In this episode of the Epigenetics Podcast, we talked with Mitch Guttman from California Institute of Technology about his work on characterising the 3D interactions of the genome using Split-Pool Recognition of Interactions by Tag Extension (SPRITE).
Mitch Guttman discusses his exploration of the long non-coding RNA Xist, which plays a crucial role in X chromosome inactivation. He explains how they discovered that Xist is present everywhere in the nucleus, not just in specific locations on the X chromosome. Through their research, they identified critical proteins like SHARP that are involved in X chromosome silencing.
The discussion then shifts to SPRITE, a method they developed to map multi-way contacts and generalize beyond DNA to include RNA and proteins. They compare SPRITE to classical proximity ligation methods like Hi-C and discuss how cluster sizes in SPRITE can estimate 3D distances between molecules. The conversation also touches upon the potential of applying SPRITE to single-cell experiments, allowing for the mapping of higher order nucleic acid interactions and tracking the connectivity of DNA fragments in individual cells.
 
References

Jesse M. Engreitz et al., The Xist lncRNA Exploits Three-Dimensional Genome Architecture to Spread Across the X Chromosome. Science 341,1237973(2013). DOI:10.1126/science.1237973


Chun-Kan Chen et al., Xist recruits the X chromosome to the nuclear lamina to enable chromosome-wide silencing. Science 354, 468-472(2016). DOI: 10.1126/science.aae0047


Quinodoz, S. A., Ollikainen, N., Tabak, B., Palla, A., Schmidt, J. M., Detmar, E., Lai, M. M., Shishkin, A. A., Bhat, P., Takei, Y., Trinh, V., Aznauryan, E., Russell, P., Cheng, C., Jovanovic, M., Chow, A., Cai, L., McDonel, P., Garber, M., & Guttman, M. (2018). Higher-Order Inter-chromosomal Hubs Shape 3D Genome Organization in the Nucleus. Cell, 174(3), 744-757.e24. https://doi.org/10.1016/j.cell.2018.05.024


Goronzy, I. N., Quinodoz, S. A., Jachowicz, J. W., Ollikainen, N., Bhat, P., & Guttman, M. (2022). Simultaneous mapping of 3D structure and nascent RNAs argues against nuclear compartments that preclude transcription. Cell Reports, 41(9), 111730. https://doi.org/10.1016/j.celrep.2022.111730


Perez, A. A., Goronzy, I. N., Blanco, M. R., Guo, J. K., & Guttman, M. (2023). ChIP-DIP: A multiplexed method for mapping hundreds of proteins to DNA uncovers diverse regulatory elements controlling gene expression [Preprint]. Genomics. https://doi.org/10.1101/2023.12.14.571730


 
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Split-Pool Recognition of Interactions by Tag Extension (SPRITE) (Mitch Guttman)

In this episode of the Epigenetics Podcast, we talked with Yali Dou from Keck School of Medicine of USC about her work on MLL Proteins in Mixed-Lineage Leukemia.
To start off this Interview Yali describes her early work on MLL1 and its function in transcription, particularly its involvement in histone modification. She explains her successful purification of the MLL complex and the discovery of MOF as one of the proteins involved.
Next, the interview focuses on her work in reconstituting the MLL core complex and the insights gained from this process. She shares her experience of reconstituting the MLL complex and discusses her focus on the crosstalk of H3K4 and H3K79 methylation, regulated by H2BK34 ubiquitination.
The podcast then delves into the therapeutic potential of MLL1, leading to the discovery of a small molecule inhibitor. Finally, we talk about the importance of the protein WDR5 in the assembly of MLL complexes and how targeting the WDR5-ML interaction can inhibit MLL activity.
 
References

Dou, Y., Milne, T., Ruthenburg, A. et al. Regulation of MLL1 H3K4 methyltransferase activity by its core components. Nat Struct Mol Biol 13, 713–719 (2006). https://doi.org/10.1038/nsmb1128


Wu, L., Zee, B. M., Wang, Y., Garcia, B. A., & Dou, Y. (2011). The RING Finger Protein MSL2 in the MOF Complex Is an E3 Ubiquitin Ligase for H2B K34 and Is Involved in Crosstalk with H3 K4 and K79 Methylation. Molecular Cell, 43(1), 132–144. https://doi.org/10.1016/j.molcel.2011.05.015


Cao, F., Townsend, E. C., Karatas, H., Xu, J., Li, L., Lee, S., Liu, L., Chen, Y., Ouillette, P., Zhu, J., Hess, J. L., Atadja, P., Lei, M., Qin, Z. S., Malek, S., Wang, S., & Dou, Y. (2014). Targeting MLL1 H3K4 Methyltransferase Activity in Mixed-Lineage Leukemia. Molecular Cell, 53(2), 247–261. https://doi.org/10.1016/j.molcel.2013.12.001


Park, S.H., Ayoub, A., Lee, YT. et al. Cryo-EM structure of the human MLL1 core complex bound to the nucleosome. Nat Commun 10, 5540 (2019). https://doi.org/10.1038/s41467-019-13550-2


 
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MLL Proteins in Mixed-Lineage Leukemia (Yali Dou)

In this episode of the Epigenetics Podcast, we talked with Sam Buckberry from the Telethon Kids Institute about his work on gene imprinting, sex-biased gene expression, DNA regulatory landscapes, and genomics in the indigenous population of Australia.
Sam Buckberry's research career started with working on the imprinting of H19, IGF2, and IGF2R genes in the placenta. We talk about the controversy surrounding the imprinting of IGF2R and how his study used pyrosequencing to quantify gene expression. We also discuss Sam's work on sex-biased gene expression in the placenta and the identification of a cluster of genes related to placental development and pregnancy.
In addition, we talk about Sam's research on reprogramming and the characterization of DNA regulatory landscapes during the process. We discuss the challenges of working with sequencing data, the discovery of epigenetic memories, and erasing them during reprogramming. Towards the end of the conversation, Sam mentions his current work in setting up an epigenetics group focused on indigenous genomics. They are conducting a large-scale, multi-omics study on cardiometabolic conditions in samples from indigenous Australian communities, with the goal of identifying biomarkers and better understanding the molecular basis of these conditions.
 
References

Buckberry, S., Liu, X., Poppe, D. et al. Transient naive reprogramming corrects hiPS cells functionally and epigenetically. Nature 620, 863–872 (2023). https://doi.org/10.1038/s41586-023-06424-7


Knaupp AS1, Buckberry S1, Pflueger J, Lim SM, Ford E, Larcombe MR, Rossello FJ, de Mendoza A, Alaei S, Firas J, Holmes ML, Nair SS, Clark SJ, Nefzger CM, Lister R and Polo JM (2017). Transient and permanent reconfiguration of chromatin and transcription factor occupancy drive reprogramming. Cell Stem Cell 21, 1-12 1 Co-first author


 
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Sex-biased Imprinting and DNA Regulatory Landscapes During Reprogramming (Sam Buckberry)

In this episode of the Epigenetics Podcast, we talked with Kyle Eagen from Baylor College of Medicine about his work on BET Proteins and their role in chromosome folding and compartmentalization.
In the early days of his research career Dr. Eagen made use of genomics and microscopy to study chromosomes, particularly polytene chromosomes in Drosophila. The correlation between the folding patterns detected by Hi-C and polytene bands highlights the similarities between the two, bridging traditional cytology with modern NGS methods. This work formed the basis of Kyle's thesis and sparked his interest in nuclear organization and chromosome 3D structure.
In his independent lab Kyle then studied compartments in chromatin structure and focused on the relationship between histone modifications and the 3D structure of chromosomes. The discovery of BRD4-NUT, a fusion oncoprotein that reprograms chromosome 3D structure, is highlighted as a significant step forward in understanding chromatin structure.
The conversation then shifts to the use of a tool to test hypotheses about the involvement of BRD4 in a specific process, leading to consistent results and considerations for manipulating chromosome organization for therapeutic purposes. The role of BET proteins in genome folding and the need for further research on other factors involved in 3D genome structure are discussed. 
 
References

Rosencrance, C. D., Ammouri, H. N., Yu, Q., Ge, T., Rendleman, E. J., Marshall, S. A., & Eagen, K. P. (2020). Chromatin Hyperacetylation Impacts Chromosome Folding by Forming a Nuclear Subcompartment. Molecular Cell, 78(1), 112-126.e12. https://doi.org/10.1016/j.molcel.2020.03.018


Huang, Y., Durall, R. T., Luong, N. M., Hertzler, H. J., Huang, J., Gokhale, P. C., Leeper, B. A., Persky, N. S., Root, D. E., Anekal, P. V., Montero Llopis, P. D. L. M., David, C. N., Kutok, J. L., Raimondi, A., Saluja, K., Luo, J., Zahnow, C. A., Adane, B., Stegmaier, K., … French, C. A. (2023). EZH2 Cooperates with BRD4-NUT to Drive NUT Carcinoma Growth by Silencing Key Tumor Suppressor Genes. Cancer Research, 83(23), 3956–3973. https://doi.org/10.1158/0008-5472.CAN-23-1475


 
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BET Proteins and Their Role in Chromosome Folding and Compartmentalization (Kyle Eagen)

In this episode of the Epigenetics Podcast, we talked with Francesca Telese from UC San Diego and Jessica Zhou from Cold Spring Harbour about their work on the molecular underpinnings of human addiction.
Francesca Telese worked on neuronal enhancers and their pivotal role in governing gene activity. She sheds light on her remarkable findings concerning the epigenetic signature of neuronal enhancers that are intricately involved in synaptic plasticity.
Jessica Zhou joined Francesca Telese's lab as a PhD student where she worked on elucidating the effects of chronic cannabis use on memory and behavior in mice. She takes us through the fascinating correlation between THC and gene co-expression networks. Francesca and Jessicathen discuss the utilization of genetically diverse outbred rats in their research, along with the crucial exploration of cell type specificity in gene expression studies. They then delve into the long-term changes that occur in the brain after drug exposure and the profound implications for relapse. Additionally, they touch upon the challenges they face in analyzing single-cell data.
 
References

Zhou, J. L., de Guglielmo, G., Ho, A. J., Kallupi, M., Pokhrel, N., Li, H. R., Chitre, A. S., Munro, D., Mohammadi, P., Carrette, L. L. G., George, O., Palmer, A. A., McVicker, G., & Telese, F. (2023). Single-nucleus genomics in outbred rats with divergent cocaine addiction-like behaviors reveals changes in amygdala GABAergic inhibition. Nature neuroscience, https://doi.org/10.1038/s41593-023-01452-y


Wang, J., Telese, F., Tan, Y., Li, W., Jin, C., He, X., Basnet, H., Ma, Q., Merkurjev, D., Zhu, X., Liu, Z., Zhang, J., Ohgi, K., Taylor, H., White, R. R., Tazearslan, C., Suh, Y., Macfarlan, T. S., Pfaff, S. L., & Rosenfeld, M. G. (2015). LSD1n is an H4K20 demethylase regulating memory formation via transcriptional elongation control. Nature neuroscience, 18(9), 1256–1264. https://doi.org/10.1038/nn.4069


 
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Epigenetic Underpinnings of Human Addiction (Francesca Telese & Jessica Zhou)

In this episode of the Epigenetics Podcast, we talked with Tanja Vogel from the University Clinics Freiburg about her work on epigenetic modifications in stem cells during central nervous system development.
During our discussion, Dr. Vogel shared that she and her team have investigated H3K79 methylation and its functional significance, which remains a topic of debate in the scientific community. They’ve also investigated the role of DOT1L in neural development and its implications for neuronal networks, as disrupting DOT1L can lead to conditions such as epilepsy and schizophrenia. They explored the function of the SOX2 enhancer in the presence or absence of DOT1L enzymatic inhibition.
The conversation then shifts to FoxG1, a vital player in forebrain development. The team uncovered its role in chromatin accessibility and its connection to microRNA processing. Their study, utilizing ChIP-Seq, reveals FoxG1&#39;s interactions with enhancer regions and other transcription factors, like NeuroD1.
 
### References

Britanova, O., de Juan Romero, C., Cheung, A., Kwan, K. Y., Schwark, M., Gyorgy, A., Vogel, T., Akopov, S., Mitkovski, M., Agoston, D., Sestan, N., Molnár, Z., &amp; Tarabykin, V. (2008). Satb2 is a postmitotic determinant for upper-layer neuron specification in the neocortex. Neuron, 57(3), 378–392. https://doi.org/10.1016/j.neuron.2007.12.028


Büttner, N., Johnsen, S. A., Kügler, S., &amp; Vogel, T. (2010). Af9/Mllt3 interferes with Tbr1 expression through epigenetic modification of histone H3K79 during development of the cerebral cortex. Proceedings of the National Academy of Sciences of the United States of America, 107(15), 7042–7047. https://doi.org/10.1073/pnas.0912041107


Franz, H., Villarreal, A., Heidrich, S., Videm, P., Kilpert, F., Mestres, I., Calegari, F., Backofen, R., Manke, T., &amp; Vogel, T. (2019). DOT1L promotes progenitor proliferation and primes neuronal layer identity in the developing cerebral cortex. Nucleic acids research, 47(1), 168–183. https://doi.org/10.1093/nar/gky953


Ferrari, F., Arrigoni, L., Franz, H., Izzo, A., Butenko, L., Trompouki, E., Vogel, T., &amp; Manke, T. (2020). DOT1L-mediated murine neuronal differentiation associates with H3K79me2 accumulation and preserves SOX2-enhancer accessibility. Nature communications, 11(1), 5200. https://doi.org/10.1038/s41467-020-19001-7


Akol, I., Izzo, A., Gather, F., Strack, S., Heidrich, S., Ó hAilín, D., Villarreal, A., Hacker, C., Rauleac, T., Bella, C., Fischer, A., Manke, T., &amp; Vogel, T. (2023). Multimodal epigenetic changes and altered NEUROD1 chromatin binding in the mouse hippocampus underlie FOXG1 syndrome. Proceedings of the National Academy of Sciences of the United States of America, 120(2), e2122467120. https://doi.org/10.1073/pnas.2122467120
 


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In this episode of the Epigenetics Podcast, we talked with Maria Gambetta from the University of Lausanne about her work on the function of insulators in 3D genome folding.
Maria Gambetta focuses on investigating 3D contact dynamics between enhancers and promoters, providing insights into tissue-specific gene activation. The team used capture-C to analyze dynamic looping events, emphasizing the significance of accessible chromatin peaks in enhancer-promoter interactions. Furthermore, they focused on gene insulation and CTCF&#39;s role in forming topologically associating domains in Drosophila. Hi-C analysis on CTCF mutants revealed the conservation of TAD boundary mechanisms, identifying CP-190 as a potential binding protein.
Their findings on the loss of TAD boundaries in mutants and the role of transcription in TAD boundary formation are discussed as well as the function of CP190 and insulators in preventing interactions between promoters and enhancers. Their work challenges existing models of insulator function and seeks to understand their mechanisms better. The conversation concludes with insights into long-range regulatory associations in Drosophila, emphasizing the punctual interactions between transcription factor binding sites and their effect on neural gene transcription and genome folding.
 
References

Gambetta, M. C., Oktaba, K., &amp; Müller, J. (2009). Essential role of the glycosyltransferase sxc/Ogt in polycomb repression. Science (New York, N.Y.), 325(5936), 93–96. https://doi.org/10.1126/science.1169727


Kaushal, A., Mohana, G., Dorier, J., Özdemir, I., Omer, A., Cousin, P., Semenova, A., Taschner, M., Dergai, O., Marzetta, F., Iseli, C., Eliaz, Y., Weisz, D., Shamim, M. S., Guex, N., Lieberman Aiden, E., &amp; Gambetta, M. C. (2021). CTCF loss has limited effects on global genome architecture in Drosophila despite critical regulatory functions. Nature communications, 12(1), 1011. https://doi.org/10.1038/s41467-021-21366-2


Hoencamp, C., Dudchenko, O., Elbatsh, A. M. O., Brahmachari, S., Raaijmakers, J. A., van Schaik, T., Sedeño Cacciatore, Á., Contessoto, V. G., van Heesbeen, R. G. H. P., van den Broek, B., Mhaskar, A. N., Teunissen, H., St Hilaire, B. G., Weisz, D., Omer, A. D., Pham, M., Colaric, Z., Yang, Z., Rao, S. S. P., Mitra, N., … Rowland, B. D. (2021). 3D genomics across the tree of life reveals condensin II as a determinant of architecture type. Science (New York, N.Y.), 372(6545), 984–989. https://doi.org/10.1126/science.abe2218


Mohana, G., Dorier, J., Li, X., Mouginot, M., Smith, R. C., Malek, H., Leleu, M., Rodriguez, D., Khadka, J., Rosa, P., Cousin, P., Iseli, C., Restrepo, S., Guex, N., McCabe, B. D., Jankowski, A., Levine, M. S., &amp; Gambetta, M. C. (2023). Chromosome-level organization of the regulatory genome in the Drosophila nervous system. Cell, 186(18), 3826–3844.e26. https://doi.org/10.1016/j.cell.2023.07.008
 


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In this episode of the Epigenetics Podcast, we talked with Jason Carroll from the Cambridge Research Institute about his work on contribution of estrogen receptor to breast cancer progression.
The Podcast centers around the crucial role of the forkhead protein FOXA1 in breast cancer. FOXA1 acts as a pioneer transcription factor, facilitating gene regulation by recruiting nuclear receptors to chromatin, profoundly influencing gene expression in various breast cancer subtypes. The FOXA1-positive subtype of triple-negative breast cancer, despite being estrogen receptor-negative, shares gene expression profiles with estrogen receptor-positive breast cancer, shedding light on the importance of targeting the androgen receptor for treatment.
The challenges of studying transcription factor mappings from clinical samples are explored, with a focus on the ChIP-seq method&#39;s success in mapping estrogen receptor binding sites. Various techniques for transcription factor mapping, including CUT&amp;RUN, CUT&amp;Tag, and ChIP-exo, are discussed, as well as the potential of mass spec techniques like the RIME method in analyzing protein interactions. An intriguing experiment involving the purification of multiple proteins to identify interactions is highlighted.
 
References

Carroll, J. S., Meyer, C. A., Song, J., Li, W., Geistlinger, T. R., Eeckhoute, J., Brodsky, A. S., Keeton, E. K., Fertuck, K. C., Hall, G. F., Wang, Q., Bekiranov, S., Sementchenko, V., Fox, E. A., Silver, P. A., Gingeras, T. R., Liu, X. S., &amp; Brown, M. (2006). Genome-wide analysis of estrogen receptor binding sites. Nature genetics, 38(11), 1289–1297. https://doi.org/10.1038/ng1901


Hurtado, A., Holmes, K. A., Geistlinger, T. R., Hutcheson, I. R., Nicholson, R. I., Brown, M., Jiang, J., Howat, W. J., Ali, S., &amp; Carroll, J. S. (2008). Regulation of ERBB2 by oestrogen receptor-PAX2 determines response to tamoxifen. Nature, 456(7222), 663–666. https://doi.org/10.1038/nature07483


Ross-Innes, C. S., Stark, R., Teschendorff, A. E., Holmes, K. A., Ali, H. R., Dunning, M. J., Brown, G. D., Gojis, O., Ellis, I. O., Green, A. R., Ali, S., Chin, S. F., Palmieri, C., Caldas, C., &amp; Carroll, J. S. (2012). Differential oestrogen receptor binding is associated with clinical outcome in breast cancer. Nature, 481(7381), 389–393. https://doi.org/10.1038/nature10730


Mohammed, H., Russell, I. A., Stark, R., Rueda, O. M., Hickey, T. E., Tarulli, G. A., Serandour, A. A., Birrell, S. N., Bruna, A., Saadi, A., Menon, S., Hadfield, J., Pugh, M., Raj, G. V., Brown, G. D., D&#39;Santos, C., Robinson, J. L., Silva, G., Launchbury, R., Perou, C. M., … Carroll, J. S. (2015). Progesterone receptor modulates ERα action in breast cancer. Nature, 523(7560), 313–317. https://doi.org/10.1038/nature14583
 


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Contribution of the Estrogen Receptor to Breast Cancer Progression (Jason Carroll)

In this episode of the Epigenetics Podcast, we caught up with Sheila Teves from the University of British Columbia to talk about her work on the inheritance of transcriptional memory by mitotic bookmarking.
Early in her research career, Sheila Teves focused on the impact of nucleosomes on torsional stress and gene regulation. She also highlights the development of a genome-wide approach to measure torsional stress and its relationship to nucleosome dynamics and RNA polymerase regulation.
The conversation then shifts to her focus on transcriptional memory and mitotic bookmarking during her postdoc in the Tijan lab. She explores the concept of mitotic bookmarking, whereby certain transcription factors remain bound to their target sites during mitosis, facilitating efficient reactivation of transcription after cell division. She discusses her findings on the behavior of transcription factors on mitotic chromosomes, challenging the notion that they are excluded during mitosis. She also discusses the differences in binding behavior between the general transcription factor TBP and other transcription factors. Finally, the effect of formaldehyde fixation on the potential to find transcription factors bound to mitotic chromosomes is discussed.
 
References

Teves, S., Henikoff, S. Transcription-generated torsional stress destabilizes nucleosomes. Nat Struct Mol Biol 21, 88–94 (2014). https://doi.org/10.1038/nsmb.2723


Sheila S Teves, Luye An, Anders S Hansen, Liangqi Xie, Xavier Darzacq, Robert Tjian (2016) A dynamic mode of mitotic bookmarking by transcription factors eLife 5:e22280. https://doi.org/10.7554/eLife.22280


Sheila S Teves, Luye An, Aarohi Bhargava-Shah, Liangqi Xie, Xavier Darzacq, Robert Tjian (2018) A stable mode of bookmarking by TBP recruits RNA polymerase II to mitotic chromosomes eLife 7:e35621. https://doi.org/10.7554/eLife.35621


Kwan, J. Z. J., Nguyen, T. F., Uzozie, A. C., Budzynski, M. A., Cui, J., Lee, J. M. C., Van Petegem, F., Lange, P. F., & Teves, S. S. (2023). RNA Polymerase II transcription independent of TBP in murine embryonic stem cells. eLife, 12, e83810. https://doi.org/10.7554/eLife.83810


Price, R. M., Budzyński, M. A., Shen, J., Mitchell, J. E., Kwan, J. Z. J., & Teves, S. S. (2023). Heat shock transcription factors demonstrate a distinct mode of interaction with mitotic chromosomes. Nucleic acids research, 51(10), 5040–5055. https://doi.org/10.1093/nar/gkad304
 


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Inheritance of Transcriptional Memory by Mitotic Bookmarking (Sheila Teves)

In this episode of the Epigenetics Podcast, we talked with Janine La Salle from UC Davis about her work on differential methylated regions in autism spectrum disorders.
In our discussion, Janine LaSalle highlights her work on the placental epigenetic signature, which offers insights into the impact of fetal exposures and gene-environment interactions during the perinatal period. She emphasizes the placenta&#39;s value as a surrogate tissue for understanding human diseases. Her research on DNA methylation in the placenta across different mammalian species reveals consistent patterns in partially methylated and highly methylated domains. She explains the critical role of higher methylation levels in specific regions for gene expression and how this knowledge helps trace the placenta&#39;s developmental history.
The conversation then delves into Dr. LaSalle&#39;s research on the link between placental DNA methylation and autism. Through epigenome-wide association studies, she discovered a novel autism gene and explored the effects of prenatal exposures on DNA methylation profiles. Additionally, she discusses the impact of maternal obesity on offspring neurodevelopment. Ultimately, the goal of her research is to contribute to precision public health and preventative healthcare with epigenetic signatures offering high potential for predicting and preventing future health problems.
 
References

Schroeder, D. I., Blair, J. D., Lott, P., Yu, H. O., Hong, D., Crary, F., Ashwood, P., Walker, C., Korf, I., Robinson, W. P., &amp; LaSalle, J. M. (2013). The human placenta methylome. Proceedings of the National Academy of Sciences of the United States of America, 110(15), 6037–6042. https://doi.org/10.1073/pnas.1215145110


Zhu, Y., Gomez, J. A., Laufer, B. I., Mordaunt, C. E., Mouat, J. S., Soto, D. C., Dennis, M. Y., Benke, K. S., Bakulski, K. M., Dou, J., Marathe, R., Jianu, J. M., Williams, L. A., Gutierrez Fugón, O. J., Walker, C. K., Ozonoff, S., Daniels, J., Grosvenor, L. P., Volk, H. E., Feinberg, J. I., … LaSalle, J. M. (2022). Placental methylome reveals a 22q13.33 brain regulatory gene locus associated with autism. Genome biology, 23(1), 46. https://doi.org/10.1186/s13059-022-02613-1


Laufer, B. I., Hasegawa, Y., Zhang, Z., Hogrefe, C. E., Del Rosso, L. A., Haapanen, L., Hwang, H., Bauman, M. D., Van de Water, J., Taha, A. Y., Slupsky, C. M., Golub, M. S., Capitanio, J. P., VandeVoort, C. A., Walker, C. K., &amp; LaSalle, J. M. (2022). Multi-omic brain and behavioral correlates of cell-free fetal DNA methylation in macaque maternal obesity models. Nature communications, 13(1), 5538. https://doi.org/10.1038/s41467-022-33162-7


Coulson, R. L., Yasui, D. H., Dunaway, K. W., Laufer, B. I., Vogel Ciernia, A., Zhu, Y., Mordaunt, C. E., Totah, T. S., &amp; LaSalle, J. M. (2018). Snord116-dependent diurnal rhythm of DNA methylation in mouse cortex. Nature communications, 9(1), 1616. https://doi.org/10.1038/s41467-018-03676-0


Neier, K.

Differential Methylated Regions in Autism Spectrum Disorders (Janine La Salle)

In this episode of the Epigenetics Podcast, we caught up with Björn Schumacher from the Institute for Genome Stability in Ageing and Disease at the University of Cologne to talk about his work on DNA damage in longevity and ageing.
In this episode Björn Schumacher discusses his research on DNA repair and its impact on ageing. We explore his insights on the effects of DNA damage on transcription, the importance of studying development, and the role of histone modifications. We also discuss paternal DNA damage inheritance and the DREAM complex as a master regulator of DNA repair. The lab’s goal is to enhance somatic DNA repair for healthier ageing and disease prevention.
 
References

Schumacher, B., van der Pluijm, I., Moorhouse, M. J., Kosteas, T., Robinson, A. R., Suh, Y., Breit, T. M., van Steeg, H., Niedernhofer, L. J., van Ijcken, W., Bartke, A., Spindler, S. R., Hoeijmakers, J. H., van der Horst, G. T., & Garinis, G. A. (2008). Delayed and accelerated aging share common longevity assurance mechanisms. PLoS genetics, 4(8), e1000161. https://doi.org/10.1371/journal.pgen.1000161


Ermolaeva, M. A., Segref, A., Dakhovnik, A., Ou, H. L., Schneider, J. I., Utermöhlen, O., Hoppe, T., & Schumacher, B. (2013). DNA damage in germ cells induces an innate immune response that triggers systemic stress resistance. Nature, 501(7467), 416–420. https://doi.org/10.1038/nature12452


Wang, S., Meyer, D. H., & Schumacher, B. (2023). Inheritance of paternal DNA damage by histone-mediated repair restriction. Nature, 613(7943), 365–374. https://doi.org/10.1038/s41586-022-05544-w


Bujarrabal-Dueso, A., Sendtner, G., Meyer, D. H., Chatzinikolaou, G., Stratigi, K., Garinis, G. A., & Schumacher, B. (2023). The DREAM complex functions as conserved master regulator of somatic DNA-repair capacities. Nature structural & molecular biology, 30(4), 475–488. https://doi.org/10.1038/s41594-023-00942-8
 


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DNA Damage in Longevity and Ageing (Björn Schumacher)

In this episode of the Epigenetics Podcast, we talked with Capucine van Rechem from Stanford University about her work on the impact of chromatin modifiers on disease development and progression. 
During her postdoctoral work, Capucine van Rechem studied the effects of Single nucleotide polymorphisms (SNPs) in KDM4A on lung cancer cell lines and discovered a link between KDM4A and mTOR. She found that cells with the SNP had decreased KDM4A levels and increased sensitivity to inhibitors of the translation pathway. In addition, she found that a combination of histone marks was more predictive of replication timing than RNA expression alone, and identified the specific stages of the cell cycle where KDM4 primarily acts. 
Now in her own lab, the focus of her work shifted to SWI-SNF. The team has discovered the role of SWI-SNF in translation through polysome profiling and confirmed the interaction between SWI-SNF and translation. They are currently working to understand the functions of different complexes in translation and their connection to transcription.
 
References

Black, J. C., Manning, A. L., Van Rechem, C., Kim, J., Ladd, B., Cho, J., Pineda, C. M., Murphy, N., Daniels, D. L., Montagna, C., Lewis, P. W., Glass, K., Allis, C. D., Dyson, N. J., Getz, G., & Whetstine, J. R. (2013). KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors. Cell, 154(3), 541–555. https://doi.org/10.1016/j.cell.2013.06.051


Van Rechem, C., Ji, F., Mishra, S., Chakraborty, D., Murphy, S. E., Dillingham, M. E., Sadreyev, R. I., & Whetstine, J. R. (2020). The lysine demethylase KDM4A controls the cell-cycle expression of replicative canonical histone genes. Biochimica et biophysica acta. Gene regulatory mechanisms, 1863(10), 194624. https://doi.org/10.1016/j.bbagrm.2020.194624


Van Rechem, C., Ji, F., Chakraborty, D., Black, J. C., Sadreyev, R. I., & Whetstine, J. R. (2021). Collective regulation of chromatin modifications predicts replication timing during cell cycle. Cell reports, 37(1), 109799. https://doi.org/10.1016/j.celrep.2021.109799


Ulicna, L., Kimmey, S. C., Weber, C. M., Allard, G. M., Wang, A., Bui, N. Q., Bendall, S. C., Crabtree, G. R., Bean, G. R., & Van Rechem, C. (2022). The Interaction of SWI/SNF with the Ribosome Regulates Translation and Confers Sensitivity to Translation Pathway Inhibitors in Cancers with Complex Perturbations. Cancer research, 82(16), 2829–2837. https://doi.org/10.1158/0008-5472.CAN-21-1360
 


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The Impact of Chromatin Modifiers on Disease Development and Progression (Capucine van Rechem)

In this episode of the Epigenetics Podcast, we caught up with Luca Giorgetti from the Friedrich Miescher Institute to hear about his work on long-range transcriptional control by 3D chromosome structure.
Luca Giorgetti's research focuses on chromosomal interactions, transcriptional output, and the dynamics of enhancer-promoter relationships. His lab investigated the causal relationship between chromosome interactions and transcriptional events. They’ve found that by manipulating the contact probabilities between an enhancer and a promoter by changing their distance, these changes had a substantial effect on transcription levels. This project was an experiment that Luca Giorgetti was eager to do, and it allowed him to establish a smooth functional relationship between contact probabilities and changes in transcription levels.
 
References

Giorgetti, L., Galupa, R., Nora, E. P., Piolot, T., Lam, F., Dekker, J., Tiana, G., & Heard, E. (2014). Predictive polymer modeling reveals coupled fluctuations in chromosome conformation and transcription. Cell, 157(4), 950–963. https://doi.org/10.1016/j.cell.2014.03.025


Redolfi, J., Zhan, Y., Valdes-Quezada, C., Kryzhanovska, M., Guerreiro, I., Iesmantavicius, V., Pollex, T., Grand, R. S., Mulugeta, E., Kind, J., Tiana, G., Smallwood, S. A., de Laat, W., & Giorgetti, L. (2019). DamC reveals principles of chromatin folding in vivo without crosslinking and ligation. Nature structural & molecular biology, 26(6), 471–480. https://doi.org/10.1038/s41594-019-0231-0


Zuin, J., Roth, G., Zhan, Y., Cramard, J., Redolfi, J., Piskadlo, E., Mach, P., Kryzhanovska, M., Tihanyi, G., Kohler, H., Eder, M., Leemans, C., van Steensel, B., Meister, P., Smallwood, S., & Giorgetti, L. (2022). Nonlinear control of transcription through enhancer-promoter interactions. Nature, 604(7906), 571–577. https://doi.org/10.1038/s41586-022-04570-y


Mach, P., Kos, P. I., Zhan, Y., Cramard, J., Gaudin, S., Tünnermann, J., Marchi, E., Eglinger, J., Zuin, J., Kryzhanovska, M., Smallwood, S., Gelman, L., Roth, G., Nora, E. P., Tiana, G., & Giorgetti, L. (2022). Cohesin and CTCF control the dynamics of chromosome folding. Nature genetics, 54(12), 1907–1918. https://doi.org/10.1038/s41588-022-01232-7
 


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Long-Range Transcriptional Control by 3D Chromosome Structure (Luca Giorgetti)

In this episode of the Epigenetics Podcast, we talked with Mary Gehring from MIT about her work on transgenerational inheritance and epigenetic imprinting in plants.
Mary Gehring and her team are focusing on plant epigenetics and genetic imprinting in plants, studying DNA methylation in Arabidopsis. They have found significant differences in DNA methylation between the embryo and endosperm of plants, particularly in relation to imprinted genes. She also discusses their work on hydroxymethylcytosine (5-hmC) in Arabidopsis and the challenges of detecting and studying this epigenetic modification.
Next, we discuss the regulatory circuit involving ROS1, a DNA glycosylase involved in demethylation, and its role in maintaining epigenetic homeostasis. The interview concludes with a discussion of CUT&RUN, which the lab has adapted for use in plants. Due to its low input requirements this method has been valuable in studying various plant tissues and has influenced Mary Gehring's research on imprinting in Arabidopsis endosperm.
 
References

Gehring, M., Bubb, K. L., & Henikoff, S. (2009). Extensive demethylation of repetitive elements during seed development underlies gene imprinting. Science (New York, N.Y.), 324(5933), 1447–1451. https://doi.org/10.1126/science.1171609


Pignatta, D., Erdmann, R. M., Scheer, E., Picard, C. L., Bell, G. W., & Gehring, M. (2014). Natural epigenetic polymorphisms lead to intraspecific variation in Arabidopsis gene imprinting. eLife, 3, e03198. https://doi.org/10.7554/eLife.03198


Klosinska, M., Picard, C. L., & Gehring, M. (2016). Conserved imprinting associated with unique epigenetic signatures in the Arabidopsis genus. Nature plants, 2, 16145. https://doi.org/10.1038/nplants.2016.145


Zheng, X. Y., & Gehring, M. (2019). Low-input chromatin profiling in Arabidopsis endosperm using CUT&RUN. Plant reproduction, 32(1), 63–75. https://doi.org/10.1007/s00497-018-00358-1
 


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Transgenerational Inheritance and Epigenetic Imprinting in Plants (Mary Gehring)

In this episode of the Epigenetics Podcast, we talked to Claudio Cantù from Linköping University about his work on peak blacklists, peak concordance and what is a peak in CUT&RUN.
Our host Stefan Dillinger and guest Claudio Cantù dive into the topic of when we can be sure that a peak is a peak. To help with this, Claudio Cantù's group has been working on defining a set of suspicious peaks that can be used as a "peak blacklist" and can be subtracted to clean up CUT&RUN data sets. The lab also worked on a method called ICEBERG (Increased Capture of Enrichment By Exhaustive Replicate aGgregation) to help define peaks from a number of experimental replicates. By using this algorithm, the team is trying to discover the beta-catenin binding profile, not the tip of the beta-catenin binding iceberg, but the whole of the beta-catenin binding profile.
 
References

Zambanini, G., Nordin, A., Jonasson, M., Pagella, P., & Cantù, C. (2022). A new CUT&RUN low volume-urea (LoV-U) protocol optimized for transcriptional co-factors uncovers Wnt/β-catenin tissue-specific genomic targets. Development (Cambridge, England), 149(23), dev201124. https://doi.org/10.1242/dev.201124


Nordin, A., Zambanini, G., Pagella, P., & Cantù, C. (2022). The CUT&RUN Blacklist of Problematic Regions of the Genome [Preprint]. Genomics. https://doi.org/10.1101/2022.11.11.516118


Nordin, A., Pagella, P., Zambanini, G., & Cantu, C. (2023). Exhaustive identification of genome-wide binding events of transcriptional regulators with ICEBERG [Preprint]. Genomics. https://doi.org/10.1101/2023.06.29.547050


 
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When is a Peak a Peak? (Claudio Cantù)

In this episode of the Epigenetics Podcast, we talked with Alistair Boettiger from Stanford University about his work on the analysis of 3D chromatin structure of single cells using super-resolution imaging.
Alistair Boettiger and his team focus on developing advanced microscopy techniques to understand gene regulation at the level of 3D genome organization. They have developed Optical Reconstruction of Chromatin Architecture (ORCA), a microscopy approach to trace the 3-dimensional DNA path in the nucleus with genomic resolution down to 2 kb and a throughput of ~10,000 cells per experiment. These methods enable the identification of structural features with comparable resolution to Hi-C, while the advantages of microscopy such as single cell resolution and multimodal measurements remain.
 
References

Boettiger, A., Bintu, B., Moffitt, J. et al. Super-resolution imaging reveals distinct chromatin folding for different epigenetic states. Nature 529, 418–422 (2016). https://doi.org/10.1038/nature16496


Bogdan Bintu et al., Super-resolution chromatin tracing reveals domains and cooperative interactions in single cells. Science 362, eaau1783 (2018). DOI:10.1126/science.aau1783


Mateo, L.J., Sinnott-Armstrong, N. & Boettiger, A.N. Tracing DNA paths and RNA profiles in cultured cells and tissues with ORCA. Nat Protoc 16, 1647–1713 (2021). https://doi.org/10.1038/s41596-020-00478-x


Rajpurkar, A.R., Mateo, L.J., Murphy, S.E. et al. Deep learning connects DNA traces to transcription to reveal predictive features beyond enhancer–promoter contact. Nat Commun 12, 3423 (2021). https://doi.org/10.1038/s41467-021-23831-4


Tzu-Chiao Hung, David M. Kingsley, & Alistair Boettiger. (2023). Boundary stacking interactions enable cross-TAD enhancer-promoter communication during limb development. BioRxiv, 2023.02.06.527380. https://doi.org/10.1101/2023.02.06.527380


Hafner, A., Park, M., Berger, S. E., Murphy, S. E., Nora, E. P., & Boettiger, A. N. (2023). Loop stacking organizes genome folding from TADs to chromosomes. Molecular cell, 83(9), 1377–1392.e6. https://doi.org/10.1016/j.molcel.2023.04.008
 


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Analysis of 3D Chromatin Structure Using Super-Resolution Imaging (Alistair Boettiger)

In this episode of the Epigenetics Podcast, we caught up with Claudia Keller Valsecchi from the Institute for Molecular Biology in Mainz to talk about her work on gene dosage alterations in evolution and ageing.
Claudia Keller-Valsecchi's team focuses on understanding the fundamental mechanisms of how cellular function in eukaryotes is influenced by gene copy number variation. Recent findings indicate that precise MSL2-mediated gene dosage is highly relevant for organismal development. Since 2020 Claudia Keller-Valsecchi runs her own lab at the IMB in Mainz, Germany, where she tries to understand from a molecular mechanistic point of view how gene dosage compensation works, with projects in mosquitoes and in Artemia franciscanagene, as well as dosage regulation in the mammalian system regarding development and disease.
 
References

Keller, C., Adaixo, R., Stunnenberg, R., Woolcock, K. J., Hiller, S., & Bühler, M. (2012). HP1Swi6 Mediates the Recognition and Destruction of Heterochromatic RNA Transcripts. Molecular Cell, 47(2), 215–227. https://doi.org/10.1016/j.molcel.2012.05.009


Valsecchi, C.I.K., Basilicata, M.F., Georgiev, P. et al. RNA nucleation by MSL2 induces selective X chromosome compartmentalization. Nature 589, 137–142 (2021). https://doi.org/10.1038/s41586-020-2935-z


Keller Valsecchi, C. I., Marois, E., Basilicata, M. F., Georgiev, P., & Akhtar, A. (2021). Distinct mechanisms mediate X chromosome dosage compensation in Anopheles and Drosophila. Life Science Alliance, 4(9), e202000996. https://doi.org/10.26508/lsa.202000996
 


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Gene Dosage Alterations in Evolution and Ageing (Claudia Keller Valsecchi)

In this episode of the Epigenetics Podcast, we caught up with Lucas Farnung from Harvard Medical School to talk about his work on the structural analysis of nucleosomes during transcription.
Lucas Farnung started his scientific career in Patrick Cramer's lab, trying to solve the cryo-EM structure of RNA polymerase II transcribing through a nucleosome. This project spanned some time before being published in 2018, during which time Dr. Farnung accomplished several other goals. The team solved the cryo-electron microscopy structure of Chd1 from the yeast Saccharomyces cerevisiae bound to a nucleosome at a resolution of 4.8 Å, solved the structure of the nucleosome-CHD4 chromatin remodeler, and investigated the structural basis of nucleosome transcription mediated by Chd1 and FACT. In 2021, he started his own lab and is now working on structural analysis of nucleosomes during transcription and how chromatin remodelers work on the chromatin template.
References

Farnung, L., Vos, S. M., Wigge, C., & Cramer, P. (2017). Nucleosome-Chd1 structure and implications for chromatin remodelling. Nature, 550(7677), 539–542. https://doi.org/10.1038/nature24046


Farnung, L., Vos, S. M., & Cramer, P. (2018). Structure of transcribing RNA polymerase II-nucleosome complex. Nature communications, 9(1), 5432. https://doi.org/10.1038/s41467-018-07870-y


Filipovski, M., Soffers, J. H. M., Vos, S. M., & Farnung, L. (2022). Structural basis of nucleosome retention during transcription elongation. Science (New York, N.Y.), 376(6599), 1313–1316. https://doi.org/10.1126/science.abo3851
 


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Structural Analysis of Nucleosomes During Transcription (Lucas Farnung)

In this episode of the Epigenetics Podcast, we caught up with Paula Desplats from the University of California San Diego to talk about her work on DNA Methylation Alterations in Neurodegenerative Diseases.
The laboratory of Paula desalts focuses on decoding the role of epigenetic mechanisms, like DNA methylation, on the onset and progression of neurodegenerative diseases like Parkinson’s and Alzheimer’s. In doing so, on of the goals of the Desplats team is to develop a biomarker panel based on quantification of DNA methylation of selected genes that can discriminate Parkison's Disease patients from healthy subjects in a simple blood test. More recently, the team also focused on the role of the circadian rhythm on neurodegenerative diseases and finding a way how interventions can help in managing the disease. 
 
References

Masliah, E., Dumaop, W., Galasko, D., & Desplats, P. (2013). Distinctive patterns of DNA methylation associated with Parkinson disease: identification of concordant epigenetic changes in brain and peripheral blood leukocytes. Epigenetics, 8(10), 1030–1038. https://doi.org/10.4161/epi.25865


Cronin, P., McCarthy, M. J., Lim, A., Salmon, D. P., Galasko, D., Masliah, E., De Jager, P. L., Bennett, D. A., & Desplats, P. (2017). Circadian alterations during early stages of Alzheimer's disease are associated with aberrant cycles of DNA methylation in BMAL1. Alzheimer's & dementia : the journal of the Alzheimer's Association, 13(6), 689–700. https://doi.org/10.1016/j.jalz.2016.10.003


Henderson-Smith, A., Fisch, K. M., Hua, J., Liu, G., Ricciardelli, E., Jepsen, K., Huentelman, M., Stalberg, G., Edland, S. D., Scherzer, C. R., Dunckley, T., & Desplats, P. (2019). DNA methylation changes associated with Parkinson's disease progression: outcomes from the first longitudinal genome-wide methylation analysis in blood. Epigenetics, 14(4), 365–382. https://doi.org/10.1080/15592294.2019.1588682


Nasamran, C. A., Sachan, A., Mott, J., Kuras, Y. I., Scherzer, C. R., Study, H. B., Ricciardelli, E., Jepsen, K., Edland, S. D., Fisch, K. M., & Desplats, P. (2021). Differential blood DNA methylation across Lewy body dementias. Alzheimer's & dementia (Amsterdam, Netherlands), 13(1), e12156. https://doi.org/10.1002/dad2.12156
 


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DNA Methylation Alterations in Neurodegenerative Diseases (Paula Desplats)

In this episode of the Epigenetics Podcast, we caught up with Jop Kind from Hubrecht Institute to talk about his work on single cell DamID, EpiDamID, and Lamina Associated Domains (LADs).
Jop Kind started out developing single cell DamID (scDamID), based on the DamID technique. First, this technique was adapted to a microscopic readout which enabled them to follow the localisation of chromatin domains after cell division. Next, the lab expanded this technique into the NGS space and created genome-wide maps of nuclear lamina Interactions in single human cells. Since LADs are in a heterochromatic chromatin context, the lab expanded scDamID into the epigenetic space. They first combined it with a transcriptional readout.  Later-on they developed EpiDamID, a method to target a diverse set of chromatin types by taking advantage of the binding specificities of single-chain variable fragment antibodies, engineered chromatin reader domains, and endogenous chromatin-binding proteins.
 
References

Kind, J., Pagie, L., Ortabozkoyun, H., Boyle, S., de Vries, S. S., Janssen, H., Amendola, M., Nolen, L. D., Bickmore, W. A., &amp; van Steensel, B. (2013). Single-Cell Dynamics of Genome-Nuclear Lamina Interactions. Cell, 153(1), 178–192. https://doi.org/10.1016/j.cell.2013.02.028


Kind, J., Pagie, L., de Vries, S. S., Nahidiazar, L., Dey, S. S., Bienko, M., Zhan, Y., Lajoie, B., de Graaf, C. A., Amendola, M., Fudenberg, G., Imakaev, M., Mirny, L. A., Jalink, K., Dekker, J., van Oudenaarden, A., &amp; van Steensel, B. (2015). Genome-wide Maps of Nuclear Lamina Interactions in Single Human Cells. Cell, 163(1), 134–147. https://doi.org/10.1016/j.cell.2015.08.040


Borsos, M., Perricone, S.M., Schauer, T. et al. Genome–lamina interactions are established de novo in the early mouse embryo. Nature 569, 729–733 (2019). https://doi.org/10.1038/s41586-019-1233-0


Markodimitraki, C. M., Rang, F. J., Rooijers, K., de Vries, S. S., Chialastri, A., de Luca, K. L., Lochs, S. J. A., Mooijman, D., Dey, S. S., &amp; Kind, J. (2020). Simultaneous quantification of protein–DNA interactions and transcriptomes in single cells with scDam&amp;T-seq. Nature Protocols, 15(6), 1922–1953. https://doi.org/10.1038/s41596-020-0314-8


Rang, F. J., de Luca, K. L., de Vries, S. S., Valdes-Quezada, C., Boele, E., Nguyen, P. D., Guerreiro, I., Sato, Y., Kimura, H., Bakkers, J., &amp; Kind, J. (2022). Single-cell profiling of transcriptome and histone modifications with EpiDamID. Molecular Cell, 82(10), 1956-1970.e14. https://doi.org/10.1016/j.molcel.2022.03.009
 


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