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2. H1 histones control the epigenetic landscape by local chromatin compaction

Author

Willcockson, Michael A., Healton, Sean E., Weiss, Cary N., Bartholdy, Boris A., Botbol, Yair, Mishra, Laxmi N., Sidhwani, Dhruv S., Wilson, Tommy J., Pinto, Hugo B., Maron, Maxim I., Skalina, Karin A., Toro, Laura Norwood, Zhao, Jie, Lee, Chul-Hwan, Hou, Harry, Yusufova, Nevin, Meydan, Cem, Osunsade, Adewola, David, Yael, Cesarman, Ethel, Melnick, Ari M., Sidoli, Simone, Garcia, Benjamin A., Edelmann, Winfried, Macian, Fernando, and Skoultchi, Arthur I.

Published
2021
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3. Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

Author

Yusufova, Nevin, Kloetgen, Andreas, Teater, Matt, Osunsade, Adewola, Camarillo, Jeannie M., Chin, Christopher R., Doane, Ashley S., Venters, Bryan J., Portillo-Ledesma, Stephanie, Conway, Joseph, Phillip, Jude M., Elemento, Olivier, Scott, David W., Béguelin, Wendy, Licht, Jonathan D., Kelleher, Neil L., Staudt, Louis M., Skoultchi, Arthur I., Keogh, Michael-Christopher, Apostolou, Effie, Mason, Christopher E., Imielinski, Marcin, Schlick, Tamar, David, Yael, Tsirigos, Aristotelis, Allis, C. David, Soshnev, Alexey A., Cesarman, Ethel, and Melnick, Ari M.

Published
2021
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5. Single-molecule imaging of transcription dynamics in somatic stem cells

Author

Wheat, Justin C., Sella, Yehonatan, Willcockson, Michael, Skoultchi, Arthur I., Bergman, Aviv, Singer, Robert H., and Steidl, Ulrich

Subjects
Stem cells -- Physiological aspects, Somatic cells -- Physiological aspects -- Methods, Genetic transcription -- Observations -- Physiological aspects -- Methods, Imaging systems -- Methods -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Molecular noise is a natural phenomenon that is inherent to all biological systems.sup.1,2. How stochastic processes give rise to the robust outcomes that support tissue homeostasis remains unclear. Here we use single-molecule RNA fluorescent in situ hybridization (smFISH) on mouse stem cells derived from haematopoietic tissue to measure the transcription dynamics of three key genes that encode transcription factors: PU.1 (also known as Spi1), Gata1 and Gata2. We find that infrequent, stochastic bursts of transcription result in the co-expression of these antagonistic transcription factors in the majority of haematopoietic stem and progenitor cells. Moreover, by pairing smFISH with time-lapse microscopy and the analysis of pedigrees, we find that although individual stem-cell clones produce descendants that are in transcriptionally related states--akin to a transcriptional priming phenomenon--the underlying transition dynamics between states are best captured by stochastic and reversible models. As such, a stochastic process can produce cellular behaviours that may be incorrectly inferred to have arisen from deterministic dynamics. We propose a model whereby the intrinsic stochasticity of gene expression facilitates, rather than impedes, the concomitant maintenance of transcriptional plasticity and stem cell robustness. Single-molecule fluorescence in situ hybridization and live-cell imaging are used to study the contribution of transcriptional noise to stem cell heterogeneity, revealing that stochastic transcription dynamics are conducive to concomitant stem-cell maintenance and tissue homeostasis., Author(s): Justin C. Wheat [sup.1] [sup.2] , Yehonatan Sella [sup.3] , Michael Willcockson [sup.1] , Arthur I. Skoultchi [sup.1] , Aviv Bergman [sup.3] [sup.4] [sup.5] [sup.6] , Robert H. Singer [...]

Published
2020
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6. Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution

Author

Vierstra, Jeff, Rynes, Eric, Sandstrom, Richard, Zhang, Miaohua, Canfield, Theresa, Hansen, R Scott, Stehling-Sun, Sandra, Sabo, Peter J, Byron, Rachel, Humbert, Richard, Thurman, Robert E, Johnson, Audra K, Vong, Shinny, Lee, Kristen, Bates, Daniel, Neri, Fidencio, Diegel, Morgan, Giste, Erika, Haugen, Eric, Dunn, Douglas, Wilken, Matthew S, Josefowicz, Steven, Samstein, Robert, Chang, Kai-Hsin, Eichler, Evan E, De Bruijn, Marella, Reh, Thomas A, Skoultchi, Arthur, Rudensky, Alexander, Orkin, Stuart H, Papayannopoulou, Thalia, Treuting, Piper M, Selleri, Licia, Kaul, Rajinder, Groudine, Mark, Bender, MA, and Stamatoyannopoulos, John A

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Biological Sciences, Biotechnology, Human Genome, Genetics, Generic health relevance, Animals, Base Sequence, Conserved Sequence, DNA, Deoxyribonuclease I, Evolution, Molecular, Genome, Human, Humans, Mice, Regulatory Sequences, Nucleic Acid, Restriction Mapping, Transcription Factors, General Science & Technology
Abstract

To study the evolutionary dynamics of regulatory DNA, we mapped >1.3 million deoxyribonuclease I-hypersensitive sites (DHSs) in 45 mouse cell and tissue types, and systematically compared these with human DHS maps from orthologous compartments. We found that the mouse and human genomes have undergone extensive cis-regulatory rewiring that combines branch-specific evolutionary innovation and loss with widespread repurposing of conserved DHSs to alternative cell fates, and that this process is mediated by turnover of transcription factor (TF) recognition elements. Despite pervasive evolutionary remodeling of the location and content of individual cis-regulatory regions, within orthologous mouse and human cell types the global fraction of regulatory DNA bases encoding recognition sites for each TF has been strictly conserved. Our findings provide new insights into the evolutionary forces shaping mammalian regulatory DNA landscapes.

Published
2014

17. A comparative encyclopedia of DNA elements in the mouse genome

Author

Yue, Feng, Cheng, Yong, Breschi, Alessandra, Vierstra, Jeff, Wu, Weisheng, Ryba, Tyrone, Sandstrom, Richard, Ma, Zhihai, Davis, Carrie, Pope, Benjamin D., Shen, Yin, Pervouchine, Dmitri D., Djebali, Sarah, Thurman, Robert E., Kaul, Rajinder, Rynes, Eric, Kirilusha, Anthony, Marinov, Georgi K., Williams, Brian A., Trout, Diane, Amrhein, Henry, Fisher-Aylor, Katherine, Antoshechkin, Igor, DeSalvo, Gilberto, See, Lei-Hoon, Fastuca, Meagan, Drenkow, Jorg, Zaleski, Chris, Dobin, Alex, Prieto, Pablo, Lagarde, Julien, Bussotti, Giovanni, Tanzer, Andrea, Denas, Olgert, Li, Kanwei, Bender, M. A., Zhang, Miaohua, Byron, Rachel, Groudine, Mark T., McCleary, David, Pham, Long, Ye, Zhen, Kuan, Samantha, Edsall, Lee, Wu, Yi-Chieh, Rasmussen, Matthew D., Bansal, Mukul S., Kellis, Manolis, Keller, Cheryl A., Morrissey, Christapher S., Mishra, Tejaswini, Jain, Deepti, Dogan, Nergiz, Harris, Robert S., Cayting, Philip, Kawli, Trupti, Boyle, Alan P., Euskirchen, Ghia, Kundaje, Anshul, Lin, Shin, Lin, Yiing, Jansen, Camden, Malladi, Venkat S., Cline, Melissa S., Erickson, Drew T., Kirkup, Vanessa M., Learned, Katrina, Sloan, Cricket A., Rosenbloom, Kate R., Lacerda de Sousa, Beatriz, Beal, Kathryn, Pignatelli, Miguel, Flicek, Paul, Lian, Jin, Kahveci, Tamer, Lee, Dongwon, James Kent, W., Ramalho Santos, Miguel, Herrero, Javier, Notredame, Cedric, Johnson, Audra, Vong, Shinny, Lee, Kristen, Bates, Daniel, Neri, Fidencio, Diegel, Morgan, Canfield, Theresa, Sabo, Peter J., Wilken, Matthew S., Reh, Thomas A., Giste, Erika, Shafer, Anthony, Kutyavin, Tanya, Haugen, Eric, Dunn, Douglas, Reynolds, Alex P., Neph, Shane, Humbert, Richard, Scott Hansen, R., De Bruijn, Marella, Selleri, Licia, Rudensky, Alexander, Josefowicz, Steven, Samstein, Robert, Eichler, Evan E., Orkin, Stuart H., Levasseur, Dana, Papayannopoulou, Thalia, Chang, Kai-Hsin, Skoultchi, Arthur, Gosh, Srikanta, Disteche, Christine, Treuting, Piper, Wang, Yanli, Weiss, Mitchell J., Blobel, Gerd A., Cao, Xiaoyi, Zhong, Sheng, Wang, Ting, Good, Peter J., Lowdon, Rebecca F., Adams, Leslie B., Zhou, Xiao-Qiao, Pazin, Michael J., Feingold, Elise A., Wold, Barbara, Taylor, James, Mortazavi, Ali, Weissman, Sherman M., Stamatoyannopoulos, John A., Snyder, Michael P., Guigo, Roderic, Gingeras, Thomas R., Gilbert, David M., Hardison, Ross C., Beer, Michael A., and Ren, Bing

Subjects
Man -- Genetic aspects, Genetic research, Human beings -- Genetic aspects, Genomes -- Comparative analysis, Mice -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The laboratory mouse shares the majority of its protein-coding genes with humans, making it the premier model organism in biomedical research, yet the two mammals differ in significant ways. To gain greater insights into both shared and species-specific transcriptional and cellular regulatory programs in the mouse, the Mouse ENCODE Consortium has mapped transcription, DNase I hypersensitivity, transcription factor binding, chromatin modifications and replication domains throughout the mouse genome in diverse cell and tissue types. By comparing with the human genome, we not only confirm substantial conservation in the newly annotated potential functional sequences, but also find a large degree of divergence of sequences involved in transcriptional regulation, chromatin state and higher order chromatin organization. Our results illuminate the wide range of evolutionary forces acting on genes and their regulatory regions, and provide a general resource for research into mammalian biology and mechanisms of human diseases., Author(s): Feng Yue [1, 2]; Yong Cheng [3]; Alessandra Breschi [4]; Jeff Vierstra [5]; Weisheng Wu [6]; Tyrone Ryba [7]; Richard Sandstrom [5]; Zhihai Ma [3]; Carrie Davis [8]; Benjamin [...]

Published
2014
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32. MOUSE GENOMICS: Mouse regulatory DNA landscapes reveal global principles of cis-regulatory evolution

Author

Vierstra, Jeff, Rynes, Eric, Sandstrom, Richard, Zhang, Miaohua, Canfield, Theresa, Hansen, Scott R., Stehling-Sun, Sandra, Sabo, Peter J., Byron, Rachel, Humbert, Richard, Thurman, Robert E., Johnson, Audra K., Vong, Shinny, Lee, Kristen, Bates, Daniel, Neri, Fidencio, Diegel, Morgan, Giste, Erika, Haugen, Eric, Dunn, Douglas, Wilken, Matthew S., Josefowicz, Steven, Samstein, Robert, Chang, Kai-Hsin, Eichler, Evan E., De Bruijn, Marella, Reh, Thomas A., Skoultchi, Arthur, Rudensky, Alexander, Orkin, Stuart H., Papayannopoulou, Thalia, Treuting, Piper M., Selleri, Licia, Kaul, Rajinder, Groudine, Mark, Bender, M. A., and Stamatoyannopoulos, John A.

Published
2014
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38. Histone H1 depletion in mammals alters global chromatin structure but causes specific changes in gene regulation

Author

Yuhong Fan, Nikitina, Tatiana, Woodcock, Christopher L., Jie Zhao, Fleury, Tomara J., Bouhassira, Eric E., Bhattacharyya, Riddhi, and Skoultchi, Arthur I.

Subjects
Gene expression -- Research, Methylation -- Research, Chromatin -- Research, Genetic research, Biological sciences
Abstract

Linker histone H1 plays an important role in chromatin folding in vitro and in order to study the role of H1 in vivo, mouse embryonic stem cells null for three H1 genes were derived and were found to have 50% of the normal level of H1. Results indicate that linker histones can participate in epigenetic regulation of gene expression by contributing to the maintenance or establishment of specific DNA methylation patterns.

Published
2005

39. Histone H1 loss drives lymphoma by disrupting 3D chromatin architecture

Author

Yusufova, Nevin, primary, Kloetgen, Andreas, additional, Teater, Matt, additional, Osunsade, Adewola, additional, Camarillo, Jeannie M., additional, Chin, Christopher R., additional, Doane, Ashley S., additional, Venters, Bryan J., additional, Portillo-Ledesma, Stephanie, additional, Conway, Joseph, additional, Phillip, Jude M., additional, Elemento, Olivier, additional, Scott, David W., additional, Béguelin, Wendy, additional, Licht, Jonathan D., additional, Kelleher, Neil L., additional, Staudt, Louis M., additional, Skoultchi, Arthur I., additional, Keogh, Michael-Christopher, additional, Apostolou, Effie, additional, Mason, Christopher E., additional, Imielinski, Marcin, additional, Schlick, Tamar, additional, David, Yael, additional, Tsirigos, Aristotelis, additional, Allis, C. David, additional, Soshnev, Alexey A., additional, Cesarman, Ethel, additional, and Melnick, Ari M., additional

Published
2020
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40. H1 histones control the epigenetic landscape by local chromatin compaction

Author

Willcockson, Michael A., primary, Healton, Sean E., additional, Weiss, Cary N., additional, Bartholdy, Boris A., additional, Botbol, Yair, additional, Mishra, Laxmi N., additional, Sidhwani, Dhruv S., additional, Wilson, Tommy J., additional, Pinto, Hugo B., additional, Maron, Maxim I., additional, Skalina, Karin A., additional, Toro, Laura Norwood, additional, Zhao, Jie, additional, Lee, Chul-Hwan, additional, Hou, Harry, additional, Yusufova, Nevin, additional, Meydan, Cem, additional, Osunsade, Adewola, additional, David, Yael, additional, Cesarman, Ethel, additional, Melnick, Ari M., additional, Sidoli, Simone, additional, Garcia, Benjamin A., additional, Edelmann, Winfried, additional, Macian, Fernando, additional, and Skoultchi, Arthur I., additional

Published
2020
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41. Pax3 functions at a nodal point in melanocyte stem cell differentiation

Author

Lang, Deborah, Lu, Min Min, Huang, Li, Engleka, Kurt A., Zhang, Maozhen, Chu, Emily Y., Lipner, Shari, Skoultchi, Arthur, Millar, Sarah E., and Epstein, Jonathan A.

Subjects
Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Author(s): Deborah Lang [1, 4]; Min Min Lu [1]; Li Huang [1]; Kurt A. Engleka [1]; Maozhen Zhang [1]; Emily Y. Chu [2]; Shari Lipner [3]; Arthur Skoultchi [3]; Sarah [...]

Published
2005
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43. TBX1 is responsible for cardiovascular defects in velo-cardio-facial/DiGeorge syndrome

Author

Merscher, Sandra, Funke, Birgit, Epstein, Jonathan A., Heyer, Joerg, Puech, Anne, Lu, Min Min, Xavier, Ramnik J., Demay, Marie B., Russell, Robert G., Factor, Stephen, Tokooya, Kazuhito, Jore, Bruno St., Lopez, Melissa, Lia, Marie, Pandita, Raj K., Carrion, Danaise, Xu, Hui, Schorle, Hubert, Kobler, James B., Scambler, Peter, Wynshaw-Boris, Anthony, Skoultchi, Arthur I., Morrow, Bernice E., and Kucherlapati, Raju

Subjects
Cell research -- Analysis, Cardiovascular diseases -- Causes of, Immunological deficiency syndromes -- Causes of, Diseases -- Causes and theories of causation, Biological sciences
Abstract

Research has been conducted on the velo-cardio-facial/DiGeorge syndrome characterized by the phenotypic features such as cardiovascular defects. The cre-loxP strategy in generating the mice which are hemizygous for the deletion has been used to investigate the etiology of the cardiovascular disorder and the results are presented.

Published
2001

47. Histone 1 Mutations Drive Lymphomagenesis By Inducing Primitive Stem Cell Functions and Epigenetic Instructions through Profound 3D Re-Organization of the B-Cell Genome

Author

Yusufova, Nevin, primary, Teater, Matthew R, primary, Soshnev, Alexey, primary, Kloetgen, Andreas, primary, Osunsade, Adewola, primary, Conway, Joseph, primary, Doane, Ashley, primary, Skoultchi, Arthur, primary, Tsirigos, Aristotelis, primary, David, Yael, primary, Allis, C. David, primary, Cesarman, Ethel, primary, and Melnick, Ari, primary

Published
2019
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48. Direct interaction of hematopoietic transcription factors PU-1 and GATA-1: functional antagonism in erythroid cells

Author

Rekhtman, Natasha, Radparvar, Farshid, Evans, Todd, and Skoultchi, Arthur I.

Subjects
Erythropoiesis -- Genetic aspects, Mouse leukemia complex -- Genetic aspects, Cell differentiation -- Genetic aspects, Hematopoiesis -- Genetic aspects, Biological sciences
Abstract

Functional antagonism related to direct interaction of hematopoietic transcription factors GATA-1 and PU.1 exists in erythroid cells. Malignant transformation usually inhibits terminal cell differentiation but the mechanisms are not clear. PU.1 is a hematopoietic-specific Ets family transcription factor required for development of some lymphoid and myeloid lineages. It can act as an oncoprotein. Activation of expression in erythroid precursors by transgenesis or proviral insertion brings on erythroleukemias in mice. Stoichiometry of directly interacting, opposing transcription factors may be crucial as a determinant for governing processes of malignant transformation and normal differentiation. Ectopic expression of PU-1 in Xenopus embryos will block erythropoiesis in normal development.

Published
1999

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