In this episode of the Epigenetics Podcast, we caught up with Ian Maze from Ichan School of Medicine at Mount Sinai and a Howard Hughes Medical Institute (HHMI) Investigator to talk about his work on the role of histone dopaminylation and serotinylation in neuronal plasticity.

The Maze group focuses on understanding the complex interplay between chromatin regulatory mechanisms in brain and neuronal plasticity. The lab places an emphasis on psychiatric disorders associated with monoaminergic (e.g., serotonin, dopamine, etc.) dysfunction, such as major depressive disorder and drug addiction. In particular the Maze team has investigated cocaine addiction and its effect on chromatin by serotonylation and dopaminylation of Histone H3 Tails.

 

References

  • Maze, I., Covington, H. E., Dietz, D. M., LaPlant, Q., Renthal, W., Russo, S. J., Mechanic, M., Mouzon, E., Neve, R. L., Haggarty, S. J., Ren, Y., Sampath, S. C., Hurd, Y. L., Greengard, P., Tarakhovsky, A., Schaefer, A., & Nestler, E. J. (2010). Essential Role of the Histone Methyltransferase G9a in Cocaine-Induced Plasticity. Science, 327(5962), 213–216. https://doi.org/10.1126/science.1179438

  • Farrelly, L. A., Thompson, R. E., Zhao, S., Lepack, A. E., Lyu, Y., Bhanu, N. V., Zhang, B., Loh, Y.-H. E., Ramakrishnan, A., Vadodaria, K. C., Heard, K. J., Erikson, G., Nakadai, T., Bastle, R. M., Lukasak, B. J., Zebroski, H., Alenina, N., Bader, M., Berton, O., … Maze, I. (2019). Histone serotonylation is a permissive modification that enhances TFIID binding to H3K4me3. Nature, 567(7749), 535–539. https://doi.org/10.1038/s41586-019-1024-7

  • Lepack, A. E., Werner, C. T., Stewart, A. F., Fulton, S. L., Zhong, P., Farrelly, L. A., Smith, A. C. W., Ramakrishnan, A., Lyu, Y., Bastle, R. M., Martin, J. A., Mitra, S., O’Connor, R. M., Wang, Z.-J., Molina, H., Turecki, G., Shen, L., Yan, Z., Calipari, E. S., … Maze, I. (2020). Dopaminylation of histone H3 in ventral tegmental area regulates cocaine seeking. Science, 368(6487), 197–201. https://doi.org/10.1126/science.aaw8806

     

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In this episode of the Epigenetics Podcast, we caught up with Erna Magnúsdóttir from the University of Iceland to talk about her work on the role of Blimp-1 in immune-cell differentiation.

The Magnúsdóttir Lab is interested in how the mammalian genome is interpreted in a context dependent manner, leading to different cellular states, by using mouse primordial germ cells as well as mouse and human B-cells as model systems. More specifically, the team is interested in the Transcription Factor Blimp-1 and its effect on immune cell differentiation. Next to its function in immune cells, Blimp-1 also plays a role in Waldenström’s macroglobulinemia. The lab hopes to reveal the intricacies in disease progression and alteration in cellular states to increasingly aggressive tumor behavior.

 

References

  • Magnúsdóttir, E., Dietmann, S., Murakami, K. et al. A tripartite transcription factor network regulates primordial germ cell specification in mice. Nat Cell Biol 15, 905–915 (2013). https://doi.org/10.1038/ncb2798

  • Anderson, K.J., Ósvaldsdóttir, Á.B., Atzinger, B. et al. The BLIMP1—EZH2 nexus in a non-Hodgkin lymphoma. Oncogene 39, 5138–5151 (2020). https://doi.org/10.1038/s41388-020-1347-8

     

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In this episode of the Epigenetics Podcast, we speak with Peter Smibert, Vice President of Biology at 10X Genomics to talk about an exciting new method in Multimodal Characterization of Cellular Identity using Barcoding.

During his time at the New York Genome Center, Peter Smibert was instrumental in the development of a new method called "Cellular Indexing of Transcriptomes and Epitopes by Sequencing" short CITE-Seq. This method enables the characterization of a cell's transcriptome, while at the same time, also allows the characterization of the cell's protein surface markers - at the single cell level. In CITE-Seq, sequencing adapters are coupled to antibodies that recognize surface proteins, which can then be detected by sequencing.

Further advancements of the CITE-Seq method led to the launch of BioLegend’s TOTAL-Seq and the integration of scATAC-Seq into the workflow. With the integration of scATAC-Seq in the CITE-Seq protocol, it is now possible to characterize single-cells along the path of the central dogma of biology, this is why the method called DOGMA-Seq.

 

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In this episode of the Epigenetics Podcast, we caught up with Sara Wickström, Director at the Max Planck Institute for Molecular Biomedicine in Münster, to talk about her work on the effect of mechanotransduction on chromatin structure and transcription in stem cells.

Sara Wickström and her team focus on the stem cell niche and how that niche affects stem cell function. In order to study the native niche and to even be able to manipulate it, the Wickström Lab was able to develop a ex vivo culture system, allowing systematic identification of factors driving stem cell dynamics and plasticity.

Stem cells in the stem cell niche are exposed to external stimuli such as physical forces which control their growth, fate and self renewal. Recent work in the Wickström lab showed how mechanical signals influence transcriptional regulation, chromatin organization, and nuclear architecture and how this affects aging or lineage commitment. In this Episode we also discuss how chromatin can act as a sensor of mechanical signals taking advantage of the different physical properties of eu- and heterochromatin.

 

References

  • Le, H. Q., Ghatak, S., Yeung, C. Y., Tellkamp, F., Günschmann, C., Dieterich, C., Yeroslaviz, A., Habermann, B., Pombo, A., Niessen, C. M., & Wickström, S. A. (2016). Mechanical regulation of transcription controls Polycomb-mediated gene silencing during lineage commitment. Nature cell biology, 18(8), 864–875. https://doi.org/10.1038/ncb3387

  • Nava, M. M., Miroshnikova, Y. A., Biggs, L. C., Whitefield, D. B., Metge, F., Boucas, J., Vihinen, H., Jokitalo, E., Li, X., García Arcos, J. M., Hoffmann, B., Merkel, R., Niessen, C. M., Dahl, K. N., & Wickström, S. A. (2020). Heterochromatin-Driven Nuclear Softening Protects the Genome against Mechanical Stress-Induced Damage. Cell, 181(4), 800–817.e22. https://doi.org/10.1016/j.cell.2020.03.052

  • Koester, J., Miroshnikova, Y. A., Ghatak, S., Chacón-Martínez, C. A., Morgner, J., Li, X., Atanassov, I., Altmüller, J., Birk, D. E., Koch, M., Bloch, W., Bartusel, M., Niessen, C. M., Rada-Iglesias, A., & Wickström, S. A. (2021). Niche stiffening compromises hair follicle stem cell potential during ageing by reducing bivalent promoter accessibility. Nature cell biology, 23(7), 771–781. https://doi.org/10.1038/s41556-021-00705-x

  • Maki, K., Nava, M. M., Villeneuve, C., Chang, M., Furukawa, K. S., Ushida, T., & Wickström, S. A. (2021). Hydrostatic pressure prevents chondrocyte differentiation through heterochromatin remodeling. Journal of cell science, 134(2), jcs247643. https://doi.org/10.1242/jcs.247643

     

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In this episode of the Epigenetics Podcast, we caught up with Ben Hindson, Chief Scientific Officer at 10X Genomics, to talk about single-cell technologies using microfluidics.

Epigenetics has moved well past a simple understanding of a single epigenetic layer of control at genomic regions of interest, thanks to advances in many techniques and the application of “multiomics”. We can now analyze genome-wide histone modification patterns, transcription factor binding profiles, chromatin accessibility profiles, three-dimensional chromosomal conformation, and DNA methylation dynamics combined with transcriptomic analyses and associated analytical platforms.

Bulk Assays, like ATAC-Seq or ChIP, despite all their advantages, do not provide information about the chromatin states of individual subpopulations of cells within a sample. To identify chromatin features in heterogeneous populations, such as blood, pancreas, and brain, those analysis need to be performed at a single-cell level. 10X Genomics has been at the forefront of the movement into the single cell space and in this Episode we discuss this work with Ben Hindson, CSO of 10X genomics.

 

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In this episode of the Epigenetics Podcast, we caught up with Eleni Tomazou from St. Anna Children's Cancer Research Institute in Vienna to talk about her work on Epigenome-based precision medicine.

The Tomazou lab studies Ewing sarcoma and the effects of Epigenetic factors on this disease. Ewing sarcoma is a type of cancer that affects bone and soft tissue of children and young adults, with a peak incidence at the age of 15. Ewing sarcoma is among the pediatric cancer types with the lowest survival rates and the development of novel therapies was obstructed by the limited understanding of the mechanisms behind the disease.

Work done in Eleni Tomazou's group identified an epigenetic signature of Ewing sarcoma which, ultimately, lead to the possibility to diagnose Ewing sarcoma from liquid biopsies. The team is now looking to find actionable targets like enhancers to develop therapies, finding biomarkers to enable disease monitoring, and to further characterize these tumors to decipher intra-tumor epigenetic heterogeneity and characterize the developmental stage of the cell of origin.

 

References

  • Tomazou, E. M., Sheffield, N. C., Schmidl, C., Schuster, M., Schönegger, A., Datlinger, P., Kubicek, S., Bock, C., & Kovar, H. (2015). Epigenome Mapping Reveals Distinct Modes of Gene Regulation and Widespread Enhancer Reprogramming by the Oncogenic Fusion Protein EWS-FLI1. Cell Reports, 10(7), 1082–1095. https://doi.org/10.1016/j.celrep.2015.01.042

  • Sheffield, N. C., Pierron, G., Klughammer, J., Datlinger, P., Schönegger, A., Schuster, M., Hadler, J., Surdez, D., Guillemot, D., Lapouble, E., Freneaux, P., Champigneulle, J., Bouvier, R., Walder, D., Ambros, I. M., Hutter, C., Sorz, E., Amaral, A. T., de Álava, E., … Tomazou, E. M. (2017). DNA methylation heterogeneity defines a disease spectrum in Ewing sarcoma. Nature Medicine, 23(3), 386–395. https://doi.org/10.1038/nm.4273

  • Terlecki-Zaniewicz, S., Humer, T., Eder, T., Schmoellerl, J., Heyes, E., Manhart, G., Kuchynka, N., Parapatics, K., Liberante, F. G., Müller, A. C., Tomazou, E. M., & Grebien, F. (2021). Biomolecular condensation of NUP98 fusion proteins drives leukemogenic gene expression. Nature Structural & Molecular Biology, 28(2), 190–201. https://doi.org/10.1038/s41594-020-00550-w

  • Peneder, P., Stütz, A. M., Surdez, D., Krumbholz, M., Semper, S., Chicard, M., Sheffield, N. C., Pierron, G., Lapouble, E., Tötzl, M., Ergüner, B., Barreca, D., Rendeiro, A. F., Agaimy, A., Boztug, H., Engstler, G., Dworzak, M., Bernkopf, M., Taschner-Mandl, S., … Tomazou, E. M. (2021). Multimodal analysis of cell-free DNA whole-genome sequencing for pediatric cancers with low mutational burden. Nature Communications, 12(1), 3230. https://doi.org/10.1038/s41467-021-23445-w

     

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In this episode of the Epigenetics Podcast, we caught up with Manel Esteller, Director of the Josep Carreras Leukemia Research Institute to talk about his work on Epigenetics and Epitranscriptomics in Cancer.

The focus of Manel Esteller's research career and the focus of his current team is to characterize the epigenome and epitranscriptome of cancer cells in comparison to healthy cells, and their interplay. Ultimately, their goal is to use this knowledge to develop new therapies for cancer. Key achievements from the Esteller lab began with the discovery of the first miRNA that undergoes specific cancer-methylation associated silencing. The team further identified many more miRNAs that also play a role in cancer. Next to miRNAs, Manel Esteller studied the influence of lncRNAs, enhancers and DNA methylation on cancer development and progression, insights that may be used to develop cancer biomarkers and potential treatments.  

 

References

  • Guil, S., Soler, M., Portela, A., Carrère, J., Fonalleras, E., Gómez, A., Villanueva, A., & Esteller, M. (2012). Intronic RNAs mediate EZH2 regulation of epigenetic targets. Nature Structural & Molecular Biology, 19(7), 664–670. https://doi.org/10.1038/nsmb.2315

  • Vizoso, M., Ferreira, H. J., Lopez-Serra, P., Carmona, F. J., Martínez-Cardús, A., Girotti, M. R., Villanueva, A., Guil, S., Moutinho, C., Liz, J., Portela, A., Heyn, H., Moran, S., Vidal, A., Martinez-Iniesta, M., Manzano, J. L., Fernandez-Figueras, M. T., Elez, E., Muñoz-Couselo, E., … Esteller, M. (2015). Epigenetic activation of a cryptic TBC1D16 transcript enhances melanoma progression by targeting EGFR. Nature Medicine, 21(7), 741–750. https://doi.org/10.1038/nm.3863

  • Agrelo, R., Cheng, W.-H., Setien, F., Ropero, S., Espada, J., Fraga, M. F., Herranz, M., Paz, M. F., Sanchez-Cespedes, M., Artiga, M. J., Guerrero, D., Castells, A., von Kobbe, C., Bohr, V. A., & Esteller, M. (2006). Epigenetic inactivation of the premature aging Werner syndrome gene in human cancer. Proceedings of the National Academy of Sciences of the United States of America, 103(23), 8822–8827. https://doi.org/10.1073/pnas.0600645103

  • Lopez-Serra, P., Marcilla, M., Villanueva, A., Ramos-Fernandez, A., Palau, A., Leal, L., Wahi, J. E., Setien-Baranda, F., Szczesna, K., Moutinho, C., Martinez-Cardus, A., Heyn, H., Sandoval, J., Puertas, S., Vidal, A., Sanjuan, X., Martinez-Balibrea, E., Viñals, F., Perales, J. C., … Esteller, M. (2014). A DERL3-associated defect in the degradation of SLC2A1 mediates the Warburg effect. Nature Communications, 5, 3608. https://doi.org/10.1038/ncomms4608

  • Rosselló-Tortella, M., Llinàs-Arias, P., Sakaguchi, Y., Miyauchi, K., Davalos, V., Setien, F., Calleja-Cervantes, M. E., Piñeyro, D., Martínez-Gómez, J., Guil, S., Joshi, R., Villanueva, A., Suzuki, T., & Esteller, M. (2020). Epigenetic loss of the transfer RNA-modifying enzyme TYW2 induces ribosome frameshifts in colon cancer. Proceedings of the National Academy of Sciences of the United States of America, 117(34), 20785–20793. https://doi.org/10.1073/pnas.2003358117

  • Castro de Moura, M., Davalos, V., Planas-Serra, L., Alvarez-Errico, D., Arribas, C., Ruiz, M., Aguilera-Albesa, S., Troya, J., Valencia-Ramos, J., Vélez-Santamaria, V., Rodríguez-Palmero, A., Villar-Garcia, J., Horcajada, J. P., Albu, S., Casasnovas, C., Rull, A., Reverte, L., Dietl, B., Dalmau, D., … Esteller, M. (2021). Epigenome-wide association study of COVID-19 severity with respiratory failure. EBioMedicine, 66, 103339. https://doi.org/10.1016/j.ebiom.2021.103339

     

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In this episode of the Epigenetics Podcast, we caught up with Yad Ghavi-Helm from the Institut de Génomique Functionnelle de Lyon to talk about her work on enhancer-promoter interactions during development.

The Laboratory of Yad Ghavi-Helm focuses on how developmental genes are regulated by enhancers. Their work shows that developmental genes are often regulated by more than one enhancer and that those enhancers can often be located many kilobases away on the linear chromosome. Furthermore, their research also indicates that the interactions between promoters and their respective enhancers are usually established before the expression of the target gene is switched on, and that those interactions are generally stable during embryogenesis. In addition, those stable interactions seem to coincide with paused RNA Pol II being located at those promoters before gene activation.

References

  • Ghavi-Helm, Y., Michaut, M., Acker, J., Aude, J.-C., Thuriaux, P., Werner, M., & Soutourina, J. (2008). Genome-wide location analysis reveals a role of TFIIS in RNA polymerase III transcription. Genes & Development, 22(14), 1934–1947. https://doi.org/10.1101/gad.471908

  • Ghavi-Helm, Y., Klein, F. A., Pakozdi, T., Ciglar, L., Noordermeer, D., Huber, W., & Furlong, E. E. M. (2014). Enhancer loops appear stable during development and are associated with paused polymerase. Nature, 512(7512), 96–100. https://doi.org/10.1038/nature13417

  • Ghavi-Helm, Y., Jankowski, A., Meiers, S., Viales, R. R., Korbel, J. O., & Furlong, E. E. M. (2019). Highly rearranged chromosomes reveal uncoupling between genome topology and gene expression. Nature Genetics, 51(8), 1272–1282. https://doi.org/10.1038/s41588-019-0462-3

     

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In this episode of the Epigenetics Podcast, we caught up with Folami Ideraabdullah from the University of Chapel Hill to talk about her work on the environmental modulation of the epigenome during development.

The lab of Folami Ideraabdullah focuses on studying how environmental factors modulate the epigenome. In particular the team investigates how Vitamin D levels influence epigenetic processes and, hence, the susceptibility for diseases like adipositas. Folami Ideraabdullah started with a genome-wide screen of DNA Methylation patterns that are observed after Vitamin D depletion. This work was then followed up by investigating the impact of Vitamin D depletion on mouse sperm DNA methylation.

 

References

  • Xue, J., Schoenrock, S. A., Valdar, W., Tarantino, L. M., & Ideraabdullah, F. Y. (2016). Maternal vitamin D depletion alters DNA methylation at imprinted loci in multiple generations. Clinical Epigenetics, 8(1), 107. https://doi.org/10.1186/s13148-016-0276-4

  • Xue, J., Gharaibeh, R. Z., Pietryk, E. W., Brouwer, C., Tarantino, L. M., Valdar, W., & Ideraabdullah, F. Y. (2018). Impact of vitamin D depletion during development on mouse sperm DNA methylation. Epigenetics, 13(9), 959–974. https://doi.org/10.1080/15592294.2018.1526027

  • Xue, J., Hutchins, E. K., Elnagheeb, M., Li, Y., Valdar, W., McRitchie, S., Sumner, S., & Ideraabdullah, F. Y. (2020). Maternal Liver Metabolic Response to Chronic Vitamin D Deficiency Is Determined by Mouse Strain Genetic Background. Current Developments in Nutrition, 4(8), nzaa106. https://doi.org/10.1093/cdn/nzaa106

     

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In this episode of the Epigenetics Podcast, we caught up with Jane Mellor from the University of Oxford to talk about her work on H3K4me3, SET proteins, Isw1 and their role in transcription.

Since the beginning of the century, Jane Mellor and her team have focused on H3K4 trimethylation and the factors that influence this mark. They discovered that H3K4me3 is an almost universal mark of the first nucleosome in every transcribed unit and all organisms. She could subsequently, together with the Kouzarides lab, identify SetD1, the enzyme that is responsible for writing this modification. Later on, the team characterized Isw1, a chromatin remodeler which “reads” H3K4me3. More recently the lab focuses on how the polymerase transcribes throughout the first nucleosomes of the transcribed region at the +2 nucleosome, with the help of Spt4.

 

References

  • Santos-Rosa, H., Schneider, R., Bannister, A. J., Sherriff, J., Bernstein, B. E., Emre, N. C. T., Schreiber, S. L., Mellor, J., & Kouzarides, T. (2002). Active genes are tri-methylated at K4 of histone H3. Nature, 419(6905), 407–411. https://doi.org/10.1038/nature01080

  • Morillon, A., O’Sullivan, J., Azad, A., Proudfoot, N., & Mellor, J. (2003). Regulation of Elongating RNA Polymerase II by Forkhead Transcription Factors in Yeast. Science, 300(5618), 492–495. https://doi.org/10.1126/science.1081379

  • Morillon, A., Karabetsou, N., O’Sullivan, J., Kent, N., Proudfoot, N., & Mellor, J. (2003). Isw1 Chromatin Remodeling ATPase Coordinates Transcription Elongation and Termination by RNA Polymerase II. Cell, 115(4), 425–435. https://doi.org/10.1016/S0092-8674(03)00880-8

  • Uzun, Ü., Brown, T., Fischl, H., Angel, A., & Mellor, J. (2021). Spt4 facilitates the movement of RNA polymerase II through the +2 nucleosomal barrier. Cell Reports, 36(13), 109755. https://doi.org/10.1016/j.celrep.2021.109755

     

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