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2. RoboCOP: Multivariate State Space Model Integrating Epigenomic Accessibility Data to Elucidate Genome-Wide Chromatin Occupancy

Author

Mitra, Sneha, Zhong, Jianling, MacAlpine, David M., Hartemink, Alexander J., Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Woeginger, Gerhard, Editorial Board Member, Yung, Moti, Editorial Board Member, and Schwartz, Russell, editor

Published
2020
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3. Comparative analysis of metazoan chromatin organization

Author

Ho, Joshua WK, Jung, Youngsook L, Liu, Tao, Alver, Burak H, Lee, Soohyun, Ikegami, Kohta, Sohn, Kyung-Ah, Minoda, Aki, Tolstorukov, Michael Y, Appert, Alex, Parker, Stephen CJ, Gu, Tingting, Kundaje, Anshul, Riddle, Nicole C, Bishop, Eric, Egelhofer, Thea A, Hu, Sheng'en Shawn, Alekseyenko, Artyom A, Rechtsteiner, Andreas, Asker, Dalal, Belsky, Jason A, Bowman, Sarah K, Chen, Q Brent, Chen, Ron A-J, Day, Daniel S, Dong, Yan, Dose, Andrea C, Duan, Xikun, Epstein, Charles B, Ercan, Sevinc, Feingold, Elise A, Ferrari, Francesco, Garrigues, Jacob M, Gehlenborg, Nils, Good, Peter J, Haseley, Psalm, He, Daniel, Herrmann, Moritz, Hoffman, Michael M, Jeffers, Tess E, Kharchenko, Peter V, Kolasinska-Zwierz, Paulina, Kotwaliwale, Chitra V, Kumar, Nischay, Langley, Sasha A, Larschan, Erica N, Latorre, Isabel, Libbrecht, Maxwell W, Lin, Xueqiu, Park, Richard, Pazin, Michael J, Pham, Hoang N, Plachetka, Annette, Qin, Bo, Schwartz, Yuri B, Shoresh, Noam, Stempor, Przemyslaw, Vielle, Anne, Wang, Chengyang, Whittle, Christina M, Xue, Huiling, Kingston, Robert E, Kim, Ju Han, Bernstein, Bradley E, Dernburg, Abby F, Pirrotta, Vincenzo, Kuroda, Mitzi I, Noble, William S, Tullius, Thomas D, Kellis, Manolis, MacAlpine, David M, Strome, Susan, Elgin, Sarah CR, Liu, Xiaole Shirley, Lieb, Jason D, Ahringer, Julie, Karpen, Gary H, and Park, Peter J

Subjects
Biochemistry and Cell Biology, Biological Sciences, Immunization, Human Genome, Genetics, 1.1 Normal biological development and functioning, Underpinning research, Generic health relevance, Animals, Caenorhabditis elegans, Cell Line, Centromere, Chromatin, Chromatin Assembly and Disassembly, DNA Replication, Drosophila melanogaster, Enhancer Elements, Genetic, Epigenesis, Genetic, Heterochromatin, Histones, Humans, Molecular Sequence Annotation, Nuclear Lamina, Nucleosomes, Promoter Regions, Genetic, Species Specificity, General Science & Technology
Abstract

Genome function is dynamically regulated in part by chromatin, which consists of the histones, non-histone proteins and RNA molecules that package DNA. Studies in Caenorhabditis elegans and Drosophila melanogaster have contributed substantially to our understanding of molecular mechanisms of genome function in humans, and have revealed conservation of chromatin components and mechanisms. Nevertheless, the three organisms have markedly different genome sizes, chromosome architecture and gene organization. On human and fly chromosomes, for example, pericentric heterochromatin flanks single centromeres, whereas worm chromosomes have dispersed heterochromatin-like regions enriched in the distal chromosomal 'arms', and centromeres distributed along their lengths. To systematically investigate chromatin organization and associated gene regulation across species, we generated and analysed a large collection of genome-wide chromatin data sets from cell lines and developmental stages in worm, fly and human. Here we present over 800 new data sets from our ENCODE and modENCODE consortia, bringing the total to over 1,400. Comparison of combinatorial patterns of histone modifications, nuclear lamina-associated domains, organization of large-scale topological domains, chromatin environment at promoters and enhancers, nucleosome positioning, and DNA replication patterns reveals many conserved features of chromatin organization among the three organisms. We also find notable differences in the composition and locations of repressive chromatin. These data sets and analyses provide a rich resource for comparative and species-specific investigations of chromatin composition, organization and function.

Published
2014

5. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster

Author

Kharchenko, Peter V, Alekseyenko, Artyom A, Schwartz, Yuri B, Minoda, Aki, Riddle, Nicole C, Ernst, Jason, Sabo, Peter J, Larschan, Erica, Gorchakov, Andrey A, Gu, Tingting, Linder-Basso, Daniela, Plachetka, Annette, Shanower, Gregory, Tolstorukov, Michael Y, Luquette, Lovelace J, Xi, Ruibin, Jung, Youngsook L, Park, Richard W, Bishop, Eric P, Canfield, Theresa K, Sandstrom, Richard, Thurman, Robert E, MacAlpine, David M, Stamatoyannopoulos, John A, Kellis, Manolis, Elgin, Sarah CR, Kuroda, Mitzi I, Pirrotta, Vincenzo, Karpen, Gary H, and Park, Peter J

Subjects
Biotechnology, Human Genome, Genetics, Prevention, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Animals, Cell Line, Chromatin, Chromatin Immunoprecipitation, Chromosomal Proteins, Non-Histone, Deoxyribonuclease I, Drosophila Proteins, Drosophila melanogaster, Exons, Gene Expression Regulation, Genes, Insect, Genome, Insect, Histones, Male, Molecular Sequence Annotation, Oligonucleotide Array Sequence Analysis, Polycomb Repressive Complex 1, RNA, Sequence Analysis, Transcription, Genetic, General Science & Technology
Abstract

Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which have an impact on cell differentiation, gene regulation and other key cellular processes. Here we present a genome-wide chromatin landscape for Drosophila melanogaster based on eighteen histone modifications, summarized by nine prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNase I hypersensitivity, GRO-Seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.

Published
2011

11. Rare codons capacitate Kras-driven de novo tumorigenesis

Author

Pershing, Nicole L.K., Lampson, Benjamin L., Belsky, Jason A., Kaltenbrun, Erin, MacAlpine, David M., and Counter, Christopher M.

Subjects
Genes -- Physiological aspects -- Research, Carcinogenesis -- Genetic aspects -- Research, Codon -- Comparative analysis -- Physiological aspects -- Research, Health care industry
Abstract

The KRAS gene is commonly mutated in human cancers, rendering the encoded small GTPase constitutively active and oncogenic. This gene has the unusual feature of being enriched for rare codons, which limit protein expression. Here, to determine the effect of the rare codon bias of the KRAS gene on de novo tumorigenesis, we introduced synonymous mutations that converted rare codons into common codons in exon 3 of the Kras gene in mice. Compared with control animals, mice with at least 1 copy of this [Kras.sup.ex3op] allele had fewer tumors following carcinogen exposure, and this allele was mutated less often, with weaker oncogenic mutations in these tumors. This reduction in tumorigenesis was attributable to higher expression of the [Kras.sup.ex3op] allele, which induced growth arrest when oncogenic and exhibited tumor-suppressive activity when not mutated. Together, our data indicate that the inherent rare codon bias of KRAS plays an integral role in tumorigenesis., Introduction The mammalian RAS family of small GTPases is composed of3 genes that encode the proteins HRAS, NRAS, KRAS4A, and KRAS4B, the latter 2 being derived from alternatively spliced transcripts. [...]

Published
2015
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15. Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE

Author

The modeENCODE Consortium, Roy, Sushmita, Ernst, Jason, Kharchenko, Peter V., Kheradpour, Pouya, Negre, Nicolas, Eaton, Matthew L., Landolin, Jane M., Bristow, Christopher A., Ma, Lijia, Lin, Michael F., Washietl, Stefan, Arshinoff, Bradley I., Ay, Ferhat, Meyer, Patrick E., Robine, Nicolas, Washington, Nicole L., Di Stefano, Luisa, Berezikov, Eugene, Brown, Christopher D., Candeias, Rogerio, Carlson, Joseph W., Carr, Adrian, Jungreis, Irwin, Marbach, Daniel, Sealfon, Rachel, Tolstorukov, Michael Y., Will, Sebastian, Alekseyenko, Artyom A., Artieri, Carlo, Booth, Benjamin W., Brooks, Angela N., Dai, Qi, Davis, Carrie A., Duff, Michael O., Feng, Xin, Gorchakov, Andrey A., Gu, Tingting, Henikoff, Jorja G., Kapranov, Philipp, Li, Renhua, MacAlpine, Heather K., Malone, John, Minoda, Aki, Nordman, Jared, Okamura, Katsutomo, Perry, Marc, Powell, Sara K., Riddle, Nicole C., Sakai, Akiko, Samsonova, Anastasia, Sandler, Jeremy E., Schwartz, Yuri B., Sher, Noa, Spokony, Rebecca, Sturgill, David, van Baren, Marijke, Wan, Kenneth H., Yang, Li, Yu, Charles, Feingold, Elise, Good, Peter, Guyer, Mark, Lowdon, Rebecca, Ahmad, Kami, Andrews, Justen, Berger, Bonnie, Brenner, Steven E., Brent, Michael R., Cherbas, Lucy, Elgin, Sarah C. R., Gingeras, Thomas R., Grossman, Robert, Hoskins, Roger A., Kaufman, Thomas C., Kent, William, Kuroda, Mitzi I., Orr-Weaver, Terry, Perrimon, Norbert, Pirrotta, Vincenzo, Posakony, James W., Ren, Bing, Russell, Steven, Cherbas, Peter, Graveley, Brenton R., Lewis, Suzanna, Micklem, Gos, Oliver, Brian, Park, Peter J., Celniker, Susan E., Henikoff, Steven, Karpen, Gary H., Lai, Eric C., MacAlpine, David M., Stein, Lincoln D., White, Kevin P., and Kellis, Manolis

Published
2010

22. Unlocking the secrets of the genome: despite the successes of genomics, little is known about how genetic information produces complex organisms. A look at the crucial functional elements of fly and worm genomes could change that

Author

Celniker, Susan E., Dillon, Laura A.L., Gerstein, Mark B., Gunsalus, Kristin C., Henikoff, Steven, Karpen, Gary H., Kellis, Manolis, Lai, Eric C., Lieb, Jason D., MacAlpine, David M., Micklem, Gos, Piano, Fabio, Snyder, Michael, Stein, Lincoln, White, Kevin P., and Waterston, Robert H.

Subjects
Diptera -- Genetic aspects -- Discovery and exploration -- Models, Human genome -- Discovery and exploration -- Models -- Genetic aspects, Worms -- Genetic aspects -- Models -- Discovery and exploration, Environmental issues, Science and technology, Zoology and wildlife conservation, Discovery and exploration, Models, Genetic aspects
Abstract

The primary objective of the Human Genome Project was to produce high-quality sequences not just for the human genome but also for those of the chief model organisms: Escherichia coli, [...]

Published
2009

30. A cis-regulatory map of the Drosophila genome

Author

Nègre, Nicolas, Brown, Christopher D., Ma, Lijia, Bristow, Christopher Aaron, Miller, Steven W., Wagner, Ulrich, Kheradpour, Pouya, Eaton, Matthew L., Loriaux, Paul, Sealfon, Rachel, Li, Zirong, Ishii, Haruhiko, Spokony, Rebecca F., Chen, Jia, Hwang, Lindsay, Cheng, Chao, Auburn, Richard P., Davis, Melissa B., Domanus, Marc, Shah, Parantu K., Morrison, Carolyn A., Zieba, Jennifer, Suchy, Sarah, Senderowicz, Lionel, Victorsen, Alec, Bild, Nicholas A., Grundstad, Jason A., Hanley, David, MacAlpine, David M., Mannervik, Mattias, Venken, Koen, Bellen, Hugo, White, Robert, Gerstein, Mark, Russell, Steven, Grossman, Robert L., Ren, Bing, Posakony, James W., Kellis, Manolis, and White, Kevin P.

Published
2011
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33. Identification of Functional Elements and Regulatory Circuits by Drosophila modENCODE

Author

Roy, Sushmita, Ernst, Jason, Kharchenko, Peter V., Kheradpour, Pouya, Negre, Nicolas, Eaton, Matthew L., Landolin, Jane M., Bristow, Christopher A., Ma, Lijia, Lin, Michael F., Washietl, Stefan, Arshinoff, Bradley I., Ay, Ferhat, Meyer, Patrick E., Robine, Nicolas, Washington, Nicole L., Stefano, Luisa Di, Berezikov, Eugene, Brown, Christopher D., Candeias, Rogerio, Carlson, Joseph W., Carr, Adrian, Jungreis, Irwin, Marbach, Daniel, Sealfon, Rachel, Tolstorukov, Michael Y., Will, Sebastian, Alekseyenko, Artyom A., Artieri, Carlo, Booth, Benjamin W., Brooks, Angela N., Dai, Qi, Davis, Carrie A., Duff, Michael O., Feng, Xin, Gorchakov, Andrey A., Gu, Tingting, Henikoff, Jorja G., Kapranov, Philipp, Li, Renhua, MacAlpine, Heather K., Malone, John, Minoda, Aki, Nordman, Jared, Okamura, Katsutomo, Perry, Marc, Powell, Sara K., Riddle, Nicole C., Sakai, Akiko, Samsonova, Anastasia, Sandler, Jeremy E., Schwartz, Yuri B., Sher, Noa, Spokony, Rebecca, Sturgill, David, van Baren, Marijke, Wan, Kenneth H., Yang, Li, Yu, Charles, Feingold, Elise, Good, Peter, Guyer, Mark, Lowdon, Rebecca, Ahmad, Kami, Andrews, Justen, Berger, Bonnie, Brenner, Steven E., Brent, Michael R., Cherbas, Lucy, Elgin, Sarah C. R., Gingeras, Thomas R., Grossman, Robert, Hoskins, Roger A., Kaufman, Thomas C., Kent, William, Kuroda, Mitzi I., Orr-Weaver, Terry, Perrimon, Norbert, Pirrotta, Vincenzo, Posakony, James W., Ren, Bing, Russell, Steven, Cherbas, Peter, Graveley, Brenton R., Lewis, Suzanna, Micklem, Gos, Oliver, Brian, Park, Peter J., Celniker, Susan E., Henikoff, Steven, Karpen, Gary H., Lai, Eric C., MacAlpine, David M., Stein, Lincoln D., White, Kevin P., and Kellis, Manolis

Published
2010
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39. Nucleosomes influence multiple steps during replication initiation

Author

Massachusetts Institute of Technology. Department of Biology, Azmi, Ishara F, Maloney, Michael Finnan, Bell, Stephen P, Watanabe, Shinya, Kang, Sukhyun, Belsky, Jason A, MacAlpine, David M., Peterson, Craig L, Massachusetts Institute of Technology. Department of Biology, Azmi, Ishara F, Maloney, Michael Finnan, Bell, Stephen P, Watanabe, Shinya, Kang, Sukhyun, Belsky, Jason A, MacAlpine, David M., and Peterson, Craig L

Abstract

Eukaryotic replication origin licensing, activation and timing are influenced by chromatin but a mechanistic understanding is lacking. Using reconstituted nucleosomal DNA replication assays, we assessed the impact of nucleosomes on replication initiation. To generate distinct nucleosomal landscapes, different chromatin-remodeling enzymes (CREs) were used to remodel nucleosomes on origin-DNA templates. Nucleosomal organization influenced two steps of replication initiation: origin licensing and helicase activation. Origin licensing assays showed that local nucleosome positioning enhanced origin specificity and modulated helicase loading by influencing ORC DNA binding. Interestingly, SWI/SNF- and RSC-remodeled nucleosomes were permissive for origin licensing but showed reduced helicase activation. Specific CREs rescued replication of these templates if added prior to helicase activation, indicating a permissive chromatin state must be established during origin licensing to allow efficient origin activation. Our studies show nucleosomes directly modulate origin licensing and activation through distinct mechanisms and provide insights into the regulation of replication initiation by chromatin., American Cancer Society (Postdoctoral Fellowship 123700-PF-13-071-01), National Cancer Institute (U.S.) (Koch Institute Support Grant P30-CA14051)

Published
2017

40. The conserved bromo-adjacent homology domain of yeast Orc1 functions in the selection of DNA replication origins within chromatin

Author

Muller, Philipp, Park, Sookhee, Shor, Erika, Huebert, Dana J., Warren, Christopher L., Ansari, Aseem Z., Weinreich, Michael, Eaton, Matthew L., Catherine A. Fox, and MacAlpine, David M.

Subjects
Chromatin -- Research, DNA replication -- Research, Homology (Biology) -- Research, Yeast fungi -- Genetic aspects, Yeast fungi -- Physiological aspects, Biological sciences
Published
2010

41. Conserved nucleosome positioning defines replication origins

Author

Eaton, Matthew L., Galani, Kyriaki, Kang, Sukhyun, Bell, Stephen, and MacAlpine, David M.

Subjects
DNA replication -- Research, Nucleosomes -- Research, Nucleotide sequencing -- Usage, Yeast fungi -- Genetic aspects, Biological sciences
Published
2010

42. Genomic profiling and expression studies reveal both positive and negative activities for the Drosophila Myb-MuvB/dREAM complex in proliferating cells

Author

Georlette, Daphne, Soyeon Ahn, MacAlpine, David M., Cheung, Evelyn, Lewis, Peter W., Beall, Eileen L., Bell, Stephen P., Speed, Terry, Manak, J. Robert, and Botchan, Michael R.

Subjects
Chromatin -- Research, Drosophila -- Genetic aspects, Genetic regulation -- Research, Mitosis -- Research, Mutation (Biology) -- Research, Biological sciences
Abstract

Proliferating Drosophila Kc tissue culture cells are used to explore the network of genes regulated by Myb-MuvB (MMB)/dREAM and genomic locations of MMB following chromatin immunoprecipitation (ChIP) and tiling array analysis. Results show many sites where MMB is a positive regulator of transcript levels that have included genes needed for mitotic functions, which have described the chromosome instability phenotypes attributed to loss of Myb function in myb mutants.

Published
2007

43. Comprehensive analysis of the chromatin landscape in Drosophila

Author

Kharchenko, Peter V., Alekseyenko, Artyom A., Schwartz, Yuri B., Minoda, Aki, Riddle, Nicole C., Ernst, Jason, Sabo, Peter J., Larschan, Erica, Gorchakov, Andrey A., Gu, Tingting, Linder-Basso, Daniela, Plachetka, Annette, Shanower, Gregory, Tolstorukov, Michael Y., Luquette, Lovelace J., Xi, Ruibin, Jung, Youngsook L., Park, Richard W., Bishop, Eric P., Canfield, Theresa P., Sandstrom, Richard, Thurman, Robert E., MacAlpine, David M., Stamatoyannopoulos, John A., Kellis, Manolis, Elgin, Sarah C. R., Kuroda, Mitzi I., Pirrotta, Vincenzo, Karpen, Gary H., and Park, Peter J.

Subjects
Article
Abstract

Summary Chromatin is composed of DNA and a variety of modified histones and non-histone proteins, which impact cell differentiation, gene regulation and other key cellular processes. We present a genome-wide chromatin landscape for Drosophila melanogaster based on 18 histone modifications, summarized by 9 prevalent combinatorial patterns. Integrative analysis with other data (non-histone chromatin proteins, DNaseI hypersensitivity, GRO-seq reads produced by engaged polymerase, short/long RNA products) reveals discrete characteristics of chromosomes, genes, regulatory elements, and other functional domains. We find that active genes display distinct chromatin signatures that are correlated with disparate gene lengths, exon patterns, regulatory functions, and genomic contexts. We also demonstrate a diversity of signatures among Polycomb targets that include a subset with paused polymerase. This systematic profiling and integrative analysis of chromatin signatures provides insights into how genomic elements are regulated, and will serve as a resource for future experimental investigations of genome structure and function.

Published
2010

46. Coordination of replication and transcription along a Drosophila chromosome

Author

MacAlpine, David M., Rodriguez, Heather K., and Bell, Stephen P.

Subjects
Chromosomes -- Research, DNA replication -- Research, Drosophila -- Genetic aspects, Genetic research, Biological sciences
Abstract

The mechanisms by which metazoan origins of DNA replication are defined, regulated, and influenced by chromosomal events are studied. A systematic approach using a Drosophila high-resolution genomic microarray is developed to determine replication timing, identify replication origins, and map protein-binding sites along a chromosome arm to gain insights into the mechanisms.

Published
2004

47. The histone modification pattern of active genes revealed through genome-wide chromatin analysis of a higher erkaryote

Author

Schubeler, Dirk, MacAlpine, David M., Scalzo, David, Wirbelauer, Christiane, Kooperberg, Charles, Delrow Jeffrey, Turner, Bryan M., Groudine, Mark, Bell, Stephen P., O'Neill, Laura P., Gottschling, Daniel E., and van, Leeuwen Fred

Subjects
Drosophila -- Genetic aspects, Histones -- Research, Genetic research, Biological sciences
Abstract

A genome-wide chromatin structure analysis in a higher eukaryote is performed to understand the interplay between various histone modifications, including acetylation and methylation. It is found that a binary pattern of histone modifications among euchromatic genes, with active genes being hyperacetylated for H3 and H4 and hypermethylated at Lys 4 and Lys 79 of H3, and inactive genes being hypomethylated and deacetylated at the same residues.

Published
2004

49. Rare Codons Regulate KRas Oncogenesis

Author

Lampson, Benjamin L., Pershing, Nicole L.K., Prinz, Joseph A., Lacsina, Joshua R., Marzluff, William F., Nicchitta, Christopher V., MacAlpine, David M., and Counter, Christopher M.

Published
2013
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50. Temporal association of ORCA/LRWD1 to late-firing origins during G1 dictates heterochromatin replication and organization

Author

Wang, Yating, primary, Khan, Abid, additional, Marks, Anna B., additional, Smith, Owen K., additional, Giri, Sumanprava, additional, Lin, Yo-Chuen, additional, Creager, Rachel, additional, MacAlpine, David M., additional, Prasanth, Kannanganattu V., additional, Aladjem, Mirit I., additional, and Prasanth, Supriya G., additional

Published
2016
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