Epigenetics Podcast

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

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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Epigenetics and X-Inactivation (Edith Heard)
Dosage Compensation in Drosophila (Asifa Akhtar)
 
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Structural Analysis of Nucleosomes During Transcription (Lucas Farnung)

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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Molecular Mechanisms of Chromatin Modifying Enzymes (Karim-Jean Armache)
Regulation of Chromatin Organization by Histone Chaperones (Geneviève Almouzni)
Transcription Elongation Control by the Paf1 Complex (Karen Arndt)
From Nucleosome Structure to Function (Karolin Luger)
 
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DNA Methylation Alterations in Neurodegenerative Diseases (Paula Desplats)

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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scDamID, EpiDamID and Lamina Associated Domains (Jop Kind)

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., & 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., & 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., & Kind, J. (2020). Simultaneous quantification of protein–DNA interactions and transcriptomes in single cells with scDam&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., & 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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Circulating Epigenetic Biomarkers in Cancer (Charlotte Proudhon)

In this episode of the Epigenetics Podcast, we caught up with Charlotte Proudhon from the Institut Curie to talk about her work on circulating tumor DNA and circulating Epi-mutations as biomarkers in cancer.
Charlotte Proudhon started out her research career by investigating circulating tumor DNA (ctDNA). This kind of DNA is shed into the bloodstream by apoptotic tumor cells and can be analyzed after collection by a simple blood draw, which makes it a very useful biomarker for cancer. Using this approach cancers can be identified by their unique mutational fingerprint. However, soon the limitations of this approach became apparent and the fact that this ctDNA is actually shed into the bloodstream as nucleosomal particles was utilized by the Proudhon team and now the methylation fingerprint of the LINE-1 repeats is used as a biomarker for cancer diagnosis and monitoring of the success of a cancer treatment.
 
References
Decraene, C., Silveira, A. B., Bidard, F. C., Vallée, A., Michel, M., Melaabi, S., Vincent-Salomon, A., Saliou, A., Houy, A., Milder, M., Lantz, O., Ychou, M., Denis, M. G., Pierga, J. Y., Stern, M. H., & Proudhon, C. (2018). Multiple Hotspot Mutations Scanning by Single Droplet Digital PCR. Clinical chemistry, 64(2), 317–328. https://doi.org/10.1373/clinchem.2017.272518
Bortolini Silveira, A., Bidard, F. C., Tanguy, M. L., Girard, E., Trédan, O., Dubot, C., Jacot, W., Goncalves, A., Debled, M., Levy, C., Ferrero, J. M., Jouannaud, C., Rios, M., Mouret-Reynier, M. A., Dalenc, F., Hego, C., Rampanou, A., Albaud, B., Baulande, S., Berger, F., … Pierga, J. Y. (2021). Multimodal liquid biopsy for early monitoring and outcome prediction of chemotherapy in metastatic breast cancer. NPJ breast cancer, 7(1), 115. https://doi.org/10.1038/s41523-021-00319-4
 
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Epigenetic Landscapes During Cancer (Luciano Di Croce)

In this episode of the Epigenetics Podcast, we caught up with Luciano Di Croce from the Center of Genomic Regulation in Barcelona to talk about his work on epigenetic landscapes in cancer.
The Di Croce Lab focuses on the Polycomb Complex and its influence on diseases like cancer. Luciano Di Croce started out his research career investigating the oncogenic transcription factor PML-RAR. They could show that in leukemic cells knockdown of SUZ12, a key component of Polycomb repressive complex 2 (PRC2), reverts not only histone modification but also induces DNA de-methylation of PML-RAR target genes. More recently the team focused on two other Polycomb related proteins Zrf1 and PHF19 and were able to characterize some of their functions in gene targeting in different disease and developmental contexts.
 
References
Di Croce, L., Raker, V. A., Corsaro, M., Fazi, F., Fanelli, M., Faretta, M., Fuks, F., Lo Coco, F., Kouzarides, T., Nervi, C., Minucci, S., & Pelicci, P. G. (2002). Methyltransferase recruitment and DNA hypermethylation of target promoters by an oncogenic transcription factor. Science (New York, N.Y.), 295(5557), 1079–1082. https://doi.org/10.1126/science.1065173
Richly, H., Rocha-Viegas, L., Ribeiro, J. D., Demajo, S., Gundem, G., Lopez-Bigas, N., Nakagawa, T., Rospert, S., Ito, T., & Di Croce, L. (2010). Transcriptional activation of polycomb-repressed genes by ZRF1. Nature, 468(7327), 1124–1128. https://doi.org/10.1038/nature09574
Jain, P., Ballare, C., Blanco, E., Vizan, P., & Di Croce, L. (2020). PHF19 mediated regulation of proliferation and invasiveness in prostate cancer cells. eLife, 9, e51373. https://doi.org/10.7554/eLife.51373
 
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Formation of CenH3-deficient Kinetochores (Ines Drinnenberg)

In this episode of the Epigenetics Podcast, we caught up with Ines Drinnenberg from Institute Curie to talk about her work on the formation of CenH3-deficient kinetochores.
The laboratory of Ines Drinneberg focuses on centromeres and how different strategies of centromere organization have evolved in different organisms. While most eukaryotes have monocentric chromosomes, where spindle attachment is restricted to a single chromosomal region resembling such classic X-shape like structures under the microscope, many lineages have evolved holocentric chromosomes where spindle microtubules attach along the entire length of the chromosome. The team was able to show the independent loss of CENH3/CENP-A in holocentric insects. Furthermore, the team focuses on how CenH3-deficient kinetochores form and were able to identify several conserved kinetochore components that emerged as a key component for CenH3-deficient kinetochore formation in Lepidoptera.
 
References
Drinnenberg, I. A., deYoung, D., Henikoff, S., & Malik, H. S. (2014). Recurrent loss of CenH3 is associated with independent transitions to holocentricity in insects. eLife, 3, e03676. https://doi.org/10.7554/eLife.03676
Molaro, A., & Drinnenberg, I. A. (2018). Studying the Evolution of Histone Variants Using Phylogeny. Methods in molecular biology (Clifton, N.J.), 1832, 273–291. https://doi.org/10.1007/978-1-4939-8663-7_15
Cortes-Silva, N., Ulmer, J., Kiuchi, T., Hsieh, E., Cornilleau, G., Ladid, I., Dingli, F., Loew, D., Katsuma, S., & Drinnenberg, I. A. (2020). CenH3-Independent Kinetochore Assembly in Lepidoptera Requires CCAN, Including CENP-T. Current biology : CB, 30(4), 561–572.e10. https://doi.org/10.1016/j.cub.2019.12.014
Senaratne, A. P., Muller, H., Fryer, K. A., Kawamoto, M., Katsuma, S., & Drinnenberg, I. A. (2021). Formation of the CenH3-Deficient Holocentromere in Lepidoptera Avoids Active Chromatin. Current biology : CB, 31(1), 173–181.e7. https://doi.org/10.1016/j.cub.2020.09.078
Vanpoperinghe, L., Carlier-Grynkorn, F., Cornilleau, G., Kusakabe, T., Drinnenberg, I. A., & Tran, P. T. (2021). Live-cell imaging reveals square shape spindles and long mitosis duration in the silkworm holocentric cells. microPublication biology, 2021, 10.17912/micropub.biology.000441. https://doi.org/10.17912/micropub.biology.000441
 
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Effects of Environmental Cues on the Epigenome and Longevity (Paul Shiels)

In this episode of the Epigenetics Podcast, we caught up with Paul Shiels from the University of Glasgow to talk about his work on the effects of environmental cues on the epigenome and longevity.
Paul Shiels and his team focus on the question on how age related health is influenced by the environment. Factors like the socio-economic position, nutrition, lifestyle and the environment can influence the microbiome and the inflammation burden on the body which in turn can alter individual trajectories of ageing and health. The lab also tries to understand the epigenetic, molecular and cellular mechanisms that link the exposome to chronic age related diseases of older people. They have shown that (1)  imbalanced nutrition is associated with a microbiota-mediated accelerated ageing in the general population, (2) a significantly higher abundance of circulatory pathogenic bacteria is found in the most biologically aged, while those less biologically aged possess more circulatory salutogenic bacteria with a capacity to metabolise and produce cytoprotective Nrf2 agonists, (3) those at lower socioeconomic position possess significantly lower betaine levels indicative of a poorer diet and poorer health span and consistent with reduced global DNA methylation levels in this group.
 
References
Harris, S. E., Deary, I. J., MacIntyre, A., Lamb, K. J., Radhakrishnan, K., Starr, J. M., Whalley, L. J., & Shiels, P. G. (2006). The association between telomere length, physical health, cognitive ageing, and mortality in non-demented older people. Neuroscience Letters, 406(3), 260–264. https://doi.org/10.1016/j.neulet.2006.07.055
Paul G. Shiels, Improving Precision in Investigating Aging: Why Telomeres Can Cause Problems, The Journals of Gerontology: Series A, Volume 65A, Issue 8, August 2010, Pages 789–791, https://doi.org/10.1093/gerona/glq095
Mafra D, Ugochukwu SA, Borges NA, et al. Food for healthier aging: power on your plate. Critical Reviews in Food Science and Nutrition. 2022 Aug:1-14. DOI: 10.1080/10408398.2022.2107611. PMID: 35959705.
Shiels PG, Stenvinkel P, Kooman JP, McGuinness D. Circulating markers of ageing and allostatic load: A slow train coming. Practical Laboratory Medicine. 2017 Apr;7:49-54. DOI: 10.1016/j.plabm.2016.04.002. PMID: 28856219; PMCID: PMC5574864.
 
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