Epigenetics Podcast

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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The Role of Non-Histone Proteins in Chromosome Structure and Function During Mitosis (Bill Earnshaw)
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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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The Epigenetics of Human Sperm Cells (Sarah Kimmins)

In this episode of the Epigenetics Podcast, we caught up with Sarah Kimmins from Université de Montreal to talk about her work on the epigenetics of human sperm cells.
The focus of Sarah Kimmins and her lab is how sperm and offspring health is impacted by the father's environment. The core of this is the sperm epigenome, which has been implicated in complex diseases such as infertility, cancer, diabetes, schizophrenia and autism. The Kimmins lab is interested which players play a role in this and came across the Histone post-translational modification H3K4me3. In this interview we talk about how the father's life choices can impact offspring health, which can also be inherited transgenerationally and how this can be used to develop intervention strategies to improve child and adult health.
 
References
Siklenka, K., Erkek, S., Godmann, M., Lambrot, R., McGraw, S., Lafleur, C., Cohen, T., Xia, J., Suderman, M., Hallett, M., Trasler, J., Peters, A. H., & Kimmins, S. (2015). Disruption of histone methylation in developing sperm impairs offspring health transgenerationally. Science (New York, N.Y.), 350(6261), aab2006. https://doi.org/10.1126/science.aab2006
Lismer, A., Siklenka, K., Lafleur, C., Dumeaux, V., & Kimmins, S. (2020). Sperm histone H3 lysine 4 trimethylation is altered in a genetic mouse model of transgenerational epigenetic inheritance. Nucleic acids research, 48(20), 11380–11393. https://doi.org/10.1093/nar/gkaa712
Lismer, A., Dumeaux, V., Lafleur, C., Lambrot, R., Brind'Amour, J., Lorincz, M. C., & Kimmins, S. (2021). Histone H3 lysine 4 trimethylation in sperm is transmitted to the embryo and associated with diet-induced phenotypes in the offspring. Developmental cell, 56(5), 671–686.e6. https://doi.org/10.1016/j.devcel.2021.01.014
 
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Transgenerational Inheritance and Evolution of Epimutations (Peter Sarkies)

In this episode of the Epigenetics Podcast, we caught up with Peter Sarkies from University of Oxford Biochemistry to talk about his work on Transgenerational Inheritance of Epimutations.
The team in the Sarkies lab focuses on investigating the connections between epigenetic gene regulation and evolution. The lab performs evolution experiments in the nematode C. elegans to determine if evolution can be influenced by epigenetic differences between individuals in a given population when no changes in the underlying DNA sequence are observed. A second area of interest of the team is evolution of piRNAs, which are present in metazoans but have been lost in nematodes during evolution.
 
References
The Selfish Gene
Sarkies, P., & Miska, E. A. (2013). Is There Social RNA? Science, 341(6145), 467–468. https://doi.org/10.1126/science.1243175
Beltran, T., Shahrezaei, V., Katju, V., & Sarkies, P. (2020). Epimutations driven by small RNAs arise frequently but most have limited duration in Caenorhabditis elegans. Nature ecology & evolution, 4(11), 1539–1548. https://doi.org/10.1038/s41559-020-01293-z
Beltran, T., Pahita, E., Ghosh, S., Lenhard, B., & Sarkies, P. (2021). Integrator is recruited to promoter-proximally paused RNA Pol II to generate Caenorhabditis elegans piRNA precursors. The EMBO journal, 40(5), e105564. https://doi.org/10.15252/embj.2020105564
 
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Transcription Elongation Control by the Paf1 Complex (Karen Arndt)

In this episode of the Epigenetics Podcast, we caught up with Karen Arndt from the University of Pittsburgh to talk about her work on transcription elongation control by the Paf1 complex.
Karen Arndt and her lab investigate the process of transcriptional elongation and how RNA polymerase II overcomes obstacles like nucleosomes. One of the proteins that helps overcome those obstacles is the Paf1 complex. This complex associates with the transcribing polymerase and helps in modifying the chromatin template by ubiquitinating Histone H2B and methylating Histone H3.
 
References
Squazzo, S. L., Costa, P. J., Lindstrom, D. L., Kumer, K. E., Simic, R., Jennings, J. L., Link, A. J., Arndt, K. M., & Hartzog, G. A. (2002). The Paf1 complex physically and functionally associates with transcription elongation factors in vivo. The EMBO journal, 21(7), 1764–1774. https://doi.org/10.1093/emboj/21.7.1764
Van Oss, S. B., Shirra, M. K., Bataille, A. R., Wier, A. D., Yen, K., Vinayachandran, V., Byeon, I. L., Cucinotta, C. E., Héroux, A., Jeon, J., Kim, J., VanDemark, A. P., Pugh, B. F., & Arndt, K. M. (2016). The Histone Modification Domain of Paf1 Complex Subunit Rtf1 Directly Stimulates H2B Ubiquitylation through an Interaction with Rad6. Molecular cell, 64(4), 815–825. https://doi.org/10.1016/j.molcel.2016.10.008
Cucinotta, C. E., Hildreth, A. E., McShane, B. M., Shirra, M. K., & Arndt, K. M. (2019). The nucleosome acidic patch directly interacts with subunits of the Paf1 and FACT complexes and controls chromatin architecture in vivo. Nucleic acids research, 47(16), 8410–8423. https://doi.org/10.1093/nar/gkz549
Hildreth, A. E., Ellison, M. A., Francette, A. M., Seraly, J. M., Lotka, L. M., & Arndt, K. M. (2020). The nucleosome DNA entry-exit site is important for transcription termination and prevention of pervasive transcription. eLife, 9, e57757. https://doi.org/10.7554/eLife.57757
 
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Molecular Mechanisms of Chromatin Modifying Enzymes (Karim-Jean Armache)

In this episode of the Epigenetics Podcast, we caught up with Karim-Jean Armache from New York University - Grossman School of Medicine to talk about his work on the structural analysis of Polycomb Complex Proteins and molecular mechanisms of chromatin modifying enzymes.
Karim-Jean Armache started his research career with the structural characterization of the 12-subunit RNA Polymerase II. After starting his own lab he used this knowledge in x-ray crystallography and electron microscopy to study how gene silencing complexes like the PRC complex act on chromatin and influence transcription. Further work in the Armache Lab focused on Dot, a  histone H3K79 methyltransferase, and how it acts on chromatin, as well as how it is regulated by Histone-Histone crosstalk.
References
Armache, K. J., Garlick, J. D., Canzio, D., Narlikar, G. J., & Kingston, R. E. (2011). Structural basis of silencing: Sir3 BAH domain in complex with a nucleosome at 3.0 Å resolution. Science (New York, N.Y.), 334(6058), 977–982. https://doi.org/10.1126/science.1210915
Lee, C. H., Holder, M., Grau, D., Saldaña-Meyer, R., Yu, J. R., Ganai, R. A., Zhang, J., Wang, M., LeRoy, G., Dobenecker, M. W., Reinberg, D., & Armache, K. J. (2018). Distinct Stimulatory Mechanisms Regulate the Catalytic Activity of Polycomb Repressive Complex 2. Molecular cell, 70(3), 435–448.e5. https://doi.org/10.1016/j.molcel.2018.03.019
De Ioannes, P., Leon, V. A., Kuang, Z., Wang, M., Boeke, J. D., Hochwagen, A., & Armache, K. J. (2019). Structure and function of the Orc1 BAH-nucleosome complex. Nature communications, 10(1), 2894. https://doi.org/10.1038/s41467-019-10609-y
Valencia-Sánchez, M. I., De Ioannes, P., Wang, M., Truong, D. M., Lee, R., Armache, J. P., Boeke, J. D., & Armache, K. J. (2021). Regulation of the Dot1 histone H3K79 methyltransferase by histone H4K16 acetylation. Science (New York, N.Y.), 371(6527), eabc6663. https://doi.org/10.1126/science.abc6663
 
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The Role of PHF13 in Chromatin and Transcription (Sarah Kinkley)

In this episode of the Epigenetics Podcast, we caught up with Sarah Kinkley from the Max Planck Institute of Molecular Genetics to talk about her work on PHF13 and its role in chromatin and transcription.
The Kinkley laboratory focuses mainly on unraveling the mechanism of action of the transcription factor PHF13 (PHC Finger Protein 13). PHF13 is a reader of the epigenetic mark H3K4 trimethylation which influences higher chromatin order, transcriptional regulation, and differentiation. The lab has shown that PHF13 plays a crucial role in phase separation and mitotic chromatin compaction.
 
References
Kinkley, S., Staege, H., Mohrmann, G., Rohaly, G., Schaub, T., Kremmer, E., Winterpacht, A., & Will, H. (2009). SPOC1: a novel PHD-containing protein modulating chromatin structure and mitotic chromosome condensation. Journal of cell science, 122(Pt 16), 2946–2956. https://doi.org/10.1242/jcs.047365
Chung, H. R., Xu, C., Fuchs, A., Mund, A., Lange, M., Staege, H., Schubert, T., Bian, C., Dunkel, I., Eberharter, A., Regnard, C., Klinker, H., Meierhofer, D., Cozzuto, L., Winterpacht, A., Di Croce, L., Min, J., Will, H., & Kinkley, S. (2016). PHF13 is a molecular reader and transcriptional co-regulator of H3K4me2/3. eLife, 5, e10607. https://doi.org/10.7554/eLife.10607
Connecting the Dots: PHF13 and cohesin promote polymer-polymer phase separation of chromatin into chromosomes. Francesca Rossi, Rene Buschow, Laura V. Glaser, Tobias Schubert, Hannah Staege, Astrid Grimme, Hans Will, Thorsten Milke, Martin Vingron, Andrea M. Chiariello, Sarah Kinkley. bioRxiv 2022.03.04.482956; doi: https://doi.org/10.1101/2022.03.04.482956
 
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Genome Organization Mediated by RNA Polymerase II (Argyrys Papantonis)

In this episode of the Epigenetics Podcast, we caught up with Akis Papantonis from the University Medical Center Göttingen to talk about his work on genome organisation mediated by RNA Polymerase II.
The research of the Papantonis Laboratory focuses on investigating how environmental signalling stimuli are integrated by chromatin to control homeostatic to deregulated functional transitions. In more detail, the team is interested in how dynamic higher-order regulatory networks are influenced by the underlying linear DNA fiber. The ultimate goal of the laboratory is to understand general rules governing transcriptional and chromatin homeostasis and finally, how those rules might affect development, ageing or malignancies.
 
References
Larkin, J. D., Cook, P. R., & Papantonis, A. (2012). Dynamic reconfiguration of long human genes during one transcription cycle. Molecular and cellular biology, 32(14), 2738–2747. https://doi.org/10.1128/MCB.00179-12
Diermeier, S., Kolovos, P., Heizinger, L., Schwartz, U., Georgomanolis, T., Zirkel, A., Wedemann, G., Grosveld, F., Knoch, T. A., Merkl, R., Cook, P. R., Längst, G., & Papantonis, A. (2014). TNFα signalling primes chromatin for NF-κB binding and induces rapid and widespread nucleosome repositioning. Genome biology, 15(12), 536. https://doi.org/10.1186/s13059-014-0536-6
Sofiadis, K., Josipovic, N., Nikolic, M., Kargapolova, Y., Übelmesser, N., Varamogianni-Mamatsi, V., Zirkel, A., Papadionysiou, I., Loughran, G., Keane, J., Michel, A., Gusmao, E. G., Becker, C., Altmüller, J., Georgomanolis, T., Mizi, A., & Papantonis, A. (2021). HMGB1 coordinates SASP-related chromatin folding and RNA homeostasis on the path to senescence. Molecular systems biology, 17(6), e9760. https://doi.org/10.15252/msb.20209760
Enhancer-promoter contact formation requires RNAPII and antagonizes loop extrusion. Shu Zhang, Nadine Übelmesser, Mariano Barbieri, Argyris Papantonis. bioRxiv 2022.07.04.498738; doi: https://doi.org/10.1101/2022.07.04.498738
 
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