Epigenetics Podcast

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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H3K4me3, SET Proteins, Isw1, and their Role in Transcription (Jane Mellor)
 
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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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Analysis of 3D Chromatin Structure Using Super-Resolution Imaging (Alistair Boettiger)

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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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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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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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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