at Cold Spring Harbor Laboratory, Eckersley-Maslin studied monoallelic expression of autosomal genes. She developed an allele-specific RNA-sequencing screen to identify genes expressed differently from their two copies, then examined nuclear positioning, chromatin marks and DNA methylation. The work revealed associations between expression and chromatin state, but did not establish which changes caused the other.

For her postdoctoral work in Wolf Reik’s lab in the UK, she investigated epigenetic regulation of zygotic genome activation, when an embryo begins transcribing its own genome. Using mouse embryonic stem cells that can enter a two-cell-like state, her research identified DPPA2 and DPPA4 as regulators of MERVL- and Zscan4-associated transcription. This work led her to consider how early-acting proteins may prime chromatin for later cell-fate decisions, even when their loss causes effects only much later in development.

Then, Eckersley-Maslin discusses the importance of allowing researchers time to read, think and develop questions, as well as recognizing when to pause projects that are not progressing. She also describes moving from developmental biology into cancer research, bringing questions about cell identity and epigenetic regulation to a cancer-focused research environment.

Her lab now studies DPPA2 and DPPA4 in cancer, including non-small-cell lung cancer. In that context, the proteins associate with chromatin domains marked by H3K4 trimethylation and H2AK119 ubiquitination, rather than the canonical bivalent combination studied in embryos. The function of these domains, including why they lack H3K27 trimethylation despite PRC2 recruitment, remains under investigation. She describes DPPA proteins as possible scaffolds that help recruit or coordinate chromatin machinery, rather than enzymes themselves.

The conversation also covers sequential ChIP, which the lab refined to study the co-occurrence of histone modifications with limited cell numbers. Eckersley-Maslin notes that newer single-cell co-profiling methods may offer greater resolution. Looking ahead, her lab aims to identify other epigenetic priming factors and understand how chromatin states are established at particular genomic regions in particular cell types.

References

Eckersley-Maslin MA, Thybert D, Bergmann JH, Marioni JC, Flicek P, Spector DL. Random monoallelic gene expression increases upon embryonic stem cell differentiation. Dev Cell. 2014 Feb 24;28(4):351-65. doi: 10.1016/j.devcel.2014.01.017. PMID: 24576421; PMCID: PMC3955261.

Eckersley-Maslin MA, Svensson V, Krueger C, Stubbs TM, Giehr P, Krueger F, Miragaia RJ, Kyriakopoulos C, Berrens RV, Milagre I, Walter J, Teichmann SA, Reik W. MERVL/Zscan4 Network Activation Results in Transient Genome-wide DNA Demethylation of mESCs. Cell Rep. 2016 Sep 27;17(1):179-192. doi: 10.1016/j.celrep.2016.08.087. PMID: 27681430; PMCID: PMC5055476.

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The Role of lncRNAs in Tumor Growth and Treatment (Sarah Diermeier)

The Discovery of Genomic Imprinting (Azim Surani)

Epigenetic Reprogramming During Mammalian Development (Wolf Reik)

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In this episode we speak with Luke Isbell, Senior Research Fellow and group leader at Adelaide University and the South Australian immunoGENomics Cancer Institute. We discuss his work on transcription factors, chromatin, and how epigenetic marks on histones can influence transcription factor binding and function, with a focus on p53 and chromatin-based ways its activity can be silenced in cancer cells.

We also talk about how he became interested in biology, starting from growing up in rural Australia and later being introduced to epigenetics through Professor Emma Whitelaw. He describes how that experience shaped his path through honours and PhD training, and how his interest in biology developed into a long-term focus on chromatin and gene regulation.

He explains his PhD work on mouse mutagenesis screens and the transcriptional repressor WIS, which was identified in a screen for genes with epigenetic function. We discuss how that work connected WIS to regulation of clustered genes in the brain and showed the value of forward genetic screening in mice.

We then turn to his postdoctoral work in Switzerland with Dirk Schübeler, where he moved toward more mechanistic and reductionist chromatin biology. He describes the value of combining wet-lab and dry-lab work, and how that approach helps connect data generation with hypothesis testing.

Finally, we discuss his current lab in Adelaide, where he studies p53 cofactors, transcription factors, and how cofactors may help interpret chromatin marks in a tissue-specific way. He also reflects on the use of AI in science and on the importance of critical thinking, and closes by emphasizing the need to be kinder to people in academia.

References

Luke Isbel, Lexie Prokopuk, Haoyu Wu, Lucia Daxinger, Harald Oey, Alex Spurling, Adam J Lawther, Matthew W Hale, Emma Whitelaw (2016) Wiz binds active promoters and CTCF-binding sites and is required for normal behaviour in the mouse eLife 5:e15082. https://doi.org/10.7554/eLife.15082

Michael, A. K., Grand, R. S., Isbel, L., Cavadini, S., Kozicka, Z., Kempf, G., Bunker, R. D., Schenk, A. D., Graff-Meyer, A., Pathare, G. R., Weiss, J., Matsumoto, S., Burger, L., Schübeler, D., & Thomä, N. H. (2020). Mechanisms of OCT4-SOX2 motif readout on nucleosomes. Science, 368 (6498), 1460–1465. https://doi.org/10.1126/science.abb0074

Related Episodes

Effects of DNA Methylation on Chromatin Structure and Transcription (Dirk Schübeler)

Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret)

The Impact of Sequence Variation on Transcription Factor Binding (Sven Heinz)

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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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