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1. 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

2. Comparative analysis of metazoan chromatin organization

Author

Ho, Joshua W. K., June, Youngsook L., Liu, Tao, Alver, Burak H., Lee, Soohyun, Ikegami, Kohta, Sohn, Kyung-Ah, Minoda, Aki, Tolstorukov, Michael Y., Appert, Alex, Parker, Stephen C. J., 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., Bowmanm, Sarah K., Chens, 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, Kingstonm, 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 C. R., Liu, Xiaole Shirley, Lieb, Jason D., Ahringer, Julie, Karpen, Gary H., Park, Peter J., Ho, Joshua W. K., June, Youngsook L., Liu, Tao, Alver, Burak H., Lee, Soohyun, Ikegami, Kohta, Sohn, Kyung-Ah, Minoda, Aki, Tolstorukov, Michael Y., Appert, Alex, Parker, Stephen C. J., 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., Bowmanm, Sarah K., Chens, 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, Kingstonm, 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 C. R., Liu, Xiaole Shirley, Lieb, Jason D., Ahringer, Julie, Karpen, Gary H., and Park, Peter J.

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(1-3). 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(4,5). 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
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3. Comparative analysis of metazoan chromatin organization.

Author

Ho, Joshua WK, 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, Park, Peter J, Ho, Joshua WK, 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

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

4. Comparative analysis of metazoan chromatin organization.

Author

Ho, Joshua WK, 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, Park, Peter J, Ho, Joshua WK, 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

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. Integrative analysis of gene amplification in Drosophila follicle cells: parameters of origin activation and repression

Author

Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Kim, Jane C., Nordman, Jared T., Xie, Fang, Orr-Weaver, Terry L., Kashevsky, Helena, Eng, Thomas, Li, Sharon, MacAlpine, David M., Xie, Fang, Ph. D. Massachusetts Institute of Technology, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Kim, Jane C., Nordman, Jared T., Xie, Fang, Orr-Weaver, Terry L., Kashevsky, Helena, Eng, Thomas, Li, Sharon, MacAlpine, David M., and Xie, Fang, Ph. D. Massachusetts Institute of Technology

Abstract

In metazoans, how replication origins are specified and subsequently activated is not well understood. Drosophila amplicons in follicle cells (DAFCs) are genomic regions that undergo rereplication to increase DNA copy number. We identified all DAFCs by comparative genomic hybridization, uncovering two new amplicons in addition to four known previously. The complete identification of all DAFCs enabled us to investigate these in vivo replicons with respect to parameters of transcription, localization of the origin recognition complex (ORC), and histone acetylation, yielding important insights into gene amplification as a metazoan replication model. Significantly, ORC is bound across domains spanning 10 or more kilobases at the DAFC rather than at a specific site. Additionally, ORC is bound at many regions that do not undergo amplification, and, in contrast to cell culture, these regions do not correlate with high gene expression. As a developmental strategy, gene amplification is not the predominant means of achieving high expression levels, even in cells capable of amplification. Intriguingly, we found that, in some strains, a new amplicon, DAFC-22B, does not amplify, a consequence of distant repression of ORC binding and origin activation. This repression is alleviated when a fragment containing the origin is placed in different genomic contexts., Damon Runyon Cancer Research Foundation (Fellowship), G. Harold and Leila Y. Mathers Foundation, National Institutes of Health (U.S.) (modENCODE project Grant 1U01HG004279), National Institutes of Health (U.S.) (Grant GM57960), American Cancer Society (Research Professor Grant)

Published
2014

6. Unlocking the Secrets of the Genome

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Kellis, Manolis, Celniker, Susan E., Dillon, Laura A. L., Gerstein, Mark B., Gunsalus, Kristin C., Henikoff, Steven, Karpen, Gary H., Lai, Eric C., Lieb, Jason D., MacAlpine, David M., Micklem, Gos, Piano, Fabio, Snyder, Michael, Stein, Lincoln, White, Kevin P., Waterston, Robert H., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, Kellis, Manolis, Celniker, Susan E., Dillon, Laura A. L., Gerstein, Mark B., Gunsalus, Kristin C., Henikoff, Steven, Karpen, Gary H., Lai, Eric C., Lieb, Jason D., MacAlpine, David M., Micklem, Gos, Piano, Fabio, Snyder, Michael, Stein, Lincoln, White, Kevin P., and Waterston, Robert H.

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, yeast (Saccharomyces cerevisiae), worm (Caenorhabditis elegans), fly (Drosophila melanogaster) and mouse (Mus musculus). Free access to the resultant data has prompted much biological research, including development of a map of common human genetic variants (the International HapMap Project)1, expression profiling of healthy and diseased cells2 and in-depth studies of many individual genes. These genome sequences have enabled researchers to carry out genetic and functional genomic studies not previously possible, revealing new biological insights with broad relevance across the animal kingdom 3, 4.

Published
2012

7. Developmental control of gene copy number by repression of replication initiation and fork progression

Author

Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Nordman, Jared T., Eaton, Matthew Lucas, Orr-Weaver, Terry L., Sher, Noa, Bell, George W., Li, Sharon, Eng, Thomas, MacAlpine, David M., Massachusetts Institute of Technology. Computer Science and Artificial Intelligence Laboratory, Massachusetts Institute of Technology. Department of Biology, Whitehead Institute for Biomedical Research, Nordman, Jared T., Eaton, Matthew Lucas, Orr-Weaver, Terry L., Sher, Noa, Bell, George W., Li, Sharon, Eng, Thomas, and MacAlpine, David M.

Abstract

Precise DNA replication is crucial for genome maintenance, yet this process has been inherently difficult to study on a genome-wide level in untransformed differentiated metazoan cells. To determine how metazoan DNA replication can be repressed, we examined regions selectively under-replicated in Drosophila polytene salivary glands, and found they are transcriptionally silent and enriched for the repressive H3K27me3 mark. In the first genome-wide analysis of binding of the origin recognition complex (ORC) in a differentiated metazoan tissue, we find that ORC binding is dramatically reduced within these large domains, suggesting reduced initiation as one mechanism leading to under-replication. Inhibition of replication fork progression by the chromatin protein SUUR is an additional repression mechanism to reduce copy number. Although repressive histone marks are removed when SUUR is mutated and copy number restored, neither transcription nor ORC binding is reinstated. Tethering of the SUUR protein to a specific site is insufficient to block replication, however. These results establish that developmental control of DNA replication, at both the initiation and elongation stages, is a mechanism to change gene copy number during differentiation., National Institutes of Health (U.S.) (Grant GM57960), American Cancer Society. Research Professor Grant, National Institutes of Health (U.S.) (Grant 1U01HG004279)

Published
2012

8. Developmental control of the DNA replication and transcription programs

Author

Whitehead Institute for Biomedical Research, Nordman, Jared T., Li, Sharon, Eng, Thomas, MacAlpine, David M., Whitehead Institute for Biomedical Research, Nordman, Jared T., Li, Sharon, Eng, Thomas, and MacAlpine, David M.

Abstract

Polyploid or polytene cells, which have more than 2C DNA content, are widespread throughout nature and present in most differentiated Drosophila tissues. These cells also can display differential replication, that is, genomic regions of increased or decreased DNA copy number relative to overall genomic ploidy. How frequently differential replication is used as a developmental strategy remains unclear. Here, we use genome-wide array-based comparative genomic hybridization (aCGH) to profile differential DNA replication in isolated and purified larval fat body and midgut tissues of Drosophila, and we compare them with recent aCGH profiles of the larval salivary gland. We identify sites of euchromatic underreplication that are common to all three tissues and others that are tissue specific. We demonstrate that both common and tissue-specific underreplicated sites are dependent on the Suppressor of Underreplication protein, SUUR. mRNA-seq profiling shows that whereas underreplicated regions are generally transcriptionally silent in the larval midgut and salivary gland, transcriptional silencing and underreplication have been uncoupled in the larval fat body. In addition to revealing the prevalence of differential replication, our results show that transcriptional silencing and underreplication can be mechanistically uncoupled., Howard Hughes Medical Institute (Fellowship), G. Harold and Leila Y. Mathers Foundation, National Institutes of Health (U.S.) (Grant HG004279)

Published
2012

9. 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 C R, Kuroda, Mitzi I, Pirrotta, Vincenzo, Karpen, Gary H, Park, Peter J, 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 C R, Kuroda, Mitzi I, Pirrotta, Vincenzo, Karpen, Gary H, and Park, Peter J

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
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10. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster.

Author

Kharchenko, Peter V, 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, Park, Peter J, Kharchenko, Peter V, 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

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. A cis-regulatory map of the Drosophila genome

Author

Negre, 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, A. Jason, 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, White, Kevin P., Negre, 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, A. Jason, 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.

Abstract

Systematic annotation of gene regulatory elements is a major challenge in genome science. Direct mapping of chromatin modification marks and transcriptional factor binding sites genome-wide(1,2) has successfully identified specific subtypes of regulatory elements(3). In Drosophila several pioneering studies have provided genome-wide identification of Polycomb response elements(4), chromatin states(5), transcription factor binding sites(6-9), RNA polymerase II regulation(8) and insulator elements(10); however, comprehensive annotation of the regulatory genome remains a significant challenge. Here we describe results from the modENCODE cis-regulatory annotation project. We produced a map of the Drosophila melanogaster regulatory genome on the basis of more than 300 chromatin immunoprecipitation data sets for eight chromatin features, five histone deacetylases and thirty-eight site-specific transcription factors at different stages of development. Using these data we inferred more than 20,000 candidate regulatory elements and validated a subset of predictions for promoters, enhancers and insulators in vivo. We identified also nearly 2,000 genomic regions of dense transcription factor binding associated with chromatin activity and accessibility. We discovered hundreds of new transcription factor co-binding relationships and defined a transcription factor network with over 800 potential regulatory relationships., authorCount :40

Published
2011
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12. Comprehensive analysis of the chromatin landscape in Drosophila melanogaster.

Author

Kharchenko, Peter V, 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, Park, Peter J, Kharchenko, Peter V, 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

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

13. 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, 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, Kellis, Manolis, 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

Abstract

To gain insight into how genomic information is translated into cellular and developmental programs, the Drosophila model organism Encyclopedia of DNA Elements (modENCODE) project is comprehensively mapping transcripts, histone modifications, chromosomal proteins, transcription factors, replication proteins and intermediates, and nucleosome properties across a developmental time course and in multiple cell lines. We have generated more than 700 data sets and discovered protein-coding, noncoding, RNA regulatory, replication, and chromatin elements, more than tripling the annotated portion of the Drosophila genome. Correlated activity patterns of these elements reveal a functional regulatory network, which predicts putative new functions for genes, reveals stage- and tissue-specific regulators, and enables gene-expression prediction. Our results provide a foundation for directed experimental and computational studies in Drosophila and related species and also a model for systematic data integration toward comprehensive genomic and functional annotation.

Published
2010
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