Epigenetics Podcast

Spatio-Temporal Alterations in Chromosome Dynamics (Jane Skok)

In this episode of the Epigenetics Podcast, we caught up with Jane Skok from New York University School of Medicine to talk about her work on spatio-temporal alterations in chromosome dynamics.
Studies demonstrating that nuclear organization and long-range chromatin interactions play essential roles in gene regulation have been the focus of the Skok Lab, where the team has played a leading role. Their initial studies focused on lymphocyte development and the control of V(D)J recombination, a key part of generating the diverse repertoire of B-cell antibodies and T-cell receptors. The Skok Lab was among the first to demonstrate the possibility of chromatin forming dynamic loops which lead to the formation of reversible intra-locus loops in the immunoglobulin and T-cell receptor loci and to a profound impact on the ability of B and T cells to generate receptor diversity.
 
References
Roldán, E., Fuxa, M., Chong, W., Martinez, D., Novatchkova, M., Busslinger, M., & Skok, J. A. (2005). Locus “decontraction” and centromeric recruitment contribute to allelic exclusion of the immunoglobulin heavy-chain gene. Nature Immunology, 6(1), 31–41. https://doi.org/10.1038/ni1150
Skok, J. A. (2014). Taking a break from the lab: Can it really be done? Trends in Cell Biology, 24(12), 725–726. https://doi.org/10.1016/j.tcb.2014.09.002
Proudhon, C., Snetkova, V., Raviram, R., Lobry, C., Badri, S., Jiang, T., Hao, B., Trimarchi, T., Kluger, Y., Aifantis, I., Bonneau, R., & Skok, J. A. (2016). Active and Inactive Enhancers Cooperate to Exert Localized and Long-Range Control of Gene Regulation. Cell Reports, 15(10), 2159–2169. https://doi.org/10.1016/j.celrep.2016.04.087
Lhoumaud, P., Sethia, G., Izzo, F., Sakellaropoulos, T., Snetkova, V., Vidal, S., Badri, S., Cornwell, M., Di Giammartino, D. C., Kim, K.-T., Apostolou, E., Stadtfeld, M., Landau, D. A., & Skok, J. (2019). EpiMethylTag: Simultaneous detection of ATAC-seq or ChIP-seq signals with DNA methylation. Genome Biology, 20(1), 248. https://doi.org/10.1186/s13059-019-1853-6
Nishana, M., Ha, C., Rodriguez-Hernaez, J., Ranjbaran, A., Chio, E., Nora, E. P., Badri, S. B., Kloetgen, A., Bruneau, B. G., Tsirigos, A., & Skok, J. A. (2020). Defining the relative and combined contribution of CTCF and CTCFL to genomic regulation. Genome Biology, 21(1), 108. https://doi.org/10.1186/s13059-020-02024-0
 
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Chromatin Organization During Development and Disease (Marieke Oudelaar)

In this episode of the Epigenetics Podcast, we caught up with Marieke Oudelaar from the Max Planck Institute for Biophysical Chemistry to talk about her work on chromatin organization during development and disease.
Marieke Oudelaar and her team focus on on developing high-resolution Chromosome Conformation Capture (3C) based techniques, like low-input Capture-C, Tri-C, and Tiled-C. Those techniques are then used in combination with other genomic techniques, genetic perturbations, and computational approaches to investigate the 3D structure of chromatin in development and disease. The team focused on the interplay between genome organisation and regulation during mammalian differentiation, and how perturbations in these processes contribute to human disease, including cancer.
 
References
Oudelaar, A. M., Davies, J. O. J., Downes, D. J., Higgs, D. R., & Hughes, J. R. (2017). Robust detection of chromosomal interactions from small numbers of cells using low-input Capture-C. Nucleic Acids Research, 45(22), e184–e184. https://doi.org/10.1093/nar/gkx1194
Oudelaar, A. M., Davies, J. O. J., Hanssen, L. L. P., Telenius, J. M., Schwessinger, R., Liu, Y., Brown, J. M., Downes, D. J., Chiariello, A. M., Bianco, S., Nicodemi, M., Buckle, V. J., Dekker, J., Higgs, D. R., & Hughes, J. R. (2018). Single-allele chromatin interactions identify regulatory hubs in dynamic compartmentalized domains. Nature Genetics, 50(12), 1744–1751. https://doi.org/10.1038/s41588-018-0253-2
Oudelaar, A. M., Beagrie, R. A., Gosden, M., de Ornellas, S., Georgiades, E., Kerry, J., Hidalgo, D., Carrelha, J., Shivalingam, A., El-Sagheer, A. H., Telenius, J. M., Brown, T., Buckle, V. J., Socolovsky, M., Higgs, D. R., & Hughes, J. R. (2020). Dynamics of the 4D genome during in vivo lineage specification and differentiation. Nature Communications, 11(1), 2722. https://doi.org/10.1038/s41467-020-16598-7
Aljahani, A., Hua, P., Karpinska, M. A., Quililan, K., Davies, J. O. J., & Oudelaar, A. M. (2021). Analysis of sub-kilobase chromatin topology reveals nano-scale regulatory interactions with variable dependence on cohesin and CTCF [Preprint]. Genomics. https://doi.org/10.1101/2021.08.10.455796
 
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Enhancers and Chromatin Remodeling in Mammary Gland Development (Camila dos Santos)

In this episode of the Epigenetics Podcast, we caught up with Camila dos Santos from Cold Spring Harbor Laboratories to talk about her work on enhancers and chromatin remodeling in mammary gland development.
The lab of Camila dos Santos focuses on epigenetic regulation of normal and malignant mammary gland development. After puberty, the next significant phase in mammary gland development occurs in pregnancy, including changes in cellular function, and tissue reorganization. A different and as significant change in mammary glands occurs in the development breast cancer.
Camila dos Santos and her lab were recently able to show that the reaction of mammary glands to a second pregnancy is different than to a first one, which is accompanied by changes in the DNA methylome of the cells. Furthermore, the lab studies the connection of pregnancy-induced epigenetic changes of chromatin and the risk of cancer development.
 
References
dos Santos, C. O., Rebbeck, C., Rozhkova, E., Valentine, A., Samuels, A., Kadiri, L. R., Osten, P., Harris, E. Y., Uren, P. J., Smith, A. D., & Hannon, G. J. (2013). Molecular hierarchy of mammary differentiation yields refined markers of mammary stem cells. Proceedings of the National Academy of Sciences, 110(18), 7123–7130. https://doi.org/10.1073/pnas.1303919110
dos Santos, C. O., Dolzhenko, E., Hodges, E., Smith, A. D., & Hannon, G. J. (2015). An Epigenetic Memory of Pregnancy in the Mouse Mammary Gland. Cell Reports, 11(7), 1102–1109. https://doi.org/10.1016/j.celrep.2015.04.015
Feigman, M. J., Moss, M. A., Chen, C., Cyrill, S. L., Ciccone, M. F., Trousdell, M. C., Yang, S.-T., Frey, W. D., Wilkinson, J. E., & dos Santos, C. O. (2020). Pregnancy reprograms the epigenome of mammary epithelial cells and blocks the development of premalignant lesions. Nature Communications, 11(1), 2649. https://doi.org/10.1038/s41467-020-16479-z
 
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The Role of SMCHD1 in Development and Disease (Marnie Blewitt)

In this episode of the Epigenetics Podcast, we caught up with Marnie Blewitt from the Walter and Eliza Hall Institute of Medical Research to talk about her work on the role of SMCHD1 in Development and Disease.
The Laboratory of Marnie Blewitt focuses finding inhibitors or activators for the epigenetic regulator SMCHD1. Marnie Blewitt identified and characterized this protein during her PhD and the findings were published in 2008 in Nature Genetics. Since then, she and her team were able to investigate the function of this protein further. By doing so, they showed the involvement of SMCHD1 in cancer and several other diseases. Currently the lab is screening for small molecules that can act as inhibitors or activators of SMCHD1 the former as potential treatments for facioscapulohumeral muscular dystrophy, the latter for Prader Willi and Schaaf-Yang syndromes, both of which have no current targeted treatments.
 
References
Blewitt, M. E., Gendrel, A.-V., Pang, Z., Sparrow, D. B., Whitelaw, N., Craig, J. M., Apedaile, A., Hilton, D. J., Dunwoodie, S. L., Brockdorff, N., Kay, G. F., & Whitelaw, E. (2008). SmcHD1, containing a structural-maintenance-of-chromosomes hinge domain, has a critical role in X inactivation. Nature Genetics, 40(5), 663–669. https://doi.org/10.1038/ng.142
Leong, H. S., Chen, K., Hu, Y., Lee, S., Corbin, J., Pakusch, M., Murphy, J. M., Majewski, I. J., Smyth, G. K., Alexander, W. S., Hilton, D. J., & Blewitt, M. E. (2013). Epigenetic Regulator Smchd1 Functions as a Tumor Suppressor. Cancer Research, 73(5), 1591–1599. https://doi.org/10.1158/0008-5472.CAN-12-3019
Gordon, C. T., Xue, S., Yigit, G., Filali, H., Chen, K., Rosin, N., Yoshiura, K., Oufadem, M., Beck, T. J., McGowan, R., Magee, A. C., Altmüller, J., Dion, C., Thiele, H., Gurzau, A. D., Nürnberg, P., Meschede, D., Mühlbauer, W., Okamoto, N., … Reversade, B. (2017). De novo mutations in SMCHD1 cause Bosma arhinia microphthalmia syndrome and abrogate nasal development. Nature Genetics, 49(2), 249–255. https://doi.org/10.1038/ng.3765
 
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Single-Molecule Imaging of the Epigenome (Efrat Shema)

In this episode of the Epigenetics Podcast, we caught up with Efrat Shema from the Weizmann Institute of Science to talk about her work on Single Molecule Imaging of chromatin, and the analysis of nucleosomes circulating in plasma.
In ChIP-Seq experiments the peak you get as a read out represents an average over, most often, millions of cells. Furthermore, one often does not know if that peak represents one or more than one nucleosome. If you then want to study multiple marks at the same time, the question remains: do those modifications occur at the same time, in the same cell?
The Laboratory of Efrat Shema works on answering those questions by developing methods to study the modification patterns on single nucleosomes with single molecule imaging. With that it is possible to study single nucleosomes in a high throughout manner to identify the modifications they are decorated with. A subsequent sequencing step makes it possible to identify the genomic location of that nucleosome.
 
References
Shema, E., Bernstein, B. E., & Buenrostro, J. D. (2019). Single-cell and single-molecule epigenomics to uncover genome regulation at unprecedented resolution. Nature Genetics, 51(1), 19–25. https://doi.org/10.1038/s41588-018-0290-x
Shema, E., Jones, D., Shoresh, N., Donohue, L., Ram, O., & Bernstein, B. E. (2016). Single-molecule decoding of combinatorially modified nucleosomes. Science, 352(6286), 717–721. https://doi.org/10.1126/science.aad7701
Shema, E., Kim, J., Roeder, R. G., & Oren, M. (2011). RNF20 Inhibits TFIIS-Facilitated Transcriptional Elongation to Suppress Pro-oncogenic Gene Expression. Molecular Cell, 42(4), 477–488. https://doi.org/10.1016/j.molcel.2011.03.011
Shema, E., Tirosh, I., Aylon, Y., Huang, J., Ye, C., Moskovits, N., Raver-Shapira, N., Minsky, N., Pirngruber, J., Tarcic, G., Hublarova, P., Moyal, L., Gana-Weisz, M., Shiloh, Y., Yarden, Y., Johnsen, S. A., Vojtesek, B., Berger, S. L., & Oren, M. (2008). The histone H2B-specific ubiquitin ligase RNF20/hBRE1 acts as a putative tumor suppressor through selective regulation of gene expression. Genes & Development, 22(19), 2664–2676. https://doi.org/10.1101/gad.1703008
 
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Heterochromatin Protein 1 and its Influence on the Structure of Chromatin (Serena Sanulli)

In this episode of the Epigenetics Podcast, we caught up with Serena Sanulli from Stanford University to talk about her work on Heterochromatin Protein 1 (HP1), the structure of chromatin on the atomic-scale and the meso-scale, and phase separation.
The Laboratory of Serena Sanulli is interested in finding connections between changes that happen on the nucleosomal level and the resulting impact on chromatin conformation on the meso-scale. They combine methods like NMR and Hydrogen-Deuterium Exchange-MS with Cell Biology and Genetics. This enables them to dissect how cells use the diverse biophysical properties of chromatin to regulate gene expression across length and time scales.
A second focus of the lab is HP1, which interacts with the nucleosome and changes its conformation, enabling the compaction of the genome into heterochromatin, effectively silencing genes in that region. A high concentration of HP1 leads to the phenomenon of phase separation in the nucleus, which the Sanulli lab is now investigating.
 
References
Sanulli, S., Justin, N., Teissandier, A., Ancelin, K., Portoso, M., Caron, M., Michaud, A., Lombard, B., da Rocha, S. T., Offer, J., Loew, D., Servant, N., Wassef, M., Burlina, F., Gamblin, S. J., Heard, E., & Margueron, R. (2015). Jarid2 Methylation via the PRC2 Complex Regulates H3K27me3 Deposition during Cell Differentiation. Molecular Cell, 57(5), 769–783. https://doi.org/10.1016/j.molcel.2014.12.020
Sanulli, S., Trnka, M. J., Dharmarajan, V., Tibble, R. W., Pascal, B. D., Burlingame, A. L., Griffin, P. R., Gross, J. D., & Narlikar, G. J. (2019). HP1 reshapes nucleosome core to promote phase separation of heterochromatin. Nature, 575(7782), 390–394. https://doi.org/10.1038/s41586-019-1669-2
Sanulli, S., & Narlikar, G. J. (2021). Generation and Biochemical Characterization of Phase‐Separated Droplets Formed by Nucleic Acid Binding Proteins: Using HP1 as a Model System. Current Protocols, 1(5). https://doi.org/10.1002/cpz1.109
 
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The Effects of Early Life Stress on Mammalian Development (Catherine J. Peña)

In this episode of the Epigenetics Podcast, we caught up with Catherine Jensen Peña from Princeton University to talk about her work on early life stress and its effects on behavior.
The Laboratory of Catherine Peña focuses on how early life experiences are encoded and maintained into adulthood, with a long-lasting impact on behavior. Recent work showed, that child maltreatment and other forms of early life stress increase the lifetime risk of depression and other mood, anxiety, and drug disorders by 2-4 fold. The Peña Lab uses genome wide approaches to investigate key brain regions with a two-hit stress model.
Using RNA-Seq, the Peña Lab has shown that depression-like gene expression patterns are programmed by early life stress, similar to observations in mice exhibiting depression-like behavior after adult stress and are visible even before behavioral changes. Furthermore, latent and unique transcriptional responses to adult stress among a subset of genes is programmed by early life stress. The role of chromatin modifications in regulating these processes are investigated using state of the art technologies like Mod-Spec or ATAC-Seq.
 
References
Kronman, H., Torres-Berrío, A., Sidoli, S., Issler, O., Godino, A., Ramakrishnan, A., Mews, P., Lardner, C. K., Parise, E. M., Walker, D. M., van der Zee, Y. Y., Browne, C. J., Boyce, B. F., Neve, R., Garcia, B. A., Shen, L., Peña, C. J., & Nestler, E. J. (2021). Long-term behavioral and cell-type-specific molecular effects of early life stress are mediated by H3K79me2 dynamics in medium spiny neurons. Nature Neuroscience, 24(5), 667–676. https://doi.org/10.1038/s41593-021-00814-8
Peña, C. J., Smith, M., Ramakrishnan, A., Cates, H. M., Bagot, R. C., Kronman, H. G., Patel, B., Chang, A. B., Purushothaman, I., Dudley, J., Morishita, H., Shen, L., & Nestler, E. J. (2019). Early life stress alters transcriptomic patterning across reward circuitry in male and female mice. Nature Communications, 10(1), 5098. https://doi.org/10.1038/s41467-019-13085-6
Peña, C. J., Kronman, H. G., Walker, D. M., Cates, H. M., Bagot, R. C., Purushothaman, I., Issler, O., Loh, Y.-H. E., Leong, T., Kiraly, D. D., Goodman, E., Neve, R. L., Shen, L., & Nestler, E. J. (2017). Early life stress confers lifelong stress susceptibility in mice via ventral tegmental area OTX2. Science, 356(6343), 1185–1188. https://doi.org/10.1126/science.aan4491
 
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Targeting COMPASS to Cure Childhood Leukemia (Ali Shilatifard)

In this episode of the Epigenetics Podcast, we caught up with Ali Shilatifard from Northwestern University to talk about his work on targeting COMPASS to cure childhood leukemia.
The Shilatifard Lab studies childhood leukemia and how it can potentially be treated using epigenetic targets. The team focuses on is SET1/COMPASS, a histone H3 lysine4 methylase. Ali Shilatifard was able to purify and identify its activity, with results published in 2001 in PNAS. This protein complex is conserved from yeast to drosophila to humans.
Surprisingly, the Shilatifard Team could show that the catalytic activity of COMPASS is not necessary for viability of drosophila. Furthermore, they found that catalytic activity was not the decisive feature of the complex, but rather its role in the context of chromatin structure, in particular a protein domain that only spans 80 amino acids within the 4000 amino acid protein.
 
References
Miller, T., Krogan, N. J., Dover, J., Erdjument-Bromage, H., Tempst, P., Johnston, M., Greenblatt, J. F., & Shilatifard, A. (2001). COMPASS: A complex of proteins associated with a trithorax-related SET domain protein. Proceedings of the National Academy of Sciences, 98(23), 12902–12907. https://doi.org/10.1073/pnas.231473398
Lin, C., Garruss, A. S., Luo, Z., Guo, F., & Shilatifard, A. (2013). The RNA Pol II Elongation Factor Ell3 Marks Enhancers in ES Cells and Primes Future Gene Activation. Cell, 152(1–2), 144–156. https://doi.org/10.1016/j.cell.2012.12.015
Wang, L., Zhao, Z., Ozark, P. A., Fantini, D., Marshall, S. A., Rendleman, E. J., Cozzolino, K. A., Louis, N., He, X., Morgan, M. A., Takahashi, Y., Collings, C. K., Smith, E. R., Ntziachristos, P., Savas, J. N., Zou, L., Hashizume, R., Meeks, J. J., & Shilatifard, A. (2018). Resetting the epigenetic balance of Polycomb and COMPASS function at enhancers for cancer therapy. Nature Medicine, 24(6), 758–769. https://doi.org/10.1038/s41591-018-0034-6
Morgan, M. A. J., & Shilatifard, A. (2020). Reevaluating the roles of histone-modifying enzymes and their associated chromatin modifications in transcriptional regulation. Nature Genetics, 52(12), 1271–1281. https://doi.org/10.1038/s41588-020-00736-4
 
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