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1. Distinct genetic liability profiles define clinically relevant patient strata across common diseases

Author

Trastulla, Lucia, Dolgalev, Georgii, Moser, Sylvain, Jiménez-Barrón, Laura T., Andlauer, Till F. M., von Scheidt, Moritz, Budde, Monika, Heilbronner, Urs, Papiol, Sergi, Teumer, Alexander, Homuth, Georg, Völzke, Henry, Dörr, Marcus, Falkai, Peter, Schulze, Thomas G., Gagneur, Julien, Iorio, Francesco, Müller-Myhsok, Bertram, Schunkert, Heribert, and Ziller, Michael J.

Published
2024
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4. Primary cilia and SHH signaling impairments in human and mouse models of Parkinson’s disease

Author

Schmidt, Sebastian, Luecken, Malte D., Trümbach, Dietrich, Hembach, Sina, Niedermeier, Kristina M., Wenck, Nicole, Pflügler, Klaus, Stautner, Constantin, Böttcher, Anika, Lickert, Heiko, Ramirez-Suastegui, Ciro, Ahmad, Ruhel, Ziller, Michael J., Fitzgerald, Julia C., Ruf, Viktoria, van de Berg, Wilma D. J., Jonker, Allert J., Gasser, Thomas, Winner, Beate, Winkler, Jürgen, Vogt Weisenhorn, Daniela M., Giesert, Florian, Theis, Fabian J., and Wurst, Wolfgang

Published
2022
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6. The systems biology simulation core algorithm

Author

Keller, Roland, Dörr, Alexander, Tabira, Akito, Funahashi, Akira, Ziller, Michael J, Adams, Richard, Rodriguez, Nicolas, Novère, Nicolas, Hiroi, Noriko, Planatscher, Hannes, Zell, Andreas, and Dräger, Andreas

Abstract

Abstract Background With the increasing availability of high dimensional time course data for metabolites, genes, and fluxes, the mathematical description of dynamical systems has become an essential aspect of research in systems biology. Models are often encoded in formats such as SBML, whose structure is very complex and difficult to evaluate due to many special cases. Results This article describes an efficient algorithm to solve SBML models that are interpreted in terms of ordinary differential equations. We begin our consideration with a formal representation of the mathematical form of the models and explain all parts of the algorithm in detail, including several preprocessing steps. We provide a flexible reference implementation as part of the Systems Biology Simulation Core Library, a community-driven project providing a large collection of numerical solvers and a sophisticated interface hierarchy for the definition of custom differential equation systems. To demonstrate the capabilities of the new algorithm, it has been tested with the entire SBML Test Suite and all models of BioModels Database. Conclusions The formal description of the mathematics behind the SBML format facilitates the implementation of the algorithm within specifically tailored programs. The reference implementation can be used as a simulation backend for Java™-based programs. Source code, binaries, and documentation can be freely obtained under the terms of the LGPL version 3 from http://simulation-core.sourceforge.net. Feature requests, bug reports, contributions, or any further discussion can be directed to the mailing list simulation-core-development@lists.sourceforge.net.

Published
2013

7. Global delay in nascent strand DNA methylation

Author

Charlton, Jocelyn, Downing, Timothy L., Smith, Zachary D., Gu, Hongcang, Clement, Kendell, Pop, Ramona, Akopian, Veronika, Klages, Sven, Santos, David P., Tsankov, Alexander M., Timmermann, Bernd, Ziller, Michael J., Kiskinis, Evangelos, Gnirke, Andreas, and Meissner, Alexander

Published
2018
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10. Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency

Author

Cacchiarelli, Davide, Trapnell, Cole, Ziller, Michael J., Soumillon, Magali, Cesana, Marcella, Karnik, Rahul, Donaghey, Julie, Smith, Zachary D., Ratanasirintrawoot, Sutheera, Zhang, Xiaolan, Ho Sui, Shannan J., Wu, Zhaoting, Akopian, Veronika, Gifford, Casey A., Doench, John, Rinn, John L., Daley, George Q., Meissner, Alexander, Lander, Eric S., and Mikkelsen, Tarjei S.

Published
2015
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11. Locally Disordered Methylation Forms the Basis of Intratumor Methylome Variation in Chronic Lymphocytic Leukemia

Author

Landau, Dan A., Clement, Kendell, Ziller, Michael J., Boyle, Patrick, Fan, Jean, Gu, Hongcang, Stevenson, Kristen, Sougnez, Carrie, Wang, Lili, Li, Shuqiang, Kotliar, Dylan, Zhang, Wandi, Ghandi, Mahmoud, Garraway, Levi, Fernandes, Stacey M., Livak, Kenneth J., Gabriel, Stacey, Gnirke, Andreas, Lander, Eric S., Brown, Jennifer R., Neuberg, Donna, Kharchenko, Peter V., Hacohen, Nir, Getz, Gad, Meissner, Alexander, and Wu, Catherine J.

Published
2014
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12. A stably self-renewing adult blood-derived induced neural stem cell exhibiting patternability and epigenetic rejuvenation

Author

Sheng, Chao, Jungverdorben, Johannes, Wiethoff, Hendrik, Lin, Qiong, Flitsch, Lea J., Eckert, Daniela, Hebisch, Matthias, Fischer, Julia, Kesavan, Jaideep, Weykopf, Beatrice, Schneider, Linda, Holtkamp, Dominik, Beck, Heinz, Till, Andreas, Wüllner, Ullrich, Ziller, Michael J., Wagner, Wolfgang, Peitz, Michael, and Brüstle, Oliver

Published
2018
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13. Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells

Author

Gifford, Casey A., Ziller, Michael J., Gu, Hongcang, Trapnell, Cole, Donaghey, Julie, Tsankov, Alexander, Shalek, Alex K., Kelley, David R., Shishkin, Alexander A., Issner, Robbyn, Zhang, Xiaolan, Coyne, Michael, Fostel, Jennifer L., Holmes, Laurie, Meldrim, Jim, Guttman, Mitchell, Epstein, Charles, Park, Hongkun, Kohlbacher, Oliver, Rinn, John, Gnirke, Andreas, Lander, Eric S., Bernstein, Bradley E., and Meissner, Alexander

Published
2013
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14. Transcription factor binding dynamics during human ES cell differentiation

Author

Tsankov, Alexander M., Gu, Hongcang, Akopian, Veronika, Ziller, Michael J., Donaghey, Julie, Amit, Ido, Gnirke, Andreas, and Meissner, Alexander

Subjects
DNA-ligand interactions -- Physiological aspects -- Analysis, Embryonic development -- Physiological aspects -- Genetic aspects, Embryonic stem cells -- Properties, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Pluripotent stem cells provide a powerful system to dissect the underlying molecular dynamics that regulate cell fate changes during mammalian development. Here we report the integrative analysis of genome-wide binding data for 38 transcription factors with extensive epigenome and transcriptional data across the differentiation of human embryonic stem cells to the three germ layers. We describe core regulatory dynamics and show the lineage-specific behaviour of selected factors. In addition to the orchestrated remodelling of the chromatin landscape, we find that the binding of several transcription factors is strongly associated with specific loss of DNA methylation in one germ layer, and in many cases a reciprocal gain in the other layers. Taken together, our work shows context-dependent rewiring of transcription factor binding, downstream signalling effectors, and the epigenome during human embryonic stem cell differentiation., Human embryonic stem (ES) cells hold great promise for tissue engineering and disease modelling; yet a key challenge to deriving mature, functional cell types is understanding the molecular mechanisms that [...]

Published
2015
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15. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Ziller, Michael J., Edri, Reuven, Yaffe, Yakey, Donaghey, Julie, Pop, Ramona, Mallard, William, Issner, Robbyn, Gifford, Casey A., Goren, Alon, Xing, Jeffrey, Gu, Hongcang, Cacchiarelli, Davide, Tsankov, Alexander M., Epstein, Charles, Rinn, John L., Mikkelsen, Tarjei S., Kohlbacher, Oliver, Gnirke, Andreas, Bernstein, Bradley E., Elkabetz, Yechiel, and Meissner, Alexander

Subjects
Neural circuitry -- Research, Genetic research, Stem cells -- Genetic aspects, Neurological research, Cell differentiation -- Research, Epigenetic inheritance -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Models derived from human pluripotent stem cells that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signalling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells in the embryonic and adult nervous system (1-3). Here we report the transcriptional and epigenomic analysis of six consecutive neural progenitor cell stages derived from a HES5::eGFP reporter human embryonic stem cell line (4). Using this system, we aimed to model cell-fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell-state transition based on the progressive remodelling of the epigenetic landscape and then validated these through a pooled short hairpin RNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and suggest here that they are mediated by combinations of core and stage-specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation., We used the human embryonic stem (ES) cell line WA9 (also known as H9) expressing GFP under the HES5 promoter (4) to isolate defined neural progenitor populations of neuroepithelial (NE), [...]

Published
2015

16. Expression of Lineage Transcription Factors Identifies Differences in Transition States of Induced Human Oligodendrocyte Differentiation

Author

Raabe, Florian J., primary, Stephan, Marius, additional, Waldeck, Jan Benedikt, additional, Huber, Verena, additional, Demetriou, Damianos, additional, Kannaiyan, Nirmal, additional, Galinski, Sabrina, additional, Glaser, Laura V., additional, Wehr, Michael C., additional, Ziller, Michael J., additional, Schmitt, Andrea, additional, Falkai, Peter, additional, and Rossner, Moritz J., additional

Published
2022
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18. Integrative analysis of 111 reference human epigenomes

Author

Consortium, Roadmap Epigenomics, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Whitaker, John W., Ward, Lucas D., Sarkar, Abhishek, Sandstrom, Richard S., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Harris, Alan R., Epstein, Charles B., Leung, Danny, Hawkins, David R., Hong, Chibo, Mungall, Andrew J., Chuah, Eric, Hansen, Scott R., Bansal, Mukul S., Dixon, Jesse R., Feizi, Soheil, Kim, Ah-Ram, Li, Daofeng, Elliott, GiNell, Neph, Shane J., Polak, Paz, Ray, Pradipta, Siebenthall, Kyle T., Thurman, Robert E., Zhou, Xin, Boyer, Laurie A., De Jager, Philip L., Fisher, Susan J., Li, Wei, McManus, Michael T., Sunyaev, Shamil, Tlsty, Thea D., Wang, Wei, Waterland, Robert A., Costello, Joseph F., Hirst, Martin, Stamatoyannopoulos, John A., Wang, Ting, Amin, Viren, Schultz, Matthew D., Quon, Gerald, Eaton, Matthew L., Pfenning, Andreas, Liu, Melina ClaussnitzerYaping, Coarfa, Cristian, Shoresh, Noam, Gjoneska, Elizabeta, Xie, Wei, Lister, Ryan, Moore, Richard, Tam, Angela, Canfield, Theresa K., Kaul, Rajinder, Sabo, Peter J., Carles, Annaick, Farh, Kai-How, Karlic, Rosa, Kulkarni, Ashwinikumar, Lowdon, Rebecca, Mercer, Tim R., Onuchic, Vitor, Rajagopal, Nisha, Sallari, Richard C., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Wu, Jie, Zhang, Bo, Abdennur, Nezar, Adli, Mazhar, Akerman, Martin, Barrera, Luis, Antosiewicz-Bourget, Jessica, Ballinger, Tracy, Barnes, Michael J., Bates, Daniel, Bell, Robert J. A., Bennett, David A., Bianco, Katherine, Bock, Christoph, Boyle, Patrick, Brinchmann, Jan, Caballero-Campo, Pedro, Camahort, Raymond, Carrasco-Alfonso, Marlene J., Charnecki, Timothy, Chen, Huaming, Chen, Zhao, Cheng, Jeffrey B., Cho, Stephanie, Chu, Andy, Chung, Wen-Yu, Cowan, Chad, Deng, Qixia Athena, Deshpande, Vikram, Diegel, Morgan, Ding, Bo, Durham, Timothy, Echipare, Lorigail, Edsall, Lee, Flowers, David, Genbacev-Krtolica, Olga, Gifford, Casey, Gillespie, Shawn, Giste, Erika, Glass, Ian A., Gnirke, Andreas, Gormley, Matthew, Gu, Hongcang, Gu, Junchen, Hafler, David A., Hangauer, Matthew J., Hariharan, Manoj, Hatan, Meital, Haugen, Eric, He, Yupeng, Heimfeld, Shelly, Herlofsen, Sarah, Hou, Zhonggang, Humbert, Richard, Issner, Robbyn, Jackson, Andrew R., Jia, Haiyang, Jiang, Peng, Johnson, Audra K., Kadlecek, Theresa, Kamoh, Baljit, Kapidzic, Mirhan, Kent, Jim, Kim, Audrey, Kleinewietfeld, Markus, Klugman, Sarit, Krishnan, Jayanth, Kuan, Samantha, Kutyavin, Tanya, Lee, Ah-Young, Lee, Kristen, Li, Jian, Li, Nan, Li, Yan, Ligon, Keith L., Lin, Shin, Lin, Yiing, Liu, Jie, Liu, Yuxuan, Luckey, John C., Ma, Yussanne P., Maire, Cecile, Marson, Alexander, Mattick, John S., Mayo, Michael, McMaster, Michael, Metsky, Hayden, Mikkelsen, Tarjei, Miller, Diane, Miri, Mohammad, Mukame, Eran, Nagarajan, Raman P., Neri, Fidencio, Nery, Joseph, Nguyen, Tung, OʼGeen, Henriette, Paithankar, Sameer, Papayannopoulou, Thalia, Pelizzola, Mattia, Plettner, Patrick, Propson, Nicholas E., Raghuraman, Sriram, Raney, Brian J., Raubitschek, Anthony, Reynolds, Alex P., Richards, Hunter, Riehle, Kevin, Rinaudo, Paolo, Robinson, Joshua F., Rockweiler, Nicole B., Rosen, Evan, Rynes, Eric, Schein, Jacqueline, Sears, Renee, Sejnowski, Terrence, Shafer, Anthony, Shen, Li, Shoemaker, Robert, Sigaroudinia, Mahvash, Slukvin, Igor, Stehling-Sun, Sandra, Stewart, Ron, Subramanian, Sai Lakshmi, Suknuntha, Kran, Swanson, Scott, Tian, Shulan, Tilden, Hannah, Tsai, Linus, Urich, Mark, Vaughn, Ian, Vierstra, Jeff, Vong, Shinny, Wagner, Ulrich, Wang, Hao, Wang, Tao, Wang, Yunfei, Weiss, Arthur, Whitton, Holly, Wildberg, Andre, Witt, Heather, Won, Kyoung-Jae, Xie, Mingchao, Xing, Xiaoyun, Xu, Iris, Xuan, Zhenyu, Ye, Zhen, Yen, Chia-an, Yu, Pengzhi, Zhang, Xian, Zhang, Xiaolan, Zhao, Jianxin, Zhou, Yan, Zhu, Jiang, Zhu, Yun, Ziegler, Steven, Beaudet, Arthur E., Farnham, Peggy J., Haussler, David, Jones, Steven J. M., Marra, Marco A., Thomson, James A., Tsai, Li-Huei, Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Ecker, Joseph R., Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, and Kellis, Manolis

Published
2015
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19. Charting a dynamic DNA methylation landscape of the human genome

Author

Ziller, Michael J., Gu, Hongcang, Muller, Fabian, Donaghey, Julie, Tsai, Linus T.-Y., Kohlbacher, Oliver, De Jager, Philip L., Rosen, Evan D., Bennett, David A., Bernstein, Bradley E., Gnirke, Andreas, and Meissner, Alexander

Subjects
Nucleotide sequencing -- Testing, Methylation -- Observations, DNA sequencing -- Testing, Chromosome mapping -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

DNA methylation is a defining feature of mammalian cellular identity and is essential for normal development (1,2). Most cell types, except germ cells and pre-implantation embryos (3-5), display relatively stable DNA methylation patterns, with 70-80% of all CpGs being methylated (6). Despite recent advances, we still have a limited understanding of when, where and how many CpGs participate in genomic regulation. Here we report the in-depth analysis of 42 whole-genome bisulphite sequencing data sets across 30 diverse human cell and tissue types. We observe dynamic regulation for only 21.8% of autosomal CpGs within a normal developmental context, most of which are distal to transcription start sites. These dynamic CpGs co-localize with gene regulatory elements, particularly enhancers and transcription-factor-binding sites, which allow identification of key lineage-specific regulators. In addition, differentially methylated regions (DMRs) often contain single nucleotide polymorphisms associated with cell-type-related diseases as determined by genome-wide association studies. The results also highlight the general inefficiency of whole-genome bisulphite sequencing, as 70-80% of the sequencing reads across these data sets provided little or no relevant information about CpG methylation. To demonstrate further the utility of our DMR set, we use it to classify unknown samples and identify representative signature regions that recapitulate major DNA methylation dynamics. In summary, although in theory every CpG can change its methylation state, our results suggest that only a fraction does so as part of coordinated regulatory programs. Therefore, our selected DMRs can serve as a starting point to guide new, more effective reduced representation approaches to capture the most informative fraction of CpGs, as well as further pinpoint putative regulatory elements., Changes in DNA methylation patterns and the resulting DMRs have been the focus of numerous studies in the context of normal development (7) and disease (8). These studies have characterized [...]

Published
2013
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21. Genome-wide tracking of dCas9-methyltransferase footprints

Author

Galonska, Christina, primary, Charlton, Jocelyn, additional, Mattei, Alexandra L., additional, Donaghey, Julie, additional, Clement, Kendell, additional, Gu, Hongcang, additional, Mohammad, Arman W., additional, Stamenova, Elena K., additional, Cacchiarelli, Davide, additional, Klages, Sven, additional, Timmermann, Bernd, additional, Cantz, Tobias, additional, Schöler, Hans R., additional, Gnirke, Andreas, additional, Ziller, Michael J., additional, and Meissner, Alexander, additional

Published
2018
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22. Information recovery from low coverage whole-genome bisulfite sequencing

Author

Libertini, Emanuele, Heath, Simon C, Hamoudi, Rifat A, Gut, Marta, Ziller, Michael J, Czyz, Agata, Ruotti, Victor, Stunnenberg, Hendrik G, Frontini, Mattia, Ouwehand, Willem H, Meissner, Alexander, Gut, Ivo G, Beck, Stephan, Heath, Simon C [0000-0002-9550-0897], Czyz, Agata [0000-0002-2642-8756], and Apollo - University of Cambridge Repository

Subjects
Genotype, Whole Genome Sequencing, Genome, Human, Science, food and beverages, Computational Biology, Reproducibility of Results, DNA Methylation, Haplotypes, Humans, Sulfites, CpG Islands, Algorithms
Abstract

The cost of whole-genome bisulfite sequencing (WGBS) remains a bottleneck for many studies and it is therefore imperative to extract as much information as possible from a given dataset. This is particularly important because even at the recommend 30X coverage for reference methylomes, up to 50% of high-resolution features such as differentially methylated positions (DMPs) cannot be called with current methods as determined by saturation analysis. To address this limitation, we have developed a tool that dynamically segments WGBS methylomes into blocks of comethylation (COMETs) from which lost information can be recovered in the form of differentially methylated COMETs (DMCs). Using this tool, we demonstrate recovery of ∼30% of the lost DMP information content as DMCs even at very low (5X) coverage. This constitutes twice the amount that can be recovered using an existing method based on differentially methylated regions (DMRs). In addition, we explored the relationship between COMETs and haplotypes in lymphoblastoid cell lines of African and European origin. Using best fit analysis, we show COMETs to be correlated in a population-specific manner, suggesting that this type of dynamic segmentation may be useful for integrated (epi)genome-wide association studies in the future.

Published
2016

24. Epigenetic Memory Underlies Cell-Autonomous Heterogeneous Behavior of Hematopoietic Stem Cells

Author

Yu, Vionnie W.C., primary, Yusuf, Rushdia Z., additional, Oki, Toshihiko, additional, Wu, Juwell, additional, Saez, Borja, additional, Wang, Xin, additional, Cook, Colleen, additional, Baryawno, Ninib, additional, Ziller, Michael J., additional, Lee, Eunjung, additional, Gu, Hongcang, additional, Meissner, Alexander, additional, Lin, Charles P., additional, Kharchenko, Peter V., additional, and Scadden, David T., additional

Published
2017
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25. Integrative Analyses of Human Reprogramming Reveal Dynamic Nature of Induced Pluripotency

Author

Massachusetts Institute of Technology. Department of Biology, Lander, Eric Steven, Cacchiarelli, Davide, Trapnell, Cole, Ziller, Michael J., Soumillon, Magali, Cesana, Marcella, Karnik, Rahul, Donaghey, Julie, Smith, Zachary D., Ratanasirintrawoot, Sutheera, Zhang, Xiaolan, Ho Sui, Shannan J., Wu, Zhaoting, Akopian, Veronika, Gifford, Casey A., Doench, John, Rinn, John L., Daley, George Q., Meissner, Alexander, Mikkelsen, Tarjei S., Massachusetts Institute of Technology. Department of Biology, Lander, Eric Steven, Cacchiarelli, Davide, Trapnell, Cole, Ziller, Michael J., Soumillon, Magali, Cesana, Marcella, Karnik, Rahul, Donaghey, Julie, Smith, Zachary D., Ratanasirintrawoot, Sutheera, Zhang, Xiaolan, Ho Sui, Shannan J., Wu, Zhaoting, Akopian, Veronika, Gifford, Casey A., Doench, John, Rinn, John L., Daley, George Q., Meissner, Alexander, and Mikkelsen, Tarjei S.

Abstract

Induced pluripotency is a promising avenue for disease modeling and therapy, but the molecular principles underlying this process, particularly in human cells, remain poorly understood due to donor-to-donor variability and intercellular heterogeneity. Here, we constructed and characterized a clonal, inducible human reprogramming system that provides a reliable source of cells at any stage of the process. This system enabled integrative transcriptional and epigenomic analysis across the human reprogramming timeline at high resolution. We observed distinct waves of gene network activation, including the ordered re-activation of broad developmental regulators followed by early embryonic patterning genes and culminating in the emergence of a signature reminiscent of pre-implantation stages. Moreover, complementary functional analyses allowed us to identify and validate novel regulators of the reprogramming process. Altogether, this study sheds light on the molecular underpinnings of induced pluripotency in human cells and provides a robust cell platform for further studies.

Published
2017

26. Locally Disordered Methylation Forms the Basis of Intratumor Methylome Variation in Chronic Lymphocytic Leukemia

Author

Lander, Eric Steven, Landau, Dan A., Clement, Kendell, Ziller, Michael J., Boyle, Patrick, Fan, Jean, Gu, Hongcang, Stevenson, Kristen, Sougnez, Carrie, Wang, Lili, Li, Shuqiang, Kotliar, Dylan, Zhang, Wandi, Ghandi, Mahmoud, Garraway, Levi, Fernandes, Stacey M., Livak, Kenneth J., Gabriel, Stacey, Gnirke, Andreas, Brown, Jennifer R., Neuberg, Donna, Kharchenko, Peter V., Hacohen, Nir, Getz, Gad, Meissner, Alexander, Wu, Catherine J., Lander, Eric Steven, Landau, Dan A., Clement, Kendell, Ziller, Michael J., Boyle, Patrick, Fan, Jean, Gu, Hongcang, Stevenson, Kristen, Sougnez, Carrie, Wang, Lili, Li, Shuqiang, Kotliar, Dylan, Zhang, Wandi, Ghandi, Mahmoud, Garraway, Levi, Fernandes, Stacey M., Livak, Kenneth J., Gabriel, Stacey, Gnirke, Andreas, Brown, Jennifer R., Neuberg, Donna, Kharchenko, Peter V., Hacohen, Nir, Getz, Gad, Meissner, Alexander, and Wu, Catherine J.

Abstract

Intratumoral heterogeneity plays a critical role in tumor evolution. To define the contribution of DNA methylation to heterogeneity within tumors, we performed genome-scale bisulfite sequencing of 104 primary chronic lymphocytic leukemias (CLLs). Compared with 26 normal B cell samples, CLLs consistently displayed higher intrasample variability of DNA methylation patterns across the genome, which appears to arise from stochastically disordered methylation in malignant cells. Transcriptome analysis of bulk and single CLL cells revealed that methylation disorder was linked to low-level expression. Disordered methylation was further associated with adverse clinical outcome. We therefore propose that disordered methylation plays a similar role to that of genetic instability, enhancing the ability of cancer cells to search for superior evolutionary trajectories., National Human Genome Research Institute (U.S.) (Grant U54HG003067)

Published
2017

28. Information recovery from low coverage whole-genome bisulfite sequencing

Author

Libertini, Emanuele, primary, Heath, Simon C., additional, Hamoudi, Rifat A., additional, Gut, Marta, additional, Ziller, Michael J., additional, Czyz, Agata, additional, Ruotti, Victor, additional, Stunnenberg, Hendrik G., additional, Frontini, Mattia, additional, Ouwehand, Willem H., additional, Meissner, Alexander, additional, Gut, Ivo G., additional, and Beck, Stephan, additional

Published
2016
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29. Saturation analysis for whole-genome bisulfite sequencing data

Author

Libertini, Emanuele, primary, Heath, Simon C, additional, Hamoudi, Rifat A, additional, Gut, Marta, additional, Ziller, Michael J, additional, Herrero, Javier, additional, Czyz, Agata, additional, Ruotti, Victor, additional, Stunnenberg, Hendrik G, additional, Frontini, Mattia, additional, Ouwehand, Willem H, additional, Meissner, Alexander, additional, Gut, Ivo G, additional, and Beck, Stephan, additional

Published
2016
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30. Integrative analysis of 111 reference human epigenomes

Author

Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, Kellis, Manolis, Roadmap Epigenomics Consortium, Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Heravi-Moussavi, Alireza, Kheradpour, Pouya, Zhang, Zhizhuo, Wang, Jianrong, Ziller, Michael J., Amin, Viren, Whitaker, John W., Schultz, Matthew D., Ward, Lucas D., Sarkar, Abhishek, Quon, Gerald, Sandstrom, Richard S., Eaton, Matthew L., Wu, Yi-Chieh, Pfenning, Andreas R., Wang, Xinchen, Claussnitzer, Melina, Liu, Yaping, Coarfa, Cristian, Harris, R. Alan, Shoresh, Noam, Epstein, Charles B., Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R. David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J., Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K., Hansen, R. Scott, Kaul, Rajinder, Sabo, Peter J., Bansal, Mukul S., Carles, Annaick, Dixon, Jesse R., Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Elliott, GiNell, Mercer, Tim R., Neph, Shane J., Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C., Siebenthall, Kyle T., Sinnott-Armstrong, Nicholas A., Stevens, Michael, Thurman, Robert E., Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E., Boyer, Laurie A., De Jager, Philip L., Farnham, Peggy J., Fisher, Susan J., Haussler, David, Jones, Steven J.M., Li, Wei, Marra, Marco A., McManus, Michael T., Sunyaev, Shamil, Thomson, James A., Tlsty, Thea D., Tsai, Li-Huei, Wang, Wei, Waterland, Robert A., Zhang, Michael Q., Chadwick, Lisa H., Bernstein, Bradley E., Costello, Joseph F., Ecker, Joseph R., Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A., Wang, Ting, and Kellis, Manolis

Abstract

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease-and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease. © 2015 Macmillan Publishers Limited.

Published
2015

31. Analysing human neural stem cell ontogeny by consecutive isolation of Notch active neural progenitors

Author

Edri, Reuven, primary, Yaffe, Yakey, additional, Ziller, Michael J., additional, Mutukula, Naresh, additional, Volkman, Rotem, additional, David, Eyal, additional, Jacob-Hirsch, Jasmine, additional, Malcov, Hagar, additional, Levy, Carmit, additional, Rechavi, Gideon, additional, Gat-Viks, Irit, additional, Meissner, Alexander, additional, and Elkabetz, Yechiel, additional

Published
2015
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32. Transcriptional and Epigenetic Dynamics during Specification of Human Embryonic Stem Cells

Author

Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Gifford, Casey A., Ziller, Michael J., Gu, Hongcang, Trapnell, Cole, Donaghey, Julie, Tsankov, Alexander, Shalek, Alex K., Kelley, David R., Shishkin, Alexander A., Issner, Robbyn, Zhang, Xiaolan, Coyne, Michael J., Fostel, Jennifer L., Holmes, Laurie, Meldrim, James C., Guttman, Mitchell, Epstein, Charles B., Park, Hongkun, Kohlbacher, Oliver, Rinn, John L., Gnirke, Andreas, Bernstein, Bradley E., Meissner, Alexander, Lander, Eric Steven, Massachusetts Institute of Technology. Department of Biology, Lander, Eric S., Gifford, Casey A., Ziller, Michael J., Gu, Hongcang, Trapnell, Cole, Donaghey, Julie, Tsankov, Alexander, Shalek, Alex K., Kelley, David R., Shishkin, Alexander A., Issner, Robbyn, Zhang, Xiaolan, Coyne, Michael J., Fostel, Jennifer L., Holmes, Laurie, Meldrim, James C., Guttman, Mitchell, Epstein, Charles B., Park, Hongkun, Kohlbacher, Oliver, Rinn, John L., Gnirke, Andreas, Bernstein, Bradley E., Meissner, Alexander, and Lander, Eric Steven

Abstract

Differentiation of human embryonic stem cells (hESCs) provides a unique opportunity to study the regulatory mechanisms that facilitate cellular transitions in a human context. To that end, we performed comprehensive transcriptional and epigenetic profiling of populations derived through directed differentiation of hESCs representing each of the three embryonic germ layers. Integration of whole-genome bisulfite sequencing, chromatin immunoprecipitation sequencing, and RNA sequencing reveals unique events associated with specification toward each lineage. Lineage-specific dynamic alterations in DNA methylation and H3K4me1 are evident at putative distal regulatory elements that are frequently bound by pluripotency factors in the undifferentiated hESCs. In addition, we identified germ-layer-specific H3K27me3 enrichment at sites exhibiting high DNA methylation in the undifferentiated state. A better understanding of these initial specification events will facilitate identification of deficiencies in current approaches, leading to more faithful differentiation strategies as well as providing insights into the rewiring of human regulatory programs during cellular transitions., Pew Charitable Trusts, New York Stem Cell Foundation (Robertson Neuroscience Investigator Award), National Institutes of Health (U.S.) (NIH grant U01ES017155), National Institutes of Health (U.S.) (NIH grant P01GM099117)

Published
2014

33. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Ziller, Michael J., primary, Edri, Reuven, additional, Yaffe, Yakey, additional, Donaghey, Julie, additional, Pop, Ramona, additional, Mallard, William, additional, Issner, Robbyn, additional, Gifford, Casey A., additional, Goren, Alon, additional, Xing, Jeffrey, additional, Gu, Hongcang, additional, Cacchiarelli, Davide, additional, Tsankov, Alexander M., additional, Epstein, Charles, additional, Rinn, John L., additional, Mikkelsen, Tarjei S., additional, Kohlbacher, Oliver, additional, Gnirke, Andreas, additional, Bernstein, Bradley E., additional, Elkabetz, Yechiel, additional, and Meissner, Alexander, additional

Published
2014
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34. Epigenomics and chromatin dynamics

Author

Akopian, Veronika, primary, Chan, Michelle M, additional, Clement, Kendell, additional, Galonska, Christina, additional, Gifford, Casey A, additional, Lehtola, Elizabeth, additional, Liao, Jing, additional, Samavarchi-Tehrani, Payman, additional, Sindhu, Camille, additional, Smith, Zachary D, additional, Tsankov, Alexander M, additional, Webster, Jamie, additional, Zhang, Yingying, additional, Ziller, Michael J, additional, and Meissner, Alexander, additional

Published
2012
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35. Genomic Distribution and Inter-Sample Variation of Non-CpG Methylation across Human Cell Types

Author

Ziller, Michael J., primary, Müller, Fabian, additional, Liao, Jing, additional, Zhang, Yingying, additional, Gu, Hongcang, additional, Bock, Christoph, additional, Boyle, Patrick, additional, Epstein, Charles B., additional, Bernstein, Bradley E., additional, Lengauer, Thomas, additional, Gnirke, Andreas, additional, and Meissner, Alexander, additional

Published
2011
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37. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells

Author

Liao, Jing, Karnik, Rahul, Gu, Hongcang, Ziller, Michael J., Clement, Kendell, Tsankov, Alexander M., Akopian, Veronika, Gifford, Casey A., Donaghey, Julie, Galonska, Christina, Pop, Ramona, Reyon, Deepak, Tsai, Shengdar Q., Mallard, William, Joung, J. Keith, Rinn, John L., Gnirke, Andreas, and Meissner, Alexander

Abstract

DNA methylation is a key epigenetic modification involved in regulating gene expression and maintaining genomic integrity. Here we inactivated all three catalytically active DNA methyltransferases in human embryonic stem cells (ESCs) using CRISPR/Cas9 genome editing to further investigate their roles and genomic targets. Disruption of DNMT3A or DNMT3B individually, as well as of both enzymes in tandem, creates viable, pluripotent cell lines with distinct effects on their DNA methylation landscape as assessed by whole-genome bisulfite sequencing. Surprisingly, in contrast to mouse, deletion of DNMT1 resulted in rapid cell death in human ESCs. To overcome the immediate lethality, we generated a doxycycline (DOX) responsive tTA-DNMT1* rescue line and readily obtained homozygous DNMT1 mutant lines. However, DOX-mediated repression of the exogenous DNMT1* initiates rapid, global loss of DNA methylation, followed by extensive cell death. Our data provide a comprehensive characterization of DNMT mutant ESCs, including single base genome-wide maps of their targets.

Published
2015
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38. Integrative analysis of 111 reference human epigenomes

Author

Kundaje, Anshul, Meuleman, Wouter, Ernst, Jason, Bilenky, Misha, Yen, Angela, Kheradpour, Pouya, Zhang, Zhizhuo, Heravi-Moussavi, Alireza, Liu, Yaping, Amin, Viren, Ziller, Michael J, Whitaker, John W, Schultz, Matthew D, Sandstrom, Richard S, Eaton, Matthew L, Wu, Yi-Chieh, Wang, Jianrong, Ward, Lucas D, Sarkar, Abhishek, Quon, Gerald, Pfenning, Andreas, Wang, Xinchen, Claussnitzer, Melina, Coarfa, Cristian, Harris, R Alan, Shoresh, Noam, Epstein, Charles B, Gjoneska, Elizabeta, Leung, Danny, Xie, Wei, Hawkins, R David, Lister, Ryan, Hong, Chibo, Gascard, Philippe, Mungall, Andrew J, Moore, Richard, Chuah, Eric, Tam, Angela, Canfield, Theresa K, Hansen, R Scott, Kaul, Rajinder, Sabo, Peter J, Bansal, Mukul S, Carles, Annaick, Dixon, Jesse R, Farh, Kai-How, Feizi, Soheil, Karlic, Rosa, Kim, Ah-Ram, Kulkarni, Ashwinikumar, Li, Daofeng, Lowdon, Rebecca, Mercer, Tim R, Neph, Shane J, Onuchic, Vitor, Polak, Paz, Rajagopal, Nisha, Ray, Pradipta, Sallari, Richard C, Siebenthall, Kyle T, Sinnott-Armstrong, Nicholas, Stevens, Michael, Thurman, Robert E, Wu, Jie, Zhang, Bo, Zhou, Xin, Beaudet, Arthur E, Boyer, Laurie A, De Jager, Philip, Farnham, Peggy J, Fisher, Susan J, Haussler, David, Jones, Steven, Li, Wei, Marra, Marco, McManus, Michael T, Sunyaev, Shamil, Thomson, James A, Tlsty, Thea D, Tsai, Li-Huei, Wang, Wei, Waterland, Robert A, Zhang, Michael, Chadwick, Lisa H, Bernstein, Bradley E, Costello, Joseph F, Ecker, Joseph R, Hirst, Martin, Meissner, Alexander, Milosavljevic, Aleksandar, Ren, Bing, Stamatoyannopoulos, John A, Wang, Ting, and Kellis, Manolis

Abstract

The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but a similar reference has lacked for epigenomic studies. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection to-date of human epigenomes for primary cells and tissues. Here, we describe the integrative analysis of 111 reference human epigenomes generated as part of the program, profiled for histone modification patterns, DNA accessibility, DNA methylation, and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically-relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation, and human disease.

Published
2015
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39. Coverage recommendations for methylation analysis by whole genome bisulfite sequencing

Author

Ziller, Michael J., Hansen, Kasper D., Meissner, Alexander, and Aryee, Martin J.

Abstract

Whole genome bisulfite sequencing (WGBS) allows genome-wide DNA methylation profiling but the associated high sequencing costs continue to limit its widespread application. We utilized several high coverage reference data sets to experimentally determine minimal sequencing requirements. Here, we present data derived recommendations for minimum sequencing depth for WGBS libraries, highlight what is gained with increasing coverage and discuss the trade off between sequencing depth and number of assayed replicates.

Published
2014
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40. Dissecting the Functional Consequences of De NovoDNA Methylation Dynamics in Human Motor Neuron Differentiation and Physiology

Author

Ziller, Michael J., Ortega, Juan A., Quinlan, Katharina A., Santos, David P., Gu, Hongcang, Martin, Eric J., Galonska, Christina, Pop, Ramona, Maidl, Susanne, Di Pardo, Alba, Huang, Mei, Meltzer, Herbert Y., Gnirke, Andreas, Heckman, C.J., Meissner, Alexander, and Kiskinis, Evangelos

Abstract

The somatic DNA methylation (DNAme) landscape is established early in development but remains highly dynamic within focal regions that overlap with gene regulatory elements. The significance of these dynamic changes, particularly in the central nervous system, remains unresolved. Here, we utilize a powerful human embryonic stem cell differentiation model for the generation of motor neurons (MNs) in combination with genetic mutations in the de novoDNAme machinery. We quantitatively dissect the role of DNAme in directing somatic cell fate with high-resolution genome-wide bisulfite-, bulk-, and single-cell-RNA sequencing. We find defects in neuralization and MN differentiation in DNMT3A knockouts (KO) that can be rescued by the targeting of DNAme to key developmental loci using catalytically inactive dCas9. We also find decreased dendritic arborization and altered electrophysiological properties in DNMT3A KO MNs. Our work provides a list of DNMT3A-regulated targets and a mechanistic link between de novoDNAme, cellular differentiation, and human MN function.

Published
2018
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41. Genome-wide tracking of dCas9-methyltransferase footprints

Author

Kendell Clement, Hans R. Schöler, Alexandra L. Mattei, Elena K. Stamenova, Julie Donaghey, Andreas Gnirke, Hongcang Gu, Alexander Meissner, Bernd Timmermann, Christina Galonska, Arman W. Mohammad, Jocelyn Charlton, Tobias Cantz, Sven Klages, Michael J. Ziller, Davide Cacchiarelli, Galonska, Christina, Charlton, Jocelyn, Mattei, Alexandra L, Donaghey, Julie, Clement, Kendell, Gu, Hongcang, Mohammad, Arman W, Stamenova, Elena K, Cacchiarelli, Davide, Klages, Sven, Timmermann, Bernd, Cantz, Tobia, Schöler, Hans R, Gnirke, Andrea, Ziller, Michael J, and Meissner, Alexander

Subjects
0301 basic medicine, Methyltransferase, Science, General Physics and Astronomy, Computational biology, Biology, Genome, General Biochemistry, Genetics and Molecular Biology, Article, Cell Line, 03 medical and health sciences, Mice, Genome editing, Bacterial Proteins, CRISPR-Associated Protein 9, Animals, Humans, Epigenetics, DNA (Cytosine-5-)-Methyltransferases, lcsh:Science, Embryonic Stem Cells, Gene Editing, Multidisciplinary, Cas9, General Chemistry, Methylation, Epigenome, Endonucleases, 030104 developmental biology, DNA methylation, lcsh:Q
Abstract

In normal mammalian development cytosine methylation is essential and is directed to specific regions of the genome. Despite notable advances through mapping its genome-wide distribution, studying the direct contribution of DNA methylation to gene and genome regulation has been limited by the lack of tools for its precise manipulation. Thus, combining the targeting capability of the CRISPR–Cas9 system with an epigenetic modifier has attracted interest in the scientific community. In contrast to profiling the genome-wide cleavage of a nuclease competent Cas9, tracing the global activity of a dead Cas9 (dCas9) methyltransferase fusion protein is challenging within a highly methylated genome. Here, we report the generation and use of an engineered, methylation depleted but maintenance competent mouse ES cell line and find surprisingly ubiquitous nuclear activity of dCas9-methyltransferases. Subsequent experiments in human somatic cells refine these observations and point to an important difference between genetic and epigenetic editing tools that require unique experimental considerations., Catalytically inactive Cas9 fused to a methyltransferase has emerged as a promising epigenome modifying tool. Here the authors generate a methylation depleted but maintenance competent mouse ES cell line and find ubiquitous off-target activity.

Published
2018

42. Genetic determinants and epigenetic effects of pioneer-factor occupancy

Author

Julie Donaghey, Kendell Clement, Jennifer S. Chen, Andreas Gnirke, Casey A. Gifford, John L. Rinn, Michael J. Ziller, Ramona Pop, Rahul Karnik, Elena K. Stamenova, Jocelyn Charlton, David R. Kelley, Sudhir Thakurela, Hongcang Gu, Alexander Meissner, Zachary D. Smith, Davide Cacchiarelli, Donaghey, Julie, Thakurela, Sudhir, Charlton, Jocelyn, Chen, Jennifer S., Smith, Zachary D., Gu, Hongcang, Pop, Ramona, Clement, Kendell, Stamenova, Elena K., Karnik, Rahul, Kelley, David R., Gifford, Casey A., Cacchiarelli, Davide, Rinn, John L., Gnirke, Andrea, Ziller, Michael J., and Meissner, Alexander

Subjects
0301 basic medicine, Computational biology, Biology, Epigenesis, Genetic, 03 medical and health sciences, chemistry.chemical_compound, Genetics, Humans, Cell Lineage, Gene Regulatory Networks, Epigenetics, Gene, Transcription factor, Cells, Cultured, reproductive and urinary physiology, Regulation of gene expression, Binding Sites, Pioneer factor, DNA replication, Computational Biology, Epistasis, Genetic, DNA, Hep G2 Cells, respiratory system, GATA4 Transcription Factor, HEK293 Cells, 030104 developmental biology, Gene Expression Regulation, chemistry, A549 Cells, embryonic structures, DNA methylation, Hepatocyte Nuclear Factor 3-beta, Octamer Transcription Factor-3, Genes, Switch, Protein Binding, Transcription Factors
Abstract

Transcription factors (TFs) direct developmental transitions by binding to target DNA sequences, influencing gene expression and establishing complex gene-regultory networks. To systematically determine the molecular components that enable or constrain TF activity, we investigated the genomic occupancy of FOXA2, GATA4 and OCT4 in several cell types. Despite their classification as pioneer factors, all three TFs exhibit cell-type-specific binding, even when supraphysiologically and ectopically expressed. However, FOXA2 and GATA4 can be distinguished by low enrichment at loci that are highly occupied by these factors in alternative cell types. We find that expression of additional cofactors increases enrichment at a subset of these sites. Finally, FOXA2 occupancy and changes to DNA accessibility can occur in G1-arrested cells, but subsequent loss of DNA methylation requires DNA replication.

Published
2018
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43. Dissecting neural differentiation regulatory networks through epigenetic footprinting

Author

Hongcang Gu, Alexander Meissner, Davide Cacchiarelli, Yakey Yaffe, Alexander M. Tsankov, Reuven Edri, Jeffrey C. Xing, Charles B. Epstein, Michael J. Ziller, John L. Rinn, Julie Donaghey, Casey A. Gifford, Tarjei S. Mikkelsen, Robbyn Issner, Oliver Kohlbacher, Bradley E. Bernstein, Ramona Pop, Alon Goren, Yechiel Elkabetz, Andreas Gnirke, William Mallard, Ziller, Michael J., Edri, Reuven, Yaffe, Yakey, Donaghey, Julie, Pop, Ramona, Mallard, William, Issner, Robbyn, Gifford, Casey A., Goren, Alon, Xing, Jeffrey, Gu, Hongcang, Cacchiarelli, Davide, Tsankov, Alexander M., Epstein, Charle, Rinn, John L., Mikkelsen, Tarjei S., Kohlbacher, Oliver, Gnirke, Andrea, Bernstein, Bradley E., Elkabetz, Yechiel, and Meissner, Alexander

Subjects
Epigenomics, Epigenomic, Transcription, Genetic, Transcription Factor, Cellular differentiation, Reproducibility of Result, Biology, Article, Epigenesis, Genetic, Neural Stem Cells, Embryonic Stem Cell, Humans, Cell Lineage, Neural Stem Cell, Progenitor cell, RNA, Small Interfering, Induced pluripotent stem cell, Embryonic Stem Cells, Genetics, Binding Sites, Multidisciplinary, Binding Site, Reproducibility of Results, Cell Differentiation, Embryonic stem cell, Neural stem cell, Stem cell, Neural development, Neuroscience, Transcription Factors, Human embryonic stem cell line, Human
Abstract

Human pluripotent stem cell derived models that accurately recapitulate neural development in vitro and allow for the generation of specific neuronal subtypes are of major interest to the stem cell and biomedical community. Notch signaling, particularly through the Notch effector HES5, is a major pathway critical for the onset and maintenance of neural progenitor cells (NPCs) in the embryonic and adult nervous system1-3. This can be exploited to isolate distinct populations of human embryonic stem (ES) cell derived NPCs4. Here, we report the transcriptional and epigenomic analysis of six consecutive stages derived from a HES5-GFP reporter ES cell line5 differentiated along the neural trajectory aimed at modeling key cell fate decisions including specification, expansion and patterning during the ontogeny of cortical neural stem and progenitor cells. In order to dissect the regulatory mechanisms that orchestrate the stage-specific differentiation process, we developed a computational framework to infer key regulators of each cell state transition based on the progressive remodeling of the epigenetic landscape and then validated these through a pooled shRNA screen. We were also able to refine our previous observations on epigenetic priming at transcription factor binding sites and show here that they are mediated by combinations of core and stage- specific factors. Taken together, we demonstrate the utility of our system and outline a general framework, not limited to the context of the neural lineage, to dissect regulatory circuits of differentiation.

Published
2015

44. Polygenic risk for schizophrenia converges on alternative polyadenylation as molecular mechanism underlying synaptic impairment.

Author

Raabe FJ, Hausruckinger A, Gagliardi M, Ahmad R, Almeida V, Galinski S, Hoffmann A, Weigert L, Rummel CK, Murek V, Trastulla L, Jimenez-Barron L, Atella A, Maidl S, Menegaz D, Hauger B, Wagner EM, Gabellini N, Kauschat B, Riccardo S, Cesana M, Papiol S, Sportelli V, Rex-Haffner M, Stolte SJ, Wehr MC, Salcedo TO, Papazova I, Detera-Wadleigh S, McMahon FJ, Schmitt A, Falkai P, Hasan A, Cacchiarelli D, Dannlowski U, Nenadić I, Kircher T, Scheuss V, Eder M, Binder EB, Spengler D, Rossner MJ, and Ziller MJ

Abstract

Schizophrenia (SCZ) is a genetically heterogenous psychiatric disorder of highly polygenic nature. Correlative evidence from genetic studies indicate that the aggregated effects of distinct genetic risk factor combinations found in each patient converge onto common molecular mechanisms. To prove this on a functional level, we employed a reductionistic cellular model system for polygenic risk by differentiating induced pluripotent stem cells (iPSCs) from 104 individuals with high polygenic risk load and controls into cortical glutamatergic neurons (iNs). Multi-omics profiling identified widespread differences in alternative polyadenylation (APA) in the 3' untranslated region of many synaptic transcripts between iNs from SCZ patients and healthy donors. On the cellular level, 3'APA was associated with a reduction in synaptic density of iNs. Importantly, differential APA was largely conserved between postmortem human prefrontal cortex from SCZ patients and healthy donors, and strongly enriched for transcripts related to synapse biology. 3'APA was highly correlated with SCZ polygenic risk and affected genes were significantly enriched for SCZ associated common genetic variation. Integrative functional genomic analysis identified the RNA binding protein and SCZ GWAS risk gene PTBP2 as a critical trans-acting factor mediating 3'APA of synaptic genes in SCZ subjects. Functional characterization of PTBP2 in iNs confirmed its key role in 3'APA of synaptic transcripts and regulation of synapse density. Jointly, our findings show that the aggregated effects of polygenic risk converge on 3'APA as one common molecular mechanism that underlies synaptic impairments in SCZ.

Published
2024
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