Search

Your search keyword '"Safi, Alexias"' showing total 42 results
Start Over Author "Safi, Alexias" Search Limiters Available in Library Collection
42 results on '"Safi, Alexias"'

1. Transcriptome and epigenome landscape of human cortical development modeled in organoids

Author

Amiri, Anahita, Coppola, Gianfilippo, Scuderi, Soraya, Wu, Feinan, Roychowdhury, Tanmoy, Liu, Fuchen, Pochareddy, Sirisha, Shin, Yurae, Safi, Alexias, Song, Lingyun, Zhu, Ying, Sousa, André MM, Gerstein, Mark, Crawford, Gregory E, Sestan, Nenad, Abyzov, Alexej, Vaccarino, Flora M, Akbarian, Schahram, An, Joon-Yong, Armoskus, Christoper, Ashley-Koch, Allison E, Beach, Thomas G, Belmont, Judson, Bendl, Jaroslav, Borrman, Tyler, Brown, Leanne, Brown, Miguel, Brown, Mimi, Brunetti, Tonya, Bryois, Julien, Burke, Emily E, Camarena, Adrian, Carlyle, Becky C, Chae, Yooree, Charney, Alexander W, Chen, Chao, Cheng, Lijun, Cherskov, Adriana, Choi, Jinmyung, Clarke, Declan, Collado-Torres, Leonardo, Dai, Rujia, De La Torre Ubieta, Luis, DelValle, Diane, Devillers, Olivia, Dracheva, Stella, Emani, Prashant S, Evgrafov, Oleg V, Farnham, Peggy J, Fitzgerald, Dominic, Flatow, Elie, Francoeur, Nancy, Fullard, John F, Gandal, Michael J, Gao, Tianliuyun, Garrett, Melanie E, Geschwind, Daniel H, Giase, Gina, Girdhar, Kiran, Giusti-Rodriguez, Paola, Goes, Fernando S, Goodman, Thomas, Grennan, Kay S, Gu, Mengting, Gürsoy, Gamze, Hadjimichael, Evi, Hahn, Chang-Gyu, Haroutunian, Vahram, Hauberg, Mads E, Hoffman, Gabriel E, Huey, Jack, Hyde, Thomas M, Ivanov, Nikolay A, Jacobov, Rivka, Jaffe, Andrew E, Jiang, Yan, Jiang, Yi, Johnson, Graham D, Kassim, Bibi S, Kefi, Amira, Kim, Yunjung, Kitchen, Robert R, Kleiman, Joel E, Knowles, James A, Kozlenkov, Alexey, Li, Mingfeng, Li, Zhen, Lipska, Barbara K, Liu, Chunyu, Liu, Shuang, Mangravite, Lara M, Mariani, Jessica, Mattei, Eugenio, Miller, Daniel J, Moore, Jill, Nairn, Angus C, Navarro, Fabio CP, Park, Royce B, Peters, Mette A, and Pinto, Dalila

Subjects
Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Embryonic - Human, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Stem Cell Research, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell, Human Genome, Intellectual and Developmental Disabilities (IDD), Autism, Brain Disorders, Biotechnology, Clinical Research, Mental Health, Pediatric, Neurosciences, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, 1.1 Normal biological development and functioning, Neurological, Cerebral Cortex, Enhancer Elements, Genetic, Epigenesis, Genetic, Gene Expression Regulation, Developmental, Humans, Induced Pluripotent Stem Cells, Models, Neurological, Neurogenesis, Organoids, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Genes implicated in neuropsychiatric disorders are active in human fetal brain, yet difficult to study in a longitudinal fashion. We demonstrate that organoids from human pluripotent cells model cerebral cortical development on the molecular level before 16 weeks postconception. A multiomics analysis revealed differentially active genes and enhancers, with the greatest changes occurring at the transition from stem cells to progenitors. Networks of converging gene and enhancer modules were assembled into six and four global patterns of expression and activity across time. A pattern with progressive down-regulation was enriched with human-gained enhancers, suggesting their importance in early human brain development. A few convergent gene and enhancer modules were enriched in autism-associated genes and genomic variants in autistic children. The organoid model helps identify functional elements that may drive disease onset.

Published
2018

2. Comprehensive functional genomic resource and integrative model for the human brain

Author

Wang, Daifeng, Liu, Shuang, Warrell, Jonathan, Won, Hyejung, Shi, Xu, Navarro, Fabio CP, Clarke, Declan, Gu, Mengting, Emani, Prashant, Yang, Yucheng T, Xu, Min, Gandal, Michael J, Lou, Shaoke, Zhang, Jing, Park, Jonathan J, Yan, Chengfei, Rhie, Suhn Kyong, Manakongtreecheep, Kasidet, Zhou, Holly, Nathan, Aparna, Peters, Mette, Mattei, Eugenio, Fitzgerald, Dominic, Brunetti, Tonya, Moore, Jill, Jiang, Yan, Girdhar, Kiran, Hoffman, Gabriel E, Kalayci, Selim, Gümüş, Zeynep H, Crawford, Gregory E, Roussos, Panos, Akbarian, Schahram, Jaffe, Andrew E, White, Kevin P, Weng, Zhiping, Sestan, Nenad, Geschwind, Daniel H, Knowles, James A, Gerstein, Mark B, Ashley-Koch, Allison E, Garrett, Melanie E, Song, Lingyun, Safi, Alexias, Johnson, Graham D, Wray, Gregory A, Reddy, Timothy E, Goes, Fernando S, Zandi, Peter, Bryois, Julien, Price, Amanda J, Ivanov, Nikolay A, Collado-Torres, Leonardo, Hyde, Thomas M, Burke, Emily E, Kleiman, Joel E, Tao, Ran, Shin, Joo Heon, Kundakovic, Marija, Brown, Leanne, Kassim, Bibi S, Park, Royce B, Wiseman, Jennifer R, Zharovsky, Elizabeth, Jacobov, Rivka, Devillers, Olivia, Flatow, Elie, Lipska, Barbara K, Lewis, David A, Haroutunian, Vahram, Hahn, Chang-Gyu, Charney, Alexander W, Dracheva, Stella, Kozlenkov, Alexey, Belmont, Judson, DelValle, Diane, Francoeur, Nancy, Hadjimichael, Evi, Pinto, Dalila, van Bakel, Harm, Fullard, John F, Bendl, Jaroslav, Hauberg, Mads E, Mangravite, Lara M, Peters, Mette A, Chae, Yooree, Peng, Junmin, Niu, Mingming, Wang, Xusheng, Webster, Maree J, Beach, Thomas G, Chen, Chao, and Jiang, Yi

Subjects
Human Genome, Biotechnology, Schizophrenia, Mental Health, Brain Disorders, Genetics, Neurosciences, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Underpinning research, Aetiology, Mental health, Brain, Datasets as Topic, Deep Learning, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Gene Regulatory Networks, Genome-Wide Association Study, Humans, Mental Disorders, Quantitative Trait Loci, Single-Cell Analysis, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Despite progress in defining genetic risk for psychiatric disorders, their molecular mechanisms remain elusive. Addressing this, the PsychENCODE Consortium has generated a comprehensive online resource for the adult brain across 1866 individuals. The PsychENCODE resource contains ~79,000 brain-active enhancers, sets of Hi-C linkages, and topologically associating domains; single-cell expression profiles for many cell types; expression quantitative-trait loci (QTLs); and further QTLs associated with chromatin, splicing, and cell-type proportions. Integration shows that varying cell-type proportions largely account for the cross-population variation in expression (with >88% reconstruction accuracy). It also allows building of a gene regulatory network, linking genome-wide association study variants to genes (e.g., 321 for schizophrenia). We embed this network into an interpretable deep-learning model, which improves disease prediction by ~6-fold versus polygenic risk scores and identifies key genes and pathways in psychiatric disorders.

Published
2018

3. Integrative functional genomic analysis of human brain development and neuropsychiatric risks

Author

Li, Mingfeng, Santpere, Gabriel, Imamura Kawasawa, Yuka, Evgrafov, Oleg V, Gulden, Forrest O, Pochareddy, Sirisha, Sunkin, Susan M, Li, Zhen, Shin, Yurae, Zhu, Ying, Sousa, André MM, Werling, Donna M, Kitchen, Robert R, Kang, Hyo Jung, Pletikos, Mihovil, Choi, Jinmyung, Muchnik, Sydney, Xu, Xuming, Wang, Daifeng, Lorente-Galdos, Belen, Liu, Shuang, Giusti-Rodríguez, Paola, Won, Hyejung, de Leeuw, Christiaan A, Pardiñas, Antonio F, Hu, Ming, Jin, Fulai, Li, Yun, Owen, Michael J, O’Donovan, Michael C, Walters, James TR, Posthuma, Danielle, Reimers, Mark A, Levitt, Pat, Weinberger, Daniel R, Hyde, Thomas M, Kleinman, Joel E, Geschwind, Daniel H, Hawrylycz, Michael J, State, Matthew W, Sanders, Stephan J, Sullivan, Patrick F, Gerstein, Mark B, Lein, Ed S, Knowles, James A, Sestan, Nenad, Willsey, A Jeremy, Oldre, Aaron, Szafer, Aaron, Camarena, Adrian, Cherskov, Adriana, Charney, Alexander W, Abyzov, Alexej, Kozlenkov, Alexey, Safi, Alexias, Jones, Allan R, Ashley-Koch, Allison E, Ebbert, Amanda, Price, Amanda J, Sekijima, Amanda, Kefi, Amira, Bernard, Amy, Amiri, Anahita, Sboner, Andrea, Clark, Andrew, Jaffe, Andrew E, Tebbenkamp, Andrew TN, Sodt, Andy J, Guillozet-Bongaarts, Angie L, Nairn, Angus C, Carey, Anita, Huttner, Anita, Chervenak, Ann, Szekely, Anna, Shieh, Annie W, Harmanci, Arif, Lipska, Barbara K, Carlyle, Becky C, Gregor, Ben W, Kassim, Bibi S, Sheppard, Brooke, Bichsel, Candace, Hahn, Chang-Gyu, Lee, Chang-Kyu, Chen, Chao, Kuan, Chihchau L, Dang, Chinh, Lau, Chris, Cuhaciyan, Christine, Armoskus, Christoper, Mason, Christopher E, Liu, Chunyu, Slaughterbeck, Cliff R, Bennet, Crissa, Pinto, Dalila, Polioudakis, Damon, Franjic, Daniel, Miller, Daniel J, Bertagnolli, Darren, and Lewis, David A

Subjects
Human Genome, Genetics, Neurosciences, Biotechnology, Pediatric, Mental Health, Brain, Epigenesis, Genetic, Epigenomics, Gene Expression Regulation, Developmental, Gene Regulatory Networks, Humans, Mental Disorders, Nervous System Diseases, Neurogenesis, Single-Cell Analysis, Transcriptome, BrainSpan Consortium, PsychENCODE Consortium, PsychENCODE Developmental Subgroup, General Science & Technology
Abstract

To broaden our understanding of human neurodevelopment, we profiled transcriptomic and epigenomic landscapes across brain regions and/or cell types for the entire span of prenatal and postnatal development. Integrative analysis revealed temporal, regional, sex, and cell type-specific dynamics. We observed a global transcriptomic cup-shaped pattern, characterized by a late fetal transition associated with sharply decreased regional differences and changes in cellular composition and maturation, followed by a reversal in childhood-adolescence, and accompanied by epigenomic reorganizations. Analysis of gene coexpression modules revealed relationships with epigenomic regulation and neurodevelopmental processes. Genes with genetic associations to brain-based traits and neuropsychiatric disorders (including MEF2C, SATB2, SOX5, TCF4, and TSHZ3) converged in a small number of modules and distinct cell types, revealing insights into neurodevelopment and the genomic basis of neuropsychiatric risks.

Published
2018

4. Transcriptome-wide isoform-level dysregulation in ASD, schizophrenia, and bipolar disorder

Author

Gandal, Michael J, Zhang, Pan, Hadjimichael, Evi, Walker, Rebecca L, Chen, Chao, Liu, Shuang, Won, Hyejung, van Bakel, Harm, Varghese, Merina, Wang, Yongjun, Shieh, Annie W, Haney, Jillian, Parhami, Sepideh, Belmont, Judson, Kim, Minsoo, Moran Losada, Patricia, Khan, Zenab, Mleczko, Justyna, Xia, Yan, Dai, Rujia, Wang, Daifeng, Yang, Yucheng T, Xu, Min, Fish, Kenneth, Hof, Patrick R, Warrell, Jonathan, Fitzgerald, Dominic, White, Kevin, Jaffe, Andrew E, Peters, Mette A, Gerstein, Mark, Liu, Chunyu, Iakoucheva, Lilia M, Pinto, Dalila, Geschwind, Daniel H, Ashley-Koch, Allison E, Crawford, Gregory E, Garrett, Melanie E, Song, Lingyun, Safi, Alexias, Johnson, Graham D, Wray, Gregory A, Reddy, Timothy E, Goes, Fernando S, Zandi, Peter, Bryois, Julien, Price, Amanda J, Ivanov, Nikolay A, Collado-Torres, Leonardo, Hyde, Thomas M, Burke, Emily E, Kleiman, Joel E, Tao, Ran, Shin, Joo Heon, Akbarian, Schahram, Girdhar, Kiran, Jiang, Yan, Kundakovic, Marija, Brown, Leanne, Kassim, Bibi S, Park, Royce B, Wiseman, Jennifer R, Zharovsky, Elizabeth, Jacobov, Rivka, Devillers, Olivia, Flatow, Elie, Hoffman, Gabriel E, Lipska, Barbara K, Lewis, David A, Haroutunian, Vahram, Hahn, Chang-Gyu, Charney, Alexander W, Dracheva, Stella, Kozlenkov, Alexey, DelValle, Diane, Francoeur, Nancy, Roussos, Panos, Fullard, John F, Bendl, Jaroslav, Hauberg, Mads E, Mangravite, Lara M, Chae, Yooree, Peng, Junmin, Niu, Mingming, Wang, Xusheng, Webster, Maree J, Beach, Thomas G, Jiang, Yi, and Grennan, Kay S

Subjects
Pharmacology and Pharmaceutical Sciences, Biological Sciences, Biomedical and Clinical Sciences, Genetics, Neurosciences, Intellectual and Developmental Disabilities (IDD), Brain Disorders, Mental Illness, Bipolar Disorder, Mental Health, Schizophrenia, Biotechnology, Serious Mental Illness, Autism, Human Genome, Aetiology, 2.1 Biological and endogenous factors, Mental health, Good Health and Well Being, Autism Spectrum Disorder, Brain, Genetic Predisposition to Disease, Humans, Protein Isoforms, RNA Splicing, Sequence Analysis, RNA, Transcriptome, PsychENCODE Consortium, General Science & Technology
Abstract

Most genetic risk for psychiatric disease lies in regulatory regions, implicating pathogenic dysregulation of gene expression and splicing. However, comprehensive assessments of transcriptomic organization in diseased brains are limited. In this work, we integrated genotypes and RNA sequencing in brain samples from 1695 individuals with autism spectrum disorder (ASD), schizophrenia, and bipolar disorder, as well as controls. More than 25% of the transcriptome exhibits differential splicing or expression, with isoform-level changes capturing the largest disease effects and genetic enrichments. Coexpression networks isolate disease-specific neuronal alterations, as well as microglial, astrocyte, and interferon-response modules defining previously unidentified neural-immune mechanisms. We integrated genetic and genomic data to perform a transcriptome-wide association study, prioritizing disease loci likely mediated by cis effects on brain expression. This transcriptome-wide characterization of the molecular pathology across three major psychiatric disorders provides a comprehensive resource for mechanistic insight and therapeutic development.

Published
2018

5. Transcriptome-wide association study of schizophrenia and chromatin activity yields mechanistic disease insights.

Author

Gusev, Alexander, Mancuso, Nicholas, Won, Hyejung, Kousi, Maria, Finucane, Hilary K, Reshef, Yakir, Song, Lingyun, Safi, Alexias, Schizophrenia Working Group of the Psychiatric Genomics Consortium, McCarroll, Steven, Neale, Benjamin M, Ophoff, Roel A, O'Donovan, Michael C, Crawford, Gregory E, Geschwind, Daniel H, Katsanis, Nicholas, Sullivan, Patrick F, Pasaniuc, Bogdan, and Price, Alkes L

Subjects
Schizophrenia Working Group of the Psychiatric Genomics Consortium, Brain, Chromatin, Animals, Zebrafish, Humans, Genetic Predisposition to Disease, Mitogen-Activated Protein Kinase 3, Microtubule-Associated Proteins, Zebrafish Proteins, Gene Expression Profiling, Schizophrenia, Gene Dosage, Multifactorial Inheritance, Quantitative Trait Loci, Protein Phosphatase 2, Genome-Wide Association Study, Human Genome, Genetics, Mental Health, Neurosciences, Brain Disorders, Serious Mental Illness, 2.1 Biological and endogenous factors, Mental health, Developmental Biology, Biological Sciences, Medical and Health Sciences
Abstract

Genome-wide association studies (GWAS) have identified over 100 risk loci for schizophrenia, but the causal mechanisms remain largely unknown. We performed a transcriptome-wide association study (TWAS) integrating a schizophrenia GWAS of 79,845 individuals from the Psychiatric Genomics Consortium with expression data from brain, blood, and adipose tissues across 3,693 primarily control individuals. We identified 157 TWAS-significant genes, of which 35 did not overlap a known GWAS locus. Of these 157 genes, 42 were associated with specific chromatin features measured in independent samples, thus highlighting potential regulatory targets for follow-up. Suppression of one identified susceptibility gene, mapk3, in zebrafish showed a significant effect on neurodevelopmental phenotypes. Expression and splicing from the brain captured most of the TWAS effect across all genes. This large-scale connection of associations to target genes, tissues, and regulatory features is an essential step in moving toward a mechanistic understanding of GWAS.

Published
2018

9. Genetic variants and cellular stressors associated with exfoliation syndrome modulate promoter activity of a lncRNA within the LOXL1 locus

Author

Hauser, Michael A., Aboobakar, Inas F., Liu, Yutao, Miura, Shiroh, Whigham, Benjamin T., Challa, Pratap, Wheeler, Joshua, Williams, Andrew, Santiago-Turla, Cecelia, Qin, Xuejun, Rautenbach, Robyn M., Ziskind, Ari, Ramsay, Michèle, Uebe, Steffen, Song, Lingyun, Safi, Alexias, Vithana, Eranga N., Mizoguchi, Takanori, Nakano, Satoko, Kubota, Toshiaki, Hayashi, Ken, Manabe, Shin-ichi, Kazama, Shigeyasu, Mori, Yosai, Miyata, Kazunori, Yoshimura, Nagahisa, Reis, Andre, Crawford, Gregory E., Pasutto, Francesca, Carmichael, Trevor R., Williams, Susan E. I., Ozaki, Mineo, Aung, Tin, Khor, Chiea-Chuen, Stamer, W. Daniel, Ashley-Koch, Allison E., and Allingham, R. Rand

Published
2015
Full Text
View/download PDF

11. Targeted long-read sequencing identifies missing disease-causing variation

Author

Miller, Danny E., primary, Sulovari, Arvis, additional, Wang, Tianyun, additional, Loucks, Hailey, additional, Hoekzema, Kendra, additional, Munson, Katherine M., additional, Lewis, Alexandra P., additional, Fuerte, Edith P. Almanza, additional, Paschal, Catherine R., additional, Walsh, Tom, additional, Thies, Jenny, additional, Bennett, James T., additional, Glass, Ian, additional, Dipple, Katrina M., additional, Patterson, Karynne, additional, Bonkowski, Emily S., additional, Nelson, Zoe, additional, Squire, Audrey, additional, Sikes, Megan, additional, Beckman, Erika, additional, Bennett, Robin L., additional, Earl, Dawn, additional, Lee, Winston, additional, Allikmets, Rando, additional, Perlman, Seth J., additional, Chow, Penny, additional, Hing, Anne V., additional, Wenger, Tara L., additional, Adam, Margaret P., additional, Sun, Angela, additional, Lam, Christina, additional, Chang, Irene, additional, Zou, Xue, additional, Austin, Stephanie L., additional, Huggins, Erin, additional, Safi, Alexias, additional, Iyengar, Apoorva K., additional, Reddy, Timothy E., additional, Majoros, William H., additional, Allen, Andrew S., additional, Crawford, Gregory E., additional, Kishnani, Priya S., additional, King, Mary-Claire, additional, Cherry, Tim, additional, Chong, Jessica X., additional, Bamshad, Michael J., additional, Nickerson, Deborah A., additional, Mefford, Heather C., additional, Doherty, Dan, additional, and Eichler, Evan E., additional

Published
2021
Full Text
View/download PDF

12. Additional file 2 of Sex dependent glial-specific changes in the chromatin accessibility landscape in late-onset Alzheimer’s disease brains

Author

Barrera, Julio, Song, Lingyun, Gamache, Julia E., Garrett, Melanie E., Safi, Alexias, Yun, Young, Premasinghe, Ivana, Sprague, Daniel, Chipman, Danielle, Li, Jeffrey, Fradin, Hélène, Soldano, Karen, Gordân, Raluca, Ashley-Koch, Allison E., Crawford, Gregory E., and Chiba-Falek, Ornit

Abstract

Additional file 2 : Supplementary Fig. 1: Pearson correlations of all potential numerical covariates and the first ten principal components of the potential numerical covariates. Supplementary Fig. 2. Association of meta variables with case-control status at a Bonferroni significance level of q

Published
2021
Full Text
View/download PDF

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
Full Text
View/download PDF

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
Full Text
View/download PDF

15. Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance

Author

Tung, Kuei-Ling, primary, Chen, Kai-Yuan, additional, Negrete, Marcos, additional, Chen, Tianyi, additional, Safi, Alexias, additional, Aljamal, Abed Alhalim, additional, Song, Lingyun, additional, Crawford, Gregory E., additional, Ding, Shengli, additional, Hsu, David S., additional, and Shen, Xiling, additional

Published
2021
Full Text
View/download PDF

16. Identification of enhancer regulatory elements that direct epicardial gene expression during zebrafish heart regeneration.

Author

Yingxi Cao, Yu Xia, Balowski, Joseph J., Jianhong Ou, Lingyun Song, Safi, Alexias, Curtis, Timothy, Crawford, Gregory E., Poss, Kenneth D., and Jingli Cao

Subjects
GENE expression, REGENERATION (Biology), CARDIAC regeneration, BRACHYDANIO, FOREST regeneration, CIS-regulatory elements (Genetics)
Abstract

The epicardium is a mesothelial tissue layer that envelops the heart. Cardiac injury activates dynamic gene expression programs in epicardial tissue, which in zebrafish enables subsequent regeneration through paracrine and vascularizing effects. To identify tissue regeneration enhancer elements (TREEs) that control injury-induced epicardial gene expression during heart regeneration, we profiled transcriptomes and chromatin accessibility in epicardial cells purified from regenerating zebrafish hearts. We identified hundreds of candidate TREEs, which are defined by increased chromatin accessibility of non-coding elements near genes with increased expression during regeneration. Several of these candidate TREEs were incorporated into stable transgenic lines, with five out of six elements directing injury-induced epicardial expression but not ontogenetic epicardial expression in larval hearts. Whereas two independent TREEs linked to the gene gnai3 showed similar functional features of gene regulation in transgenic lines, two independent ncam1a-linked TREEs directed distinct spatiotemporal domains of epicardial gene expression. Thus, multiple TREEs linked to a regeneration gene can possess either matching or complementary regulatory controls. Our study provides a new resource and principles for understanding the regulation of epicardial genetic programs during heart regeneration. [ABSTRACT FROM AUTHOR]

Published
2022
Full Text
View/download PDF

17. Integrative QTL analysis of gene expression and chromatin accessibility identifies multi-tissue patterns of genetic regulation

Author

Keele, Gregory R., primary, Quach, Bryan C., additional, Israel, Jennifer W., additional, Chappell, Grace A., additional, Lewis, Lauren, additional, Safi, Alexias, additional, Simon, Jeremy M., additional, Cotney, Paul, additional, Crawford, Gregory E., additional, Valdar, William, additional, Rusyn, Ivan, additional, and Furey, Terrence S., additional

Published
2020
Full Text
View/download PDF

19. Neuronal and glial 3D chromatin architecture informs the cellular etiology of brain disorders.

Author

Hu, Benxia, Won, Hyejung, Mah, Won, Park, Royce B., Kassim, Bibi, Spiess, Keeley, Kozlenkov, Alexey, Crowley, Cheynna A., Pochareddy, Sirisha, The PsychENCODE Consortium, Ashley-Koch, Allison E., Crawford, Gregory E., Garrett, Melanie E., Song, Lingyun, Safi, Alexias, Johnson, Graham D., Wray, Gregory A., Reddy, Timothy E., Goes, Fernando S., and Zandi, Peter

Subjects
PLANT chromosomes, GENE regulatory networks, GENETIC variation, INTERNEURONS, CHROMATIN, REGULATOR genes, ETIOLOGY of diseases
Abstract

Cellular heterogeneity in the human brain obscures the identification of robust cellular regulatory networks, which is necessary to understand the function of non-coding elements and the impact of non-coding genetic variation. Here we integrate genome-wide chromosome conformation data from purified neurons and glia with transcriptomic and enhancer profiles, to characterize the gene regulatory landscape of two major cell classes in the human brain. We then leverage cell-type-specific regulatory landscapes to gain insight into the cellular etiology of several brain disorders. We find that Alzheimer's disease (AD)-associated epigenetic dysregulation is linked to neurons and oligodendrocytes, whereas genetic risk factors for AD highlighted microglia, suggesting that different cell types may contribute to disease risk, via different mechanisms. Moreover, integration of glutamatergic and GABAergic regulatory maps with genetic risk factors for schizophrenia (SCZ) and bipolar disorder (BD) identifies shared (parvalbumin-expressing interneurons) and distinct cellular etiologies (upper layer neurons for BD, and deeper layer projection neurons for SCZ). Collectively, these findings shed new light on cell-type-specific gene regulatory networks in brain disorders. The cellular heterogeneity in brain obscures the identification of robust cellular regulatory networks. Here the authors integrate genome-wide chromosome conformation data from sorted neurons and glia, with transcriptomic and enhancer profiles, to characterize cell-type-specific gene regulatory landscapes in the human brain, and provide insights into cell-type-specific gene regulatory networks in brain disorders. [ABSTRACT FROM AUTHOR]

Published
2021
Full Text
View/download PDF

20. Open Chromatin Profiling in Adipose Tissue Marks Genomic Regions with Functional Roles in Cardiometabolic Traits

Author

Cannon, Maren E, primary, Currin, Kevin W, additional, Young, Kristin L, additional, Perrin, Hannah J, additional, Vadlamudi, Swarooparani, additional, Safi, Alexias, additional, Song, Lingyun, additional, Wu, Ying, additional, Wabitsch, Martin, additional, Laakso, Markku, additional, Crawford, Gregory E, additional, and Mohlke, Karen L, additional

Published
2019
Full Text
View/download PDF

22. Variation in DNA-Damage Responses to an Inhalational Carcinogen (1,3-Butadiene) in Relation to Strain-Specific Differences in Chromatin Accessibility and Gene Transcription Profiles in C57BL/6J and CAST/EiJ Mice

Author

Chappell, Grace A., Israel, Jennifer W., Simon, Jeremy M., Pott, Sebastian, Safi, Alexias, Eklund, Karl, Sexton, Kenneth G., Bodnar, Wanda, Lieb, Jason D., Crawford, Gregory E., Rusyn, Ivan, and Furey, Terrence S.

Subjects
Chemical carcinogenesis -- Research, Cancer genetics -- Research, DNA damage -- Research, Environmental toxicology -- Research, Chromatin -- Research, Transcription (Genetics) -- Research, Butadiene -- Health aspects, Environmental issues, Health
Abstract

BACKGROUND: The damaging effects of exposure to environmental toxicants differentially affect genetically distinct individuals, but the mechanisms contributing to these differences are poorly understood. Genetic variation affects the establishment of the gene regulatory landscape and thus gene expression, and we hypothesized that this contributes to the observed heterogeneity in individual responses to exogenous cellular insults. OBJECTIVES: We performed an in vivo study of how genetic variation and chromatin organization may dictate susceptibility to DNA damage, and influence the cellular response to such damage, caused by an environmental toxicant. MATERIALS AND METHODS: We measured DNA damage, messenger RNA (mRNA) and microRNA (miRNA) expression, and genome-wide chromatin accessibility in lung tissue from two genetically divergent inbred mouse strains, C57BL/6J and CAST/EiJ, both in unexposed mice and in mice exposed to a model DNA-damaging chemical, 1,3-butadiene. RESULTS: Our results showed that unexposed CAST/EiJ and C57BL/6J mice have very different chromatin organization and transcription profiles in the lung. Importantly, in unexposed CAST/EiJ mice, which acquired relatively less 1,3-butadiene-induced DNA damage, we observed increased transcription and a more accessible chromatin landscape around genes involved in detoxification pathways. Upon chemical exposure, chromatin was significantly remodeled in the lung of C57BL/6J mice, a strain that acquired higher levels of 1,3-butadiene-induced DNA damage, around the same genes, ultimately resembling the molecular profile of CAST/EiJ. CONCLUSIONS: These results suggest that strain-specific changes in chromatin and transcription in response to chemical exposure lead to a 'compensation' for underlying genetic-driven interindividual differences in the baseline chromatin and transcriptional state. This work represents an example of how chemical and environmental exposures can be evaluated to better understand gene-by-environment interactions, and it demonstrates the important role of chromatin response in transcriptomic changes and, potentially, in deleterious effects of exposure. https://doi.org/10.1289/EHP1937, Introduction Inter-individual genetic variation can have profound impacts on the metabolism of pharmaceutical drugs and environmental toxicants (Ma and Lu 2011; Pierce et al. 2012). The molecular consequences of chemical [...]

Published
2017
Full Text
View/download PDF

24. Glucocorticoid receptor recruits to enhancers and drives activation by motif-directed binding

Author

McDowell, Ian C., primary, Barrera, Alejandro, additional, D'Ippolito, Anthony M., additional, Vockley, Christopher M., additional, Hong, Linda K., additional, Leichter, Sarah M., additional, Bartelt, Luke C., additional, Majoros, William H., additional, Song, Lingyun, additional, Safi, Alexias, additional, Koçak, D. Dewran, additional, Gersbach, Charles A., additional, Hartemink, Alexander J., additional, Crawford, Gregory E., additional, Engelhardt, Barbara E., additional, and Reddy, Timothy E., additional

Published
2018
Full Text
View/download PDF

25. Evaluation of chromatin accessibility in prefrontal cortex of individuals with schizophrenia

Author

Bryois, Julien, primary, Garrett, Melanie E., additional, Song, Lingyun, additional, Safi, Alexias, additional, Giusti-Rodriguez, Paola, additional, Johnson, Graham D., additional, Shieh, Annie W., additional, Buil, Alfonso, additional, Fullard, John F., additional, Roussos, Panos, additional, Sklar, Pamela, additional, Akbarian, Schahram, additional, Haroutunian, Vahram, additional, Stockmeier, Craig A., additional, Wray, Gregory A., additional, White, Kevin P., additional, Liu, Chunyu, additional, Reddy, Timothy E., additional, Ashley-Koch, Allison, additional, Sullivan, Patrick F., additional, and Crawford, Gregory E., additional

Published
2018
Full Text
View/download PDF

26. Pre-established Chromatin Interactions Mediate the Genomic Response to Glucocorticoids

Author

D'Ippolito, Anthony M., primary, McDowell, Ian C., additional, Barrera, Alejandro, additional, Hong, Linda K., additional, Leichter, Sarah M., additional, Bartelt, Luke C., additional, Vockley, Christopher M., additional, Majoros, William H., additional, Safi, Alexias, additional, Song, Lingyun, additional, Gersbach, Charles A., additional, Crawford, Gregory E., additional, and Reddy, Timothy E., additional

Published
2018
Full Text
View/download PDF

31. Genome-wide specificity of DNA binding, gene regulation, and chromatin remodeling by TALE- and CRISPR/Cas9-based transcriptional activators

Author

Polstein, Lauren R., primary, Perez-Pinera, Pablo, additional, Kocak, D. Dewran, additional, Vockley, Christopher M., additional, Bledsoe, Peggy, additional, Song, Lingyun, additional, Safi, Alexias, additional, Crawford, Gregory E., additional, Reddy, Timothy E., additional, and Gersbach, Charles A., additional

Published
2015
Full Text
View/download PDF

40. 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
Full Text
View/download PDF

41. Integrated chromatin and transcriptomic profiling of patient-derived colon cancer organoids identifies personalized drug targets to overcome oxaliplatin resistance.

Author

Tung KL, Chen KY, Negrete M, Chen T, Safi A, Aljamal AA, Song L, Crawford GE, Ding S, Hsu DS, and Shen X

Abstract

Colorectal cancer is a leading cause of cancer deaths. Most colorectal cancer patients eventually develop chemoresistance to the current standard-of-care therapies. Here, we used patient-derived colorectal cancer organoids to demonstrate that resistant tumor cells undergo significant chromatin changes in response to oxaliplatin treatment. Integrated transcriptomic and chromatin accessibility analyses using ATAC-Seq and RNA-Seq identified a group of genes associated with significantly increased chromatin accessibility and upregulated gene expression. CRISPR/Cas9 silencing of fibroblast growth factor receptor 1 (FGFR1) and oxytocin receptor (OXTR) helped overcome oxaliplatin resistance. Similarly, treatment with oxaliplatin in combination with an FGFR1 inhibitor (PD166866) or an antagonist of OXTR (L-368,899) suppressed chemoresistant organoids. However, oxaliplatin treatment did not activate either FGFR1 or OXTR expression in another resistant organoid, suggesting that chromatin accessibility changes are patient-specific. The use of patient-derived cancer organoids in combination with transcriptomic and chromatin profiling may lead to precision treatments to overcome chemoresistance in colorectal cancer., Competing Interests: The authors declare no potential conflicts of interest., (© 2019 Chongqing Medical University. Production and hosting by Elsevier B.V.)

Published
2019
Full Text
View/download PDF

42. Differential contribution of cis-regulatory elements to higher order chromatin structure and expression of the CFTR locus.

Author

Yang R, Kerschner JL, Gosalia N, Neems D, Gorsic LK, Safi A, Crawford GE, Kosak ST, Leir SH, and Harris A

Subjects
CCCTC-Binding Factor, Caco-2 Cells, Cell Cycle Proteins metabolism, Cell Line, Cells, Cultured, Chromosomal Proteins, Non-Histone metabolism, Cystic Fibrosis Transmembrane Conductance Regulator metabolism, Genetic Loci, Humans, Repressor Proteins metabolism, Cohesins, Chromatin chemistry, Cystic Fibrosis Transmembrane Conductance Regulator genetics, Enhancer Elements, Genetic, Gene Expression Regulation, Insulator Elements
Abstract

Higher order chromatin structure establishes domains that organize the genome and coordinate gene expression. However, the molecular mechanisms controlling transcription of individual loci within a topological domain (TAD) are not fully understood. The cystic fibrosis transmembrane conductance regulator (CFTR) gene provides a paradigm for investigating these mechanisms.CFTR occupies a TAD bordered by CTCF/cohesin binding sites within which are cell-type-selective cis-regulatory elements for the locus. We showed previously that intronic and extragenic enhancers, when occupied by specific transcription factors, are recruited to the CFTR promoter by a looping mechanism to drive gene expression. Here we use a combination of CRISPR/Cas9 editing of cis-regulatory elements and siRNA-mediated depletion of architectural proteins to determine the relative contribution of structural elements and enhancers to the higher order structure and expression of the CFTR locus. We found the boundaries of the CFTRTAD are conserved among diverse cell types and are dependent on CTCF and cohesin complex. Removal of an upstream CTCF-binding insulator alters the interaction profile, but has little effect on CFTR expression. Within the TAD, intronic enhancers recruit cell-type selective transcription factors and deletion of a pivotal enhancer element dramatically decreases CFTR expression, but has minor effect on its 3D structure., (© The Author(s) 2015. Published by Oxford University Press on behalf of Nucleic Acids Research.)

Published
2016
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results