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1. Global reference mapping of human transcription factor footprints

Author

Vierstra, Jeff, Lazar, John, Sandstrom, Richard, Halow, Jessica, Lee, Kristen, Bates, Daniel, and Diegel, Morgan

Subjects
Binding sites (Biochemistry) -- Identification and classification -- Analysis -- Methods, Human chromosomes -- Identification and classification -- Analysis -- Methods, Transcription factors -- Analysis -- Methods, Chromosome mapping -- Methods -- Analysis, Genome-wide association studies -- Analysis -- Methods, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Combinatorial binding of transcription factors to regulatory DNA underpins gene regulation in all organisms. Genetic variation in regulatory regions has been connected with diseases and diverse phenotypic traits.sup.1, but it remains challenging to distinguish variants that affect regulatory function.sup.2. Genomic DNase I footprinting enables the quantitative, nucleotide-resolution delineation of sites of transcription factor occupancy within native chromatin.sup.3-6. However, only a small fraction of such sites have been precisely resolved on the human genome sequence.sup.6. Here, to enable comprehensive mapping of transcription factor footprints, we produced high-density DNase I cleavage maps from 243 human cell and tissue types and states and integrated these data to delineate about 4.5 million compact genomic elements that encode transcription factor occupancy at nucleotide resolution. We map the fine-scale structure within about 1.6 million DNase I-hypersensitive sites and show that the overwhelming majority are populated by well-spaced sites of single transcription factor-DNA interaction. Cell-context-dependent cis-regulation is chiefly executed by wholesale modulation of accessibility at regulatory DNA rather than by differential transcription factor occupancy within accessible elements. We also show that the enrichment of genetic variants associated with diseases or phenotypic traits in regulatory regions.sup.1,7 is almost entirely attributable to variants within footprints, and that functional variants that affect transcription factor occupancy are nearly evenly partitioned between loss- and gain-of-function alleles. Unexpectedly, we find increased density of human genetic variation within transcription factor footprints, revealing an unappreciated driver of cis-regulatory evolution. Our results provide a framework for both global and nucleotide-precision analyses of gene regulatory mechanisms and functional genetic variation. A high-density DNase I cleavage map from 243 human cell and tissue types provides a genome-wide, nucleotide-resolution map of human transcription factor footprints., Author(s): Jeff Vierstra [sup.1] , John Lazar [sup.1] [sup.2] , Richard Sandstrom [sup.1] , Jessica Halow [sup.1] , Kristen Lee [sup.1] , Daniel Bates [sup.1] , Morgan Diegel [sup.1] , [...]

Published
2020
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2. Index and biological spectrum of human DNase I hypersensitive sites

Author

Meuleman, Wouter, Muratov, Alexander, Rynes, Eric, Halow, Jessica, Lee, Kristen, Bates, Daniel, Diegel, Morgan, Dunn, Douglas, Neri, Fidencio, Teodosiadis, Athanasios, Reynolds, Alex, Haugen, Eric, Nelson, Jemma, Johnson, Audra, Frerker, Mark, Buckley, Michael, Sandstrom, Richard, Vierstra, Jeff, Kaul, Rajinder, and Stamatoyannopoulos, John

Published
2020
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4. Integrated epigenomic profiling reveals endogenous retrovirus reactivation in renal cell carcinoma

Author

Siebenthall, Kyle T., Miller, Chris P., Vierstra, Jeff D., Mathieu, Julie, Tretiakova, Maria, Reynolds, Alex, Sandstrom, Richard, Rynes, Eric, Haugen, Eric, Johnson, Audra, Nelson, Jemma, Bates, Daniel, Diegel, Morgan, Dunn, Douglass, Frerker, Mark, Buckley, Michael, Kaul, Rajinder, Zheng, Ying, Himmelfarb, Jonathan, Ruohola-Baker, Hannele, and Akilesh, Shreeram

Published
2019
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5. Integrated Functional Genomic Analysis Enables Annotation of Kidney Genome-Wide Association Study Loci

Author

Sieber, Karsten B., Batorsky, Anna, Siebenthall, Kyle, Hudkins, Kelly L., Vierstra, Jeff D., Sullivan, Shawn, Sur, Aakash, McNulty, Michelle, Sandstrom, Richard, Reynolds, Alex, Bates, Daniel, Diegel, Morgan, Dunn, Douglass, Nelson, Jemma, Buckley, Michael, Kaul, Rajinder, Sampson, Matthew G., Himmelfarb, Jonathan, Alpers, Charles E., Waterworth, Dawn, and Akilesh, Shreeram

Published
2019
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8. 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, M. A., and Stamatoyannopoulos, John A.

Published
2014

10. 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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11. Conservation of trans-acting circuitry during mammalian regulatory evolution

Author

Stergachis, Andrew B., Neph, Shane, Sandstrom, Richard, Haugen, Eric, Reynolds, Alex P., Zhang, Miaohua, Byron, Rachel, Canfield, Theresa, Stelhing-Sun, Sandra, Lee, Kristen, Thurman, Robert E., Vong, Shinny, Bates, Daniel, Neri, Fidencio, Diegel, Morgan, Giste, Erika, Dunn, Douglas, Vierstra, Jeff, Hansen, R. Scott, Johnson, Audra K., Sabo, Peter J., Wilken, Matthew S., Reh, Thomas A., Treuting, Piper M., Kaul, Rajinder, Groudine, Mark, Bender, M. A., Borenstein, Elhanan, and Stamatoyannopoulos, John A.

Subjects
Evolution -- Genetic aspects, Genetic regulation -- Methods, Mammals -- Genetic aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The basic body plan and major physiological axes have been highly conserved during mammalian evolution, yet only a small fraction of the human genome sequence appears to be subject to evolutionary constraint. To quantify cis- versus trans-acting contributions to mammalian regulatory evolution, we performed genomic DNase I footprinting of the mouse genome across 25 cell and tissue types, collectively defining [similar]8.6 million transcription factor (TF) occupancy sites at nucleotide resolution. Here we show that mouse TF footprints conjointly encode a regulatory lexicon that is [similar]95% similar with that derived from human TF footprints. However, only [similar]20% of mouse TF footprints have human orthologues. Despite substantial turnover of the cis-regulatory landscape, nearly half of all pairwise regulatory interactions connecting mouse TF genes have been maintained in orthologous human cell types through evolutionary innovation of TF recognition sequences. Furthermore, the higher-level organization of mouse TF-to-TF connections into cellular network architectures is nearly identical with human. Our results indicate that evolutionary selection on mammalian gene regulation is targeted chiefly at the level of trans-regulatory circuitry, enabling and potentiating cis-regulatory plasticity., Author(s): Andrew B. Stergachis [1]; Shane Neph [1]; Richard Sandstrom [1]; Eric Haugen [1]; Alex P. Reynolds [1]; Miaohua Zhang [2]; Rachel Byron [2]; Theresa Canfield [1]; Sandra Stelhing-Sun [1]; [...]

Published
2014
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12. 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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13. An integrated encyclopedia of DNA elements in the human genome

Author

Dunham, Ian, Kundaje, Anshul, Aldred, Shelley F., Collins, Patrick J., Davis, Carrie A., Doyle, Francis, Epstein, Charles B., Frietze, Seth, Harrow, Jennifer, Kaul, Rajinder, Khatun, Jainab, Lajoie, Bryan R., Landt, Stephen G., Lee, Bum-Kyu, Pauli, Florencia, Rosenbloom, Kate R., Sabo, Peter, Safi, Alexias, Sanyal, Amartya, Shoresh, Noam, Simon, Jeremy M., Song, Lingyun, Trinklein, Nathan D., Altshuler, Robert C., Birney, Ewan, Brown, James B., Cheng, Chao, Djebali, Sarah, Dong, Xianjun, Ernst, Jason, Furey, Terrence S., Gerstein, Mark, Giardine, Belinda, Greven, Melissa, Hardison, Ross C., Harris, Robert S., Herrero, Javier, Hoffman, Michael M., Iyer, Sowmya, Kellis, Manolis, Kheradpour, Pouya, Lassmann, Timo, Li, Qunhua, Lin, Xinying, Marinov, Georgi K., Merkel, Angelika, Mortazavi, Ali, Parker, Stephen C. J., Reddy, Timothy E., Rozowsky, Joel, Schlesinger, Felix, Thurman, Robert E., Wang, Jie, Ward, Lucas D., Whitfield, Troy W., Wilder, Steven P., Wu, Weisheng, Xi, Hualin S., Yip, Kevin Y., Zhuang, Jiali, Bernstein, Bradley E., Green, Eric D., Gunter, Chris, Snyder, Michael, Pazin, Michael J., Lowdon, Rebecca F., Dillon, Laura A. L., Adams, Leslie B., Kelly, Caroline J., Zhang, Julia, Wexler, Judith R., Good, Peter J., Feingold, Elise A., Crawford, Gregory E., Dekker, Job, Elnitski, Laura, Farnham, Peggy J., Giddings, Morgan C., Gingeras, Thomas R., Guigo, Roderic, Hubbard, Timothy J., Kent, W. James, Lieb, Jason D., Margulies, Elliott H., Myers, Richard M., Stamatoyannopoulos, John A., Tenenbaum, Scott A., Weng, Zhiping, White, Kevin P., Wold, Barbara, Yu, Yanbao, Wrobel, John, Risk, Brian A., Gunawardena, Harsha P., Kuiper, Heather C., Maier, Christopher W., Xie, Ling, Chen, Xian, Mikkelsen, Tarjei S., Gillespie, Shawn, Goren, Alon, Ram, Oren, Zhang, Xiaolan, Wang, Li, Issner, Robbyn, Coyne, Michael J., Durham, Timothy, Ku, Manching, Truong, Thanh, Eaton, Matthew L., Dobin, Alex, Tanzer, Andrea, Lagarde, Julien, Lin, Wei, Xue, Chenghai, Williams, Brian A., Zaleski, Chris, Roder, Maik, Kokocinski, Felix, Abdelhamid, Rehab F., Alioto, Tyler, Antoshechkin, Igor, Baer, Michael T., Batut, Philippe, Bell, Ian, Bell, Kimberly, Chakrabortty, Sudipto, Chrast, Jacqueline, Curado, Joao, Derrien, Thomas, Drenkow, Jorg, Dumais, Erica, Dumais, Jackie, Duttagupta, Radha, Fastuca, Megan, Fejes-Toth, Kata, Ferreira, Pedro, Foissac, Sylvain, Fullwood, Melissa J., Gao, Hui, Gonzalez, David, Gordon, Assaf, Howald, Cedric, Jha, Sonali, Johnson, Rory, Kapranov, Philipp, King, Brandon, Kingswood, Colin, Li, Guoliang, Luo, Oscar J., Park, Eddie, Preall, Jonathan B., Presaud, Kimberly, Ribeca, Paolo, Robyr, Daniel, Ruan, Xiaoan, Sammeth, Michael, Sandhu, Kuljeet Singh, Schaeffer, Lorain, See, Lei-Hoon, Shahab, Atif, Skancke, Jorgen, Suzuki, Ana Maria, Takahashi, Hazuki, Tilgner, Hagen, Trout, Diane, Walters, Nathalie, Wang, Huaien, Hayashizaki, Yoshihide, Reymond, Alexandre, Antonarakis, Stylianos E., Hannon, Gregory J., Ruan, Yijun, Carninci, Piero, Sloan, Cricket A., Learned, Katrina, Malladi, Venkat S., Wong, Matthew C., Barber, Galt P., Cline, Melissa S., Dreszer, Timothy R., Heitner, Steven G., Karolchik, Donna, Kirkup, Vanessa M., Meyer, Laurence R., Long, Jeffrey C., Maddren, Morgan, Raney, Brian J., Grasfeder, Linda L., Giresi, Paul G., Battenhouse, Anna, Sheffield, Nathan C., Showers, Kimberly A., London, Darin, Bhinge, Akshay A., Shestak, Christopher, Schaner, Matthew R., Ki Kim, Seul, Zhang, Zhuzhu Z., Mieczkowski, Piotr A., Mieczkowska, Joanna O., Liu, Zheng, McDaniell, Ryan M., Ni, Yunyun, Rashid, Naim U., Kim, Min Jae, Adar, Sheera, Zhang, Zhancheng, Wang, Tianyuan, Winter, Deborah, Keefe, Damian, Iyer, Vishwanath R., Zheng, Meizhen, Wang, Ping, Gertz, Jason, Vielmetter, Jost, Partridge, E., Varley, Katherine E., Gasper, Clarke, Bansal, Anita, Pepke, Shirley, Jain, Preti, Amrhein, Henry, Bowling, Kevin M., Anaya, Michael, Cross, Marie K., Muratet, Michael A., Newberry, Kimberly M., McCue, Kenneth, Nesmith, Amy S., Fisher-Aylor, Katherine I., Pusey, Barbara, DeSalvo, Gilberto, Parker, Stephanie L., Balasubramanian, Sreeram, Davis, Nicholas S., Meadows, Sarah K., Eggleston, Tracy, Newberry, J. Scott, Levy, Shawn E., Absher, Devin M., Wong, Wing H., Blow, Matthew J., Visel, Axel, Pennachio, Len A., Petrykowska, Hanna M., Abyzov, Alexej, Aken, Bronwen, Barrell, Daniel, Barson, Gemma, Berry, Andrew, Bignell, Alexandra, Boychenko, Veronika, Bussotti, Giovanni, Davidson, Claire, Despacio-Reyes, Gloria, Diekhans, Mark, Ezkurdia, Iakes, Frankish, Adam, Gilbert, James, Gonzalez, Jose Manuel, Griffiths, Ed, Harte, Rachel, Hendrix, David A., Hunt, Toby, Jungreis, Irwin, Kay, Mike, Khurana, Ekta, Leng, Jing, Lin, Michael F., Loveland, Jane, Lu, Zhi, Manthravadi, Deepa, Mariotti, Marco, Mudge, Jonathan, Mukherjee, Gaurab, Notredame, Cedric, Pei, Baikang, Rodriguez, Jose Manuel, Saunders, Gary, Sboner, Andrea, Searle, Stephen, Sisu, Cristina, Snow, Catherine, Steward, Charlie, Tapanari, Electra, Tress, Michael L., van Baren, Marijke J., Washietl, Stefan, Wilming, Laurens, Zadissa, Amonida, Zhang, Zhengdong, Brent, Michael, Haussler, David, Valencia, Alfonso, Addleman, Nick, Alexander, Roger P., Auerbach, Raymond K., Balasubramanian, Suganthi, Bettinger, Keith, Bhardwaj, Nitin, Boyle, Alan P., Cao, Alina R., Cayting, Philip, Charos, Alexandra, Cheng, Yong, Eastman, Catharine, Euskirchen, Ghia, Fleming, Joseph D., Grubert, Fabian, Habegger, Lukas, Hariharan, Manoj, Harmanci, Arif, Iyengar, Sushma, Jin, Victor X., Karczewski, Konrad J., Kasowski, Maya, Lacroute, Phil, Lam, Hugo, Lamarre-Vincent, Nathan, Lian, Jin, Lindahl-Allen, Marianne, Min, Renqiang, Miotto, Benoit, Monahan, Hannah, Moqtaderi, Zarmik, Mu, Xinmeng J., Ouyang, Zhengqing, Patacsil, Dorrelyn, Raha, Debasish, Ramirez, Lucia, Reed, Brian, Shi, Minyi, Slifer, Teri, Witt, Heather, Wu, Linfeng, Xu, Xiaoqin, Yan, Koon-Kiu, Yang, Xinqiong, Struhl, Kevin, Weissman, Sherman M., Penalva, Luiz O., Karmakar, Subhradip, Bhanvadia, Raj R., Choudhury, Alina, Domanus, Marc, Ma, Lijia, Moran, Jennifer, Victorsen, Alec, Auer, Thomas, Centanin, Lazaro, Eichenlaub, Michael, Gruhl, Franziska, Heermann, Stephan, Hoeckendorf, Burkhard, Inoue, Daigo, Kellner, Tanja, Kirchmaier, Stephan, Mueller, Claudia, Reinhardt, Robert, Schertel, Lea, Schneider, Stephanie, Sinn, Rebecca, Wittbrodt, Beate, Wittbrodt, Jochen, Partridge, E. Christopher, Jain, Gaurav, Balasundaram, Gayathri, Bates, Daniel L., Byron, Rachel, Canfield, Theresa K., Diegel, Morgan J., Dunn, Douglas, Ebersol, Abigail K., Frum, Tristan, Garg, Kavita, Gist, Erica, Hansen, R. Scott, Boatman, Lisa, Haugen, Eric, Humbert, Richard, Johnson, Audra K., Johnson, Ericka M., Kutyavin, Tattyana V., Lee, Kristen, Lotakis, Dimitra, Maurano, Matthew T., Neph, Shane J., Neri, Fiedencio V., Nguyen, Eric D., Qu, Hongzhu, Reynolds, Alex P., Roach, Vaughn, Rynes, Eric, Sanchez, Minerva E., Sandstrom, Richard S., Shafer, Anthony O., Stergachis, Andrew B., Thomas, Sean, Vernot, Benjamin, Vierstra, Jeff, Vong, Shinny, Weaver, Molly A., Yan, Yongqi, Zhang, Miaohua, Akey, Joshua M., Bender, Michael, Dorschner, Michael O., Groudine, Mark, MacCoss, Michael J., Navas, Patrick, Stamatoyannopoulos, George, Beal, Kathryn, Brazma, Alvis, Flicek, Paul, Johnson, Nathan, Lukk, Margus, Luscombe, Nicholas M., Sobral, Daniel, Vaquerizas, Juan M., Batzoglou, Serafim, Sidow, Arend, Hussami, Nadine, Kyriazopoulou-Panagiotopoulou, Sofia, Libbrecht, Max W., Schaub, Marc A., Miller, Webb, Bickel, Peter J., Banfai, Balazs, Boley, Nathan P., Huang, Haiyan, Li, Jingyi Jessica, Noble, William Stafford, Bilmes, Jeffrey A., Buske, Orion J., Sahu, Avinash D., Kharchenko, Peter V., Park, Peter J., Baker, Dannon, Taylor, James, and Lochovsky, Lucas

Subjects
Genetic research, Human genome -- Research, Genetic transcription -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

The human genome encodes the blueprint of life, but the function of the vast majority of its nearly three billion bases is unknown. The Encyclopedia of DNA Elements (ENCODE) project has systematically mapped regions of transcription, transcription factor association, chromatin structure and histone modification. These data enabled us to assign biochemical functions for 80% of the genome, in particular outside of the well-studied protein-coding regions. Many discovered candidate regulatory elements are physically associated with one another and with expressed genes, providing new insights into the mechanisms of gene regulation. The newly identified elements also show a statistical correspondence to sequence variants linked to human disease, and can thereby guide interpretation of this variation. Overall, the project provides new insights into the organization and regulation of our genes and genome, and is an expansive resource of functional annotations for biomedical research., Author(s): The ENCODE Project Consortium; Overall coordination (data analysis coordination); Ian Dunham [2]; Anshul Kundaje [3, 82]; Data production leads (data production); Shelley F. Aldred [4]; Patrick J. Collins [4]; [...]

Published
2012
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14. The accessible chromatin landscape of the human genome

Author

Thurman, Robert E., Rynes, Eric, Humbert, Richard, Vierstra, Jeff, Maurano, Matthew T., Haugen, Eric, Sheffield, Nathan C., Stergachis, Andrew B., Vernot, Benjamin, Garg, Kavita, John, Sam, Sandstrom, Richard, Bates, Daniel, Boatman, Lisa, Canfield, Theresa K., Diegel, Morgan, Dunn, Douglas, Ebersol, Abigail K., Frum, Tristan, Giste, Erika, Johnson, Audra K., Johnson, Ericka M., Kutyavin, Tanya, Lajoie, Bryan, Lee, Bum-Kyu, Lee, Kristen, London, Darin, Lotakis, Dimitra, Neph, Shane, Neri, Fidencio, Nguyen, Eric D., Qu, Hongzhu, Reynolds, Alex P., Roach, Vaughn, Safi, Alexias, Sanchez, Minerva E., Sanyal, Amartya, Shafer, Anthony, Simon, Jeremy M., Song, Lingyun, Vong, Shinny, Weaver, Molly, Yan, Yongqi, Zhang, Zhancheng, Zhang, Zhuzhu, Lenhard, Boris, Tewari, Muneesh, Dorschner, Michael O., Hansen, R. Scott, Navas, Patrick A., Stamatoyannopoulos, George, Iyer, Vishwanath R., Lieb, Jason D., Sunyaev, Shamil R., Akey, Joshua M., Sabo, Peter J., Kaul, Rajinder, Furey, Terrence S., Dekker, Job, Crawford, Gregory E., and Stamatoyannopoulos, John A.

Subjects
Chromatin -- Physiological aspects, DNA -- Physiological aspects, Genetic research, Human genome -- Research, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

DNase I hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify [similar]2.9 million DHSs that encompass virtually all known experimentally validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation and regulatory factor occupancy patterns. We connect [similar]580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is organized with dozens to hundreds of co-activated elements, and the transcellular DNase I sensitivity pattern at a given region can predict cell-type-specific functional behaviours. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation., Author(s): Robert E. Thurman [1, 13]; Eric Rynes [1, 13]; Richard Humbert [1, 13]; Jeff Vierstra [1]; Matthew T. Maurano [1]; Eric Haugen [1]; Nathan C. Sheffield [2]; Andrew B. [...]

Published
2012
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15. An expansive human regulatory lexicon encoded in transcription factor footprints

Author

Neph, Shane, Vierstra, Jeff, Stergachis, Andrew B., Reynolds, Alex P., Haugen, Eric, Vernot, Benjamin, Thurman, Robert E., John, Sam, Sandstrom, Richard, Johnson, Audra K., Maurano, Matthew T., Humbert, Richard, Rynes, Eric, Vong, Shinny, Lee, Kristen, Bates, Daniel, Diegel, Morgan, Roach, Vaughn, Dunn, Douglas, Neri, Jun, Schafer, Anthony, Hansen, R. Scott, Kutyavin, Tanya, Giste, Erika, Weaver, Molly, Canfield, Theresa, Sabo, Peter, Zhang, Miaohua, Balasundaram, Gayathri, Byron, Rachel, MacCoss, Michael J., Akey, Joshua M., Bender, M. A., Groudine, Mark, Kaul, Rajinder, and Stamatoyannopoulos, John A.

Subjects
Genetic research, Genetic regulation -- Research, Transcription factors -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Regulatory factor binding to genomic DNA protects the underlying sequence from cleavage by DNase I, leaving nucleotide-resolution footprints. Using genomic DNase I footprinting across 41 diverse cell and tissue types, we detected 45 million transcription factor occupancy events within regulatory regions, representing differential binding to 8.4 million distinct short sequence elements. Here we show that this small genomic sequence compartment, roughly twice the size of the exome, encodes an expansive repertoire of conserved recognition sequences for DNA-binding proteins that nearly doubles the size of the human cis-regulatory lexicon. We find that genetic variants affecting allelic chromatin states are concentrated in footprints, and that these elements are preferentially sheltered from DNA methylation. High-resolution DNase I cleavage patterns mirror nucleotide-level evolutionary conservation and track the crystallographic topography of protein-DNA interfaces, indicating that transcription factor structure has been evolutionarily imprinted on the human genome sequence. We identify a stereotyped 50-base-pair footprint that precisely defines the site of transcript origination within thousands of human promoters. Finally, we describe a large collection of novel regulatory factor recognition motifs that are highly conserved in both sequence and function, and exhibit cell-selective occupancy patterns that closely parallel major regulators of development, differentiation and pluripotency., Author(s): Shane Neph [1, 7]; Jeff Vierstra [1, 7]; Andrew B. Stergachis [1, 7]; Alex P. Reynolds [1, 7]; Eric Haugen [1]; Benjamin Vernot [1]; Robert E. Thurman [1]; Sam [...]

Published
2012
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16. 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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17. BEDOPS: high-performance genomic feature operations

Author

Neph, Shane, Kuehn, M. Scott, Reynolds, Alex P., Haugen, Eric, Thurman, Robert E., Johnson, Audra K., Rynes, Eric, Maurano, Matthew T., Vierstra, Jeff, Thomas, Sean, Sandstrom, Richard, Humbert, Richard, and Stamatoyannopoulos, John A.

Published
2012
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18. EFORGE v2.0: Updated analysis of cell type-specific signal in epigenomic data

Author

Breeze, Charles E., Reynolds, Alex P., Van Dongen, Jenny, Dunham, Ian, Lazar, John, Neph, Shane, Vierstra, Jeff, Bourque, Guillaume, Teschendorff, Andrew E., Stamatoyannopoulos, John A., Beck, Stephan, Biological Psychology, APH - Mental Health, and APH - Personalized Medicine

Subjects
SDG 12 - Responsible Consumption and Production
Abstract

The Illumina Infinium EPIC BeadChip is a new high-throughput array for DNA methylation analysis, extending the earlier 450k array by over 400 000 new sites. Previously, a method named eFORGE was developed to provide insights into cell type-specific and cell-composition effects for 450k data. Here, we present a significantly updated and improved version of eFORGE that can analyze both EPIC and 450k array data. New features include analysis of chromatin states, transcription factor motifs and DNase I footprints, providing tools for epigenome-wide association study interpretation and epigenome editing.

Published
2019
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20. The accessible chromatin landscape of the human genome

Author

Dunn, Douglas, Lee, Bum-Kyu, Vierstra, Jeff, Johnson, Ericka M., Lee, Kristen, Humbert, Richard, Lotakis, Dimitra, Sandstrom, Richard, Maurano, Matthew T., Nguyen, Eric D., Johnson, Audra K., John, Sam, Boatman, Lisa, Frum, Tristan, Lajoie, Bryan, London, Darin, Diegel, Morgan, Sheffield, Nathan C., Stergachis, Andrew B., Wang, Hao, Neph, Shane, Giste, Erika, Thurman, Robert E., Canfield, Theresa K., Neri, Fidencio, Rynes, Eric, Vernot, Benjamin, Bates, Daniel, Haugen, Eric, Ebersol, Abigail K., Garg, Kavita, and Kutyavin, Tanya

Abstract

DNaseI hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers, and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ~2.9 million DHSs that encompass virtually all known experimentally-validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation, and regulatory factor occupancy patterns. We connect ~580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is choreographed with dozens to hundreds of co-activated elements, and the trans-cellular DNaseI sensitivity pattern at a given region can predict cell type-specific functional behaviors. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.

Published
2012
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23. 53. From GWAS To the Clinic: Genome-Editing the Human BCL11A Erythroid Enhancer for Fetal Globin Elevation in the Hemoglobinopathies

Author

Reik, Andreas, Chang, Kai-Hsin, Vierstra, Jeff, Psatha, Nikoletta, Stehling-Sun, Sandra, Zhou, Yuanyue, O'Neil, Colleen M., Mich, Andrea, Miller, Jeffrey C., Lee, Gary, Tan, Siyuan, Jiang, Haiyan, Stamatoyannopoulos, George, Papayannopoulou, Thalia, Rebar, Edward J., Gregory, Philip D., Stamatoyannopoulos, John A., and Urnov, Fyodor D.

Published
2015
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24. Methylated Cytosines Mutate to Transcription Factor Binding Sites that Drive Tetrapod Evolution.

Author

Ximiao He, Tillo, Desiree, Vierstra, Jeff, Syed, Khund-Sayeed, Deng, Callie, Ray, G. Jordan, Stamatoyannopoulos, John, FitzGerald, Peter C., and Vinson, Charles

Subjects
TRANSCRIPTION factors, GENOMICS, GENOMES, BIOLOGY, EVOLUTIONARY theories
Abstract

Inmammals, the cytosine inCGdinucleotides is typically methylated producing 5-methylcytosine (5mC), a chemically less stable form of cytosine that can spontaneously deaminate to thymidine resulting in a T•G mismatched base pair. Unlike other eukaryotes that efficiently repair this mismatched base pair back to C•G, in mammals, 5mCG deamination is mutagenic, sometimes producing TG dinucleotides, explaining the depletion of CG dinucleotides in mammalian genomes. It was suggested that new TG dinucleotides generate genetic diversity that may be critical for evolutionary change. We tested this conjecture by examining the DNA sequence properties of regulatory sequences identified by DNase I hypersensitive sites (DHSs) in humanandmouse genomes. We hypothesized that the newTG dinucleotides generate transcription factor binding sites (TFBS) that become tissue-specificDHSs (TS-DHSs).We find that 8-mers containing the CG dinucleotide are enriched in DHSs in both species. However, 8-mers containing a TG and no CG dinucleotide are preferentially enriched in TS-DHSs when compared with 8-mers with neither a TG nor a CG dinucleotide. Themost enriched 8-mer with a TG and no CG dinucleotide in tissue-specific regulatory regions in both genomes is the AP-1 motif (TGA C/G TCAN), and we find evidence that TG dinucleotides in the AP-1 motif arose from CG dinucleotides. Additional TS-DHS-enriched TFBS containing the TG/CA dinucleotide are the E-Box motif (GCAGCTGC), the NF-1 motif (GGCA--TGCC), and the GR (glucocorticoid receptor) motif (G-ACA--TGT-C). Our results support the suggestion that cytosine methylation is mutagenic in tetrapods producing TG dinucleotides that create TFBS that drive evolution. [ABSTRACT FROM AUTHOR]

Published
2015
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25. Functional footprinting of regulatory DNA.

Author

Vierstra, Jeff, Reik, Andreas, Chang, Kai-Hsin, Stehling-Sun, Sandra, Zhou, Yuanyue, Hinkley, Sarah J, Paschon, David E, Zhang, Lei, Psatha, Nikoletta, Bendana, Yuri R, O'Neil, Colleen M, Song, Alexander H, Mich, Andrea K, Liu, Pei-Qi, Lee, Gary, Bauer, Daniel E, Holmes, Michael C, Orkin, Stuart H, Papayannopoulou, Thalia, and Stamatoyannopoulos, George

Subjects
*TRANSCRIPTION factors, *GENOME editing, *NUCLEOTIDE sequence, *TRANSCRIPTIONAL repressor CTCF, *SINGLE nucleotide polymorphisms
Abstract

Regulatory regions harbor multiple transcription factor (TF) recognition sites; however, the contribution of individual sites to regulatory function remains challenging to define. We describe an approach that exploits the error-prone nature of genome editing-induced double-strand break repair to map functional elements within regulatory DNA at nucleotide resolution. We demonstrate the approach on a human erythroid enhancer, revealing single TF recognition sites that gate the majority of downstream regulatory function. [ABSTRACT FROM AUTHOR]

Published
2015
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26. DNase I hypersensitivity analysis of the mouse brain and retina identifies region-specific regulatory elements.

Author

Wilken, Matthew S., Brzezinski, Joseph A., La Torre, Anna, Siebenthall, Kyle, Thurman, Robert, Sabo, Peter, Sandstrom, Richard S., Vierstra, Jeff, Canfield, Theresa K., Scott Hansen, R., Bender, Michael A., Stamatoyannopoulos, John, and Reh, Thomas A.

Subjects
ALLERGIES, SPINAL cord, CENTRAL nervous system, RETINA, GENOMES
Abstract

Background: The brain, spinal cord, and neural retina comprise the central nervous system (CNS) of vertebrates. Understanding the regulatory mechanisms that underlie the enormous cell-type diversity of the CNS is a significant challenge. Whole-genome mapping of DNase I-hypersensitive sites (DHSs) has been used to identify cis-regulatory elements in many tissues. We have applied this approach to the mouse CNS, including developing and mature neural retina, whole brain, and two well-characterized brain regions, the cerebellum and the cerebral cortex. Results: For the various regions and developmental stages of the CNS that we analyzed, there were approximately the same number of DHSs; however, there were many DHSs unique to each CNS region and developmental stage. Many of the DHSs are likely to mark enhancers that are specific to the specific CNS region and developmental stage. We validated the DNase I mapping approach for identification of CNS enhancers using the existing VISTA Browser database and with in vivo and in vitro electroporation of the retina. Analysis of transcription factor consensus sites within the DHSs shows distinct region-specific profiles of transcriptional regulators particular to each region. Clustering developmentally dynamic DHSs in the retina revealed enrichment of developmental stagespecific transcriptional regulators. Additionally, we found reporter gene activity in the retina driven from several previously uncharacterized regulatory elements surrounding the neurodevelopmental gene Otx2. Identification of DHSs shared between mouse and human showed region-specific differences in the evolution of cis-regulatory elements. Conclusions: Overall, our results demonstrate the potential of genome-wide DNase I mapping to cis-regulatory questions regarding the regional diversity within the CNS. These data represent an extensive catalogue of potential cis-regulatory elements within the CNS that display region and temporal specificity, as well as a set of DHSs common to CNS tissues. Further examination of evolutionary conservation of DHSs between CNS regions and different species may reveal important cis-regulatory elements in the evolution of the mammalian CNS. [ABSTRACT FROM AUTHOR]

Published
2015
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28. Coupling transcription factor occupancy to nucleosome architecture with DNase-FLASH.

Author

Vierstra, Jeff, Wang, Hao, John, Sam, Sandstrom, Richard, and Stamatoyannopoulos, John A

Subjects
*TRANSCRIPTION factors, *CHROMATIN, *GENOMICS, *DEOXYRIBONUCLEASES, *GENETIC regulation, *COUPLING reactions (Chemistry)
Abstract

It is currently not possible to resolve the genome-wide relationship of transcription factors (TFs) and nucleosomes at the level of individual chromatin templates despite rapidly increasing data on TF and nucleosome occupancy in the human genome. Here we describe DNase I-released fragment-length analysis of hypersensitivity (DNase-FLASH), an approach that directly couples mapping of TF occupancy, via quantification of DNA microfragments released from individual TF recognition sites in regulatory DNA, to the surrounding nucleosome architecture, via analysis of larger DNA fragments, in a single assay. DNase-FLASH enables coupling of individual TF footprints to nucleosome occupancy, identifying TFs that precisely demarcate the regulatory DNA-nucleosome interface. [ABSTRACT FROM AUTHOR]

Published
2014
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29. The accessible chromatin landscape of the human genome

Author

Thurman, Robert E., Rynes, Eric, Humbert, Richard, Vierstra, Jeff, Maurano, Matthew T., Haugen, Eric, Sheffield, Nathan C., Stergachis, Andrew B., Wang, Hao, Vernot, Benjamin, Garg, Kavita, Sandstrom, Richard, Bates, Daniel, Canfield, Theresa K., Diegel, Morgan, Dunn, Douglas, Ebersol, Abigail K., Frum, Tristan, Giste, Erika, Harding, Lisa, Johnson, Audra K., Johnson, Ericka M., Kutyavin, Tanya, Lajoie, Bryan, Lee, Bum-Kyu, Lee, Kristen, London, Darin, Lotakis, Dimitra, Neph, Shane, Neri, Fidencio, Nguyen, Eric D., Reynolds, Alex P., Roach, Vaughn, Safi, Alexias, Sanchez, Minerva E., Sanyal, Amartya, Shafer, Anthony, Simon, Jeremy M., Song, Lingyun, Vong, Shinny, Weaver, Molly, Zhang, Zhancheng, Zhang, Zhuzhu, Lenhard, Boris, Tewari, Muneesh, Dorschner, Michael O., Hansen, R. Scott, Navas, Patrick A., Stamatoyannopoulos, George, Iyer, Vishwanath R., Lieb, Jason D., Sunyaev, Shamil R., Akey, Joshua M., Sabo, Peter J., Kaul, Rajinder, Furey, Terrence S., Dekker, Job, Crawford, Gregory E., and Stamatoyannopoulos, John A.

Abstract

DNaseI hypersensitive sites (DHSs) are markers of regulatory DNA and have underpinned the discovery of all classes of cis-regulatory elements including enhancers, promoters, insulators, silencers, and locus control regions. Here we present the first extensive map of human DHSs identified through genome-wide profiling in 125 diverse cell and tissue types. We identify ~2.9 million DHSs that encompass virtually all known experimentally-validated cis-regulatory sequences and expose a vast trove of novel elements, most with highly cell-selective regulation. Annotating these elements using ENCODE data reveals novel relationships between chromatin accessibility, transcription, DNA methylation, and regulatory factor occupancy patterns. We connect ~580,000 distal DHSs with their target promoters, revealing systematic pairing of different classes of distal DHSs and specific promoter types. Patterning of chromatin accessibility at many regulatory regions is choreographed with dozens to hundreds of co-activated elements, and the trans-cellular DNaseI sensitivity pattern at a given region can predict cell type-specific functional behaviors. The DHS landscape shows signatures of recent functional evolutionary constraint. However, the DHS compartment in pluripotent and immortalized cells exhibits higher mutation rates than that in highly differentiated cells, exposing an unexpected link between chromatin accessibility, proliferative potential and patterns of human variation.

Published
2013
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30. Personal and population genomics of human regulatory variation.

Author

Vernot, Benjamin, Stergachis, Andrew B., Maurano, Matthew T., Vierstra, Jeff, Neph, Shane, Thurman, Robert E., Stamatoyannopoulos, John A., and Akey, Joshua M.

Subjects
*HUMAN genome, *DNA, *METAGENOMICS, *TRANSCRIPTION factors, *BIOMOLECULES
Abstract

The characteristics and evolutionary forces acting on regulatory variation in humans remains elusive because of the difficulty in defining functionally important noncoding DNA. Here, we combine genome-scale maps of regulatory DNA marked by DNase I hypersensitive sites (DHSs) from 138 cell and tissue types with whole-genome sequences of 53 geographically diverse individuals in order to better delimit the patterns of regulatory variation in humans. We estimate that individuals likely harbor many more functionally important variants in regulatory DNA compared with protein-coding regions, although they are likely to have, on average, smaller effect sizes. Moreover, we demonstrate that there is significant heterogeneity in the level of functional constraint in regulatory DNA among different cell types. We also find marked variability in functional constraint among transcription factor motifs in regulatory DNA, with sequence motifs for major developmental regulators, such as HOX proteins, exhibiting levels of constraint comparable to protein-coding regions. Finally, we perform a genome-wide scan of recent positive selection and identify hundreds of novel substrates of adaptive regulatory evolution that are enriched for biologically interesting pathways such as melanogenesis and adipocytokine signaling. These data and results provide new insights into patterns of regulatory variation in individuals and populations and demonstrate that a large proportion of functionally important variation lies beyond the exome. [ABSTRACT FROM AUTHOR]

Published
2012
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31. GATA1-defective immune-megakaryocytes as possible drivers of idiopathic pulmonary fibrosis.

Author

Gobbo F, Zingariello M, Verachi P, Falchi M, Arciprete F, Martelli F, Peli A, Mazzarini M, Vierstra J, Mead-Harvey C, Dueck AC, Sarli G, Nava S, Sgalla G, Richeldi L, and Migliaccio AR

Abstract

Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disorder with limited therapeutic options. Insufficient understanding of driver mutations and poor fidelity of currently available animal models has limited the development of effective therapies. Since GATA1 deficient megakaryocytes sustain myelofibrosis, we hypothesized that they may also induce fibrosis in lungs. We discovered that lungs from IPF patients and Gata1 low mice contain numerous GATA1negative immune-poised megakaryocytes that, in mice, have defective RNA-seq profiling and increased TGF-β1, CXCL1 and P-selectin content. With age, Gata1 low mice develop fibrosis in lungs. Development of lung fibrosis in this model is prevented by P-selectin deletion and rescued by P-selectin, TGF-β1 or CXCL1 inhibition. Mechanistically, P-selectin inhibition decreases TGF-β1 and CXCL1 content and increases GATA1positive megakaryocytes while TGF-β1 or CXCL1 inhibition decreased CXCL1 only. In conclusion, Gata1 low mice are a novel genetic-driven model for IPF and provide a link between abnormal immune-megakaryocytes and lung fibrosis., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ARM received funding for research from Dompé Pharmaceutics, Forbius, Novartis for other projects.

Published
2023
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32. Genomic footprinting.

Author

Vierstra J and Stamatoyannopoulos JA

Subjects
Humans, Algorithms, Chromosome Mapping methods, DNA genetics, DNA Footprinting methods, Genome, Human genetics, High-Throughput Nucleotide Sequencing methods
Abstract

The advent of DNA footprinting with DNase I more than 35 years ago enabled the systematic analysis of protein-DNA interactions, and the technique has been instrumental in the decoding of cis-regulatory elements and the identification and characterization of transcription factors and other DNA-binding proteins. The ability to analyze millions of individual genomic cleavage events via massively parallel sequencing has enabled in vivo DNase I footprinting on a genomic scale, offering the potential for global analysis of transcription factor occupancy in a single experiment. Genomic footprinting has opened unique vistas on the organization, function and evolution of regulatory DNA; however, the technology is still nascent. Here we discuss both prospects and challenges of genomic footprinting, as well as considerations for its application to complex genomes.

Published
2016
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34. Large-scale identification of sequence variants influencing human transcription factor occupancy in vivo.

Author

Maurano MT, Haugen E, Sandstrom R, Vierstra J, Shafer A, Kaul R, and Stamatoyannopoulos JA

Subjects
Genome, Human, Genomics methods, Humans, Phenotype, Protein Binding, Transcription Factors genetics, Chromatin metabolism, Gene Expression Regulation, Genetic Variation genetics, Polymorphism, Single Nucleotide genetics, Promoter Regions, Genetic genetics, Regulatory Elements, Transcriptional genetics, Transcription Factors metabolism
Abstract

The function of human regulatory regions depends exquisitely on their local genomic environment and on cellular context, complicating experimental analysis of common disease- and trait-associated variants that localize within regulatory DNA. We use allelically resolved genomic DNase I footprinting data encompassing 166 individuals and 114 cell types to identify >60,000 common variants that directly influence transcription factor occupancy and regulatory DNA accessibility in vivo. The unprecedented scale of these data enables systematic analysis of the impact of sequence variation on transcription factor occupancy in vivo. We leverage this analysis to develop accurate models of variation affecting the recognition sites for diverse transcription factors and apply these models to discriminate nearly 500,000 common regulatory variants likely to affect transcription factor occupancy across the human genome. The approach and results provide a new foundation for the analysis and interpretation of noncoding variation in complete human genomes and for systems-level investigation of disease-associated variants.

Published
2015
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35. Methylated Cytosines Mutate to Transcription Factor Binding Sites that Drive Tetrapod Evolution.

Author

He X, Tillo D, Vierstra J, Syed KS, Deng C, Ray GJ, Stamatoyannopoulos J, FitzGerald PC, and Vinson C

Subjects
5-Methylcytosine chemistry, Animals, Binding Sites, Cytosine chemistry, Humans, Mice, Oligonucleotide Array Sequence Analysis, Protein Binding, Transcription Factors chemistry, Biological Evolution, DNA Methylation, Dinucleoside Phosphates genetics, Transcription Factors genetics
Abstract

In mammals, the cytosine in CG dinucleotides is typically methylated producing 5-methylcytosine (5mC), a chemically less stable form of cytosine that can spontaneously deaminate to thymidine resulting in a T•G mismatched base pair. Unlike other eukaryotes that efficiently repair this mismatched base pair back to C•G, in mammals, 5mCG deamination is mutagenic, sometimes producing TG dinucleotides, explaining the depletion of CG dinucleotides in mammalian genomes. It was suggested that new TG dinucleotides generate genetic diversity that may be critical for evolutionary change. We tested this conjecture by examining the DNA sequence properties of regulatory sequences identified by DNase I hypersensitive sites (DHSs) in human and mouse genomes. We hypothesized that the new TG dinucleotides generate transcription factor binding sites (TFBS) that become tissue-specific DHSs (TS-DHSs). We find that 8-mers containing the CG dinucleotide are enriched in DHSs in both species. However, 8-mers containing a TG and no CG dinucleotide are preferentially enriched in TS-DHSs when compared with 8-mers with neither a TG nor a CG dinucleotide. The most enriched 8-mer with a TG and no CG dinucleotide in tissue-specific regulatory regions in both genomes is the AP-1 motif ( TG: A(C)/GT CA: N), and we find evidence that TG dinucleotides in the AP-1 motif arose from CG dinucleotides. Additional TS-DHS-enriched TFBS containing the TG/CA dinucleotide are the E-Box motif (G CA: GC TG: C), the NF-1 motif (GG CATG: CC), and the GR (glucocorticoid receptor) motif (G-A CATG: T-C). Our results support the suggestion that cytosine methylation is mutagenic in tetrapods producing TG dinucleotides that create TFBS that drive evolution., (Published by Oxford University Press on behalf of the Society for Molecular Biology and Evolution 2015. This work is written by US Government employees and is in the public domain in the US.)

Published
2015
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36. Genome-scale mapping of DNase I hypersensitivity.

Author

John S, Sabo PJ, Canfield TK, Lee K, Vong S, Weaver M, Wang H, Vierstra J, Reynolds AP, Thurman RE, and Stamatoyannopoulos JA

Subjects
Binding Sites, Gene Expression Regulation, Molecular Biology methods, Cell Nucleus genetics, Chromatin metabolism, Deoxyribonuclease I metabolism, Genome-Wide Association Study, High-Throughput Nucleotide Sequencing methods, Sequence Analysis, DNA methods
Abstract

DNase I-seq is a global and high-resolution method that uses the nonspecific endonuclease DNase I to map chromatin accessibility. These accessible regions, designated as DNase I hypersensitive sites (DHSs), define the regulatory features, (e.g., promoters, enhancers, insulators, and locus control regions) of complex genomes. In this unit, methods are described for nuclei isolation, digestion of nuclei with limiting concentrations of DNase I, and the biochemical fractionation of DNase I hypersensitive sites in preparation for high-throughput sequencing. DNase I-seq is an unbiased and robust method that is not predicated on an a priori understanding of regulatory patterns or chromatin features., (© 2013 by John Wiley & Sons, Inc.)

Published
2013
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