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.

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

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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Epigenetics Podcast on Bluesky

Dr. Stefan Dillinger on LinkedIn

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Email: [email protected]

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.

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.

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.

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.

In this episode we speak with Alon Goren from UC San Diego about his work at the intersection of genomic technology development and chromatin biology. We discuss how his lab studies how the epigenome is regulated, how disruption of that regulation contributes to disease, and how technology can be improved to make results more robust and reproducible.

We talk about his early interest in biology, how that developed through medical research training, and how a molecular biology lab shaped the direction of his career. He explains how curiosity about how cells and organisms work led him toward genomics and chromatin research.

We then discuss several methods from his career, including early direct sequencing approaches for small amounts of DNA and RNA, ChIP-based methods for chromatin regulators, and work on improving ChIP-seq workflows. He explains why antibody choice matters, why monoclonal antibodies can improve reproducibility, and how automation helped scale the process.

We also cover his work on spike-in normalization, including the risks of using exogenous chromatin incorrectly and the need for better safeguards in genome-wide comparisons. He describes a newer approach that uses two spike-ins to provide multiple checks on normalization.

Finally, we discuss his work on short tandem repeats, zebrafish heart regeneration, and SIRT6-related polymerase pausing, as well as a newer platform that converts molecular interactions into sequencing-readable barcodes. He closes by stressing the importance of validation, careful protocol design, and methods that can be used reliably by multiple people.

In this episode of the Epigenetics Podcast, we talked with Tomohisa Toda from the Max-Planck-Zentrum für Physik und Medizin about his work on the long-term maintenance of neuronal identity, with a focus on epigenetic and RNA-based mechanisms in brain stability and aging.

Dr. Toda describes how brain circuits are stabilized over time, why critical periods are temporally restricted, and how epigenetic regulation may help maintain established neural identity. This led him to postdoctoral work on neural stem cells and long-term maintenance.

We cover his work on nuclear pore and nuclear lamina proteins, including NUP153 and Lamin B1. He explains that NUP153 is enriched in neural stem cells and appears to act as a platform for recruiting factors that help maintain the stem cell epigenome. For Lamin B1, we discuss its decline during aging, how its loss can lead to stem cell exhaustion, reduced adult neurogenesis, and age-related mood dysregulation in the hippocampus.

We also discuss LINE-1 RNA, where we learn that reducing LINE-1 promotes neural progenitor differentiation. He explains that this effect is linked to the RNA sequence itself rather than retrotransposition, based on rescue experiments.

Finally, we talk about his finding that a subset of postnatally born brain cells contains nuclear RNAs that remain detectable for up to two years. He describes their nuclear enrichment, possible association with heterochromatin, and ongoing work to understand their sequence features, modifications, and biological function.

In this episode of the Epigenetics Podcast, we talked with Tae-Kyung Kim from POSTECH in South Korea about the discovery and characterisation of enhancer RNAs.

Dr. Kim describes joining Danny Reinberg’s lab as a graduate student, where he was trained in protein biochemistry and general transcription mechanisms. He recalls this period as a formative time, when research on transcription factors and RNA polymerase II was rapidly advancing and many findings were still novel.

Kim then moved into neurobiology through Michael Greenberg’s lab, where he first worked on a project related to L-type voltage-gated channels. He says his work shifted toward chromatin and gene regulation in neurons after learning that chromatin immunoprecipitation could be applied to neuronal systems and after the arrival of next-generation sequencing.

He explains that eRNAs were discovered in his lab through RNA-seq and ChIP-seq data from neuronal activity experiments, especially around the FOS locus. He later showed that eRNAs are transcribed from enhancers, are typically unstable, often lack splicing and polyadenylation, and have defined initiation sites, suggesting regulated transcription.

Kim says eRNAs can interact with transcription and epigenetic regulators, including factors involved in pause release and mediator complexes. He describes experiments showing that eRNA knockdown reduced ARC induction and that eRNA production depends on proper enhancer-promoter contact.

He concludes by describing newer work in his lab using spatial transcriptomics and eRNA-based reporter systems to map active neural populations, including studies related to cocaine-responsive circuits. He says his future work will focus on spatial technologies to better understand brain organization and function at molecular resolution.

In this episode of the Epigenetics Podcast, we talked with Peter Becker from the  Biomedical Center Munich about his successful career in Epigenetics, where he discovered the chromatin remodeler ISWI and dosage compensation complex MOF.

Dr. Becker shares thoughts about his postdoctoral work with Carl Wu, where he developed embryo extract systems for studying chromatin assembly and transcription. He explains how work on Drosophila extracts led to the purification of ATP-dependent remodeling factors, including ISWI-related complexes, and how these studies showed that such factors slide nucleosomes and help organize chromatin.

We also cover his move to EMBL and later to Munich, where his lab expanded into dosage compensation in Drosophila. He describes work on the MSL complex targeting, MRE sequences, ROX RNA, DNA shape features, and how biochemical reconstitution was used to study how the complex recognizes the X chromosome.

Finally, we discuss his later work on TIP-60 and histone acetylation, including acetylome studies, and his reflections on leadership roles at EMBL and on the use of the term epigenetics. He emphasizes that epigenetics should be understood as one layer among genetics, environment, and socialization, not as a replacement for genetics.

In this episode of the Epigenetics Podcast, we talked with Filippo Rijli from the Friedrich Miescher Institute about his work on transcriptional and epigenetic regulation of craniofacial and neuronal development.

Dr. Rijli recalls pivotal moments in his career, including his postdoctoral work where he explored the functions of HoxA2 in craniofacial development. We discuss key findings from his landmark papers, highlighting how individual transcription factors like HoxA2 can dictate the topographic organization of neuronal circuits. His exploration of the whisker-to-barrel cortex circuit in mice unveils how sensory inputs are mapped and processed through precise neuronal connections. This intricate mapping reveals how singular genes can impact the wiring of entire neurological systems.

We also reflect on the evolution of scientific communication throughout Filippo’s career, from the reliance on faxes and handwritten requests for paper reprints to today's instant access to research through digital platforms. His early experiences have instilled in him a resourcefulness that continues to inform his approach to research, particularly in environments with limited resources where collaboration becomes essential.

Our discussion shifts to his recent research endeavors that delve into transcriptional and epigenetic regulation during neuronal and craniofacial development. Dr. Rijli elaborates on a 2015 study which demonstrated how the ectopic expression of HoxA2 could lead to the creation of artificial whisker maps in the brain, providing insights into how transcription factors guide neuronal behavior and circuit formation. His work on the histone methyltransferase EZH2 reveals its crucial role in the tangential migration of cerebellar neurons and the mechanisms that ensure these neurons reach their accurate destinations during development.

Dr. Rijli's research further investigates the chromatin landscape of cranial neural crest cells, uncovering how polycomb group proteins maintain a poised state that enables these cells to respond flexibly to environmental signals. This concept of plasticity is particularly relevant in his latest research on nasal chondrocytes, suggesting that these cells retain developmental potential that may be harnessed in regenerative medicine. The discussions hint at a future where understanding these intricate mechanisms could lead to groundbreaking advancements in treating injuries or diseases.

Throughout the episode, Dr. Rijli’s enthusiasm for discovery is palpable as he shares how each research finding leads to more questions, showcasing the iterative nature of scientific research. This dialogue provides not only a deep dive into his specific studies but also a broader view of how developmental biology continues to evolve, emphasizing the importance of understanding the molecular underpinnings of cellular identity and connectivity.