Epigenetics Podcast

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

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's success in mapping estrogen receptor binding sites. Various techniques for transcription factor mapping, including CUT&RUN, CUT&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., & 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., & 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., & 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'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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Pioneer Transcription Factors and Their Influence on Chromatin Structure (Ken Zaret)
The Role of Pioneer Factors Zelda and Grainyhead at the Maternal-to-Zygotic Transition (Melissa Harrison)
 
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Inheritance of Transcriptional Memory by Mitotic Bookmarking (Sheila Teves)

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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In Vivo Nucleosome Structure and Dynamics (Srinivas Ramachandran)
From Nucleosome Structure to Function (Karolin Luger)
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Differential Methylated Regions in Autism Spectrum Disorders (Janine La Salle)

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'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's developmental history.
The conversation then delves into Dr. LaSalle'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., & 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., & 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., & 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., Grant, T. E., Palmer, R. L., Chappell, D., Hakam, S. M., Yasui, K. M., Rolston, M., Settles, M. L., Hunter, S. S., Madany, A., Ashwood, P., Durbin-Johnson, B., LaSalle, J. M., & Yasui, D. H. (2021). Sex disparate gut microbiome and metabolome perturbations precede disease progression in a mouse model of Rett syndrome. Communications biology, 4(1), 1408. https://doi.org/10.1038/s42003-021-02915-3
 
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DNA Damage in Longevity and Ageing (Björn Schumacher)

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

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

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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Transgenerational Inheritance and Epigenetic Imprinting in Plants (Mary Gehring)

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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When is a Peak a Peak? (Claudio Cantù)

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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