Search

Your search keyword '"Bernstein, Bradley"' showing total 1,086 results
Start Over Author "Bernstein, Bradley"
1,086 results on '"Bernstein, Bradley"'

1. Programs, origins and immunomodulatory functions of myeloid cells in glioma

Author

Miller, Tyler E., El Farran, Chadi A., Couturier, Charles P., Chen, Zeyu, D’Antonio, Joshua P., Verga, Julia, Villanueva, Martin A., Gonzalez Castro, L. Nicolas, Tong, Yuzhou Evelyn, Saadi, Tariq Al, Chiocca, Andrew N., Zhang, Yuanyuan, Fischer, David S., Heiland, Dieter Henrik, Guerriero, Jennifer L., Petrecca, Kevin, Suva, Mario L., Shalek, Alex K., and Bernstein, Bradley E.

Published
2025
Full Text
View/download PDF

3. Systematic decoding of cis gene regulation defines context-dependent control of the multi-gene costimulatory receptor locus in human T cells

Author

Mowery, Cody T, Freimer, Jacob W, Chen, Zeyu, Casaní-Galdón, Salvador, Umhoefer, Jennifer M, Arce, Maya M, Gjoni, Ketrin, Daniel, Bence, Sandor, Katalin, Gowen, Benjamin G, Nguyen, Vinh, Simeonov, Dimitre R, Garrido, Christian M, Curie, Gemma L, Schmidt, Ralf, Steinhart, Zachary, Satpathy, Ansuman T, Pollard, Katherine S, Corn, Jacob E, Bernstein, Bradley E, Ye, Chun Jimmie, and Marson, Alexander

Subjects
Biochemistry and Cell Biology, Biological Sciences, Biotechnology, Human Genome, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Humans, CTLA-4 Antigen, CD28 Antigens, Gene Expression Regulation, Chromatin, T-Lymphocytes, Inducible T-Cell Co-Stimulator Protein, CCCTC-Binding Factor, CRISPR-Cas Systems, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Cis-regulatory elements (CREs) interact with trans regulators to orchestrate gene expression, but how transcriptional regulation is coordinated in multi-gene loci has not been experimentally defined. We sought to characterize the CREs controlling dynamic expression of the adjacent costimulatory genes CD28, CTLA4 and ICOS, encoding regulators of T cell-mediated immunity. Tiling CRISPR interference (CRISPRi) screens in primary human T cells, both conventional and regulatory subsets, uncovered gene-, cell subset- and stimulation-specific CREs. Integration with CRISPR knockout screens and assay for transposase-accessible chromatin with sequencing (ATAC-seq) profiling identified trans regulators influencing chromatin states at specific CRISPRi-responsive elements to control costimulatory gene expression. We then discovered a critical CCCTC-binding factor (CTCF) boundary that reinforces CRE interaction with CTLA4 while also preventing promiscuous activation of CD28. By systematically mapping CREs and associated trans regulators directly in primary human T cell subsets, this work overcomes longstanding experimental limitations to decode context-dependent gene regulatory programs in a complex, multi-gene locus critical to immune homeostasis.

Published
2024

5. Exposure of iPSC-derived human microglia to brain substrates enables the generation and manipulation of diverse transcriptional states in vitro

Author

Dolan, Michael-John, Therrien, Martine, Jereb, Saša, Kamath, Tushar, Gazestani, Vahid, Atkeson, Trevor, Marsh, Samuel E, Goeva, Aleksandrina, Lojek, Neal M, Murphy, Sarah, White, Cassandra M, Joung, Julia, Liu, Bingxu, Limone, Francesco, Eggan, Kevin, Hacohen, Nir, Bernstein, Bradley E, Glass, Christopher K, Leinonen, Ville, Blurton-Jones, Mathew, Zhang, Feng, Epstein, Charles B, Macosko, Evan Z, and Stevens, Beth

Subjects
Biochemistry and Cell Biology, Biological Sciences, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Neurosciences, Aging, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Stem Cell Research, Genetics, Stem Cell Research - Induced Pluripotent Stem Cell, Alzheimer's Disease, Dementia, Brain Disorders, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Generic health relevance, Humans, Microglia, Induced Pluripotent Stem Cells, Alzheimer Disease, Brain, Neurodegenerative Diseases, Immunology, Biochemistry and cell biology
Abstract

Microglia, the macrophages of the brain parenchyma, are key players in neurodegenerative diseases such as Alzheimer's disease. These cells adopt distinct transcriptional subtypes known as states. Understanding state function, especially in human microglia, has been elusive owing to a lack of tools to model and manipulate these cells. Here, we developed a platform for modeling human microglia transcriptional states in vitro. We found that exposure of human stem-cell-differentiated microglia to synaptosomes, myelin debris, apoptotic neurons or synthetic amyloid-beta fibrils generated transcriptional diversity that mapped to gene signatures identified in human brain microglia, including disease-associated microglia, a state enriched in neurodegenerative diseases. Using a new lentiviral approach, we demonstrated that the transcription factor MITF drives a disease-associated transcriptional signature and a highly phagocytic state. Together, these tools enable the manipulation and functional interrogation of human microglial states in both homeostatic and disease-relevant contexts.

Published
2023

6. The EN-TEx resource of multi-tissue personal epigenomes & variant-impact models.

Author

Rozowsky, Joel, Gao, Jiahao, Borsari, Beatrice, Yang, Yucheng, Galeev, Timur, Gürsoy, Gamze, Epstein, Charles, Xiong, Kun, Xu, Jinrui, Li, Tianxiao, Liu, Jason, Yu, Keyang, Berthel, Ana, Chen, Zhanlin, Navarro, Fabio, Sun, Maxwell, Wright, James, Chang, Justin, Cameron, Christopher, Shoresh, Noam, Gaskell, Elizabeth, Drenkow, Jorg, Adrian, Jessika, Aganezov, Sergey, Aguet, François, Balderrama-Gutierrez, Gabriela, Banskota, Samridhi, Corona, Guillermo, Chee, Sora, Chhetri, Surya, Cortez Martins, Gabriel, Danyko, Cassidy, Davis, Carrie, Farid, Daniel, Farrell, Nina, Gabdank, Idan, Gofin, Yoel, Gorkin, David, Gu, Mengting, Hecht, Vivian, Hitz, Benjamin, Issner, Robbyn, Jiang, Yunzhe, Kirsche, Melanie, Kong, Xiangmeng, Lam, Bonita, Li, Shantao, Li, Bian, Li, Xiqi, Lin, Khine, Luo, Ruibang, Mackiewicz, Mark, Meng, Ran, Moore, Jill, Mudge, Jonathan, Nelson, Nicholas, Nusbaum, Chad, Popov, Ioann, Pratt, Henry, Qiu, Yunjiang, Ramakrishnan, Srividya, Raymond, Joe, Salichos, Leonidas, Scavelli, Alexandra, Schreiber, Jacob, Sedlazeck, Fritz, See, Lei, Sherman, Rachel, Shi, Xu, Shi, Minyi, Sloan, Cricket, Strattan, J, Tan, Zhen, Tanaka, Forrest, Vlasova, Anna, Wang, Jun, Werner, Jonathan, Williams, Brian, Xu, Min, Yan, Chengfei, Yu, Lu, Zaleski, Christopher, Zhang, Jing, Ardlie, Kristin, Cherry, J, Mendenhall, Eric, Noble, William, Weng, Zhiping, Levine, Morgan, Dobin, Alexander, Wold, Barbara, Mortazavi, Ali, Ren, Bing, Gillis, Jesse, Myers, Richard, Choudhary, Jyoti, Milosavljevic, Aleksandar, Schatz, Michael, Bernstein, Bradley, and Guigó, Roderic

Subjects
ENCODE, GTEx, allele-specific activity, eQTLs, functional epigenomes, functional genomics, genome annotations, personal genome, predictive models, structural variants, tissue specificity, transformer model, Epigenome, Quantitative Trait Loci, Genome-Wide Association Study, Genomics, Phenotype, Polymorphism, Single Nucleotide
Abstract

Understanding how genetic variants impact molecular phenotypes is a key goal of functional genomics, currently hindered by reliance on a single haploid reference genome. Here, we present the EN-TEx resource of 1,635 open-access datasets from four donors (∼30 tissues × ∼15 assays). The datasets are mapped to matched, diploid genomes with long-read phasing and structural variants, instantiating a catalog of >1 million allele-specific loci. These loci exhibit coordinated activity along haplotypes and are less conserved than corresponding, non-allele-specific ones. Surprisingly, a deep-learning transformer model can predict the allele-specific activity based only on local nucleotide-sequence context, highlighting the importance of transcription-factor-binding motifs particularly sensitive to variants. Furthermore, combining EN-TEx with existing genome annotations reveals strong associations between allele-specific and GWAS loci. It also enables models for transferring known eQTLs to difficult-to-profile tissues (e.g., from skin to heart). Overall, EN-TEx provides rich data and generalizable models for more accurate personal functional genomics.

Published
2023

7. Author Correction: Perspectives on ENCODE

Author

Snyder, Michael P, Gingeras, Thomas R, Moore, Jill E, Weng, Zhiping, Gerstein, Mark B, Ren, Bing, Hardison, Ross C, Stamatoyannopoulos, John A, Graveley, Brenton R, Feingold, Elise A, Pazin, Michael J, Pagan, Michael, Gilchrist, Daniel A, Hitz, Benjamin C, Cherry, J Michael, Bernstein, Bradley E, Mendenhall, Eric M, Zerbino, Daniel R, Frankish, Adam, Flicek, Paul, and Myers, Richard M

Subjects
ENCODE Project Consortium, General Science & Technology
Abstract

In this Article, the authors Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) were mistakenly omitted from the ENCODE Project Consortium author list. The original Article has been corrected online.

Published
2022

8. Author Correction: Expanded encyclopaedias of DNA elements in the human and mouse genomes

Author

Moore, Jill E, Purcaro, Michael J, Pratt, Henry E, Epstein, Charles B, Shoresh, Noam, Adrian, Jessika, Kawli, Trupti, Davis, Carrie A, Dobin, Alexander, Kaul, Rajinder, Halow, Jessica, Van Nostrand, Eric L, Freese, Peter, Gorkin, David U, Shen, Yin, He, Yupeng, Mackiewicz, Mark, Pauli-Behn, Florencia, Williams, Brian A, Mortazavi, Ali, Keller, Cheryl A, Zhang, Xiao-Ou, Elhajjajy, Shaimae I, Huey, Jack, Dickel, Diane E, Snetkova, Valentina, Wei, Xintao, Wang, Xiaofeng, Rivera-Mulia, Juan Carlos, Rozowsky, Joel, Zhang, Jing, Chhetri, Surya B, Zhang, Jialing, Victorsen, Alec, White, Kevin P, Visel, Axel, Yeo, Gene W, Burge, Christopher B, Lécuyer, Eric, Gilbert, David M, Dekker, Job, Rinn, John, Mendenhall, Eric M, Ecker, Joseph R, Kellis, Manolis, Klein, Robert J, Noble, William S, Kundaje, Anshul, Guigó, Roderic, Farnham, Peggy J, Cherry, J Michael, Myers, Richard M, Ren, Bing, Graveley, Brenton R, Gerstein, Mark B, Pennacchio, Len A, Snyder, Michael P, Bernstein, Bradley E, Wold, Barbara, Hardison, Ross C, Gingeras, Thomas R, Stamatoyannopoulos, John A, and Weng, Zhiping

Subjects
ENCODE Project Consortium, General Science & Technology
Abstract

In the version of this article initially published, two members of the ENCODE Project Consortium were missing from the author list. Rizi Ai (Department of Chemistry and Biochemistry, University of California, San Diego, La Jolla, CA, USA) and Shantao Li (Program in Computational Biology and Bioinformatics, Yale University, New Haven, CT, USA) are now included in the author list. These errors have been corrected in the online version of the article.

Published
2022

9. Genome-wide programmable transcriptional memory by CRISPR-based epigenome editing

Author

Nuñez, James K, Chen, Jin, Pommier, Greg C, Cogan, J Zachery, Replogle, Joseph M, Adriaens, Carmen, Ramadoss, Gokul N, Shi, Quanming, Hung, King L, Samelson, Avi J, Pogson, Angela N, Kim, James YS, Chung, Amanda, Leonetti, Manuel D, Chang, Howard Y, Kampmann, Martin, Bernstein, Bradley E, Hovestadt, Volker, Gilbert, Luke A, and Weissman, Jonathan S

Subjects
Biological Sciences, Genetics, Human Genome, Stem Cell Research, Biotechnology, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Generic health relevance, Cancer, CRISPR-Cas Systems, Cell Differentiation, Cellular Reprogramming, CpG Islands, DNA Methylation, Epigenesis, Genetic, Epigenome, Gene Editing, Gene Silencing, Histone Code, Humans, Induced Pluripotent Stem Cells, Neurons, Protein Processing, Post-Translational, CRISPR, DNA methylation, cell therapy, dCas9, epigenetics, Medical and Health Sciences, Developmental Biology, Biological sciences, Biomedical and clinical sciences
Abstract

A general approach for heritably altering gene expression has the potential to enable many discovery and therapeutic efforts. Here, we present CRISPRoff-a programmable epigenetic memory writer consisting of a single dead Cas9 fusion protein that establishes DNA methylation and repressive histone modifications. Transient CRISPRoff expression initiates highly specific DNA methylation and gene repression that is maintained through cell division and differentiation of stem cells to neurons. Pairing CRISPRoff with genome-wide screens and analysis of chromatin marks establishes rules for heritable gene silencing. We identify single guide RNAs (sgRNAs) capable of silencing the large majority of genes including those lacking canonical CpG islands (CGIs) and reveal a wide targeting window extending beyond annotated CGIs. The broad ability of CRISPRoff to initiate heritable gene silencing even outside of CGIs expands the canonical model of methylation-based silencing and enables diverse applications including genome-wide screens, multiplexed cell engineering, enhancer silencing, and mechanistic exploration of epigenetic inheritance.

Published
2021

12. The ENCODE Imputation Challenge: a critical assessment of methods for cross-cell type imputation of epigenomic profiles

Author

Schreiber, Jacob Matthew, Boix, Carles A., wook Lee, Jin, Li, Hongyang, Guan, Yuanfang, Chang, Chun-Chieh, Chang, Jen-Chien, Hawkins-Hooker, Alex, Schölkopf, Bernhard, Schweikert, Gabriele, Carulla, Mateo Rojas, Canakoglu, Arif, Guzzo, Francesco, Nanni, Luca, Masseroli, Marco, Carman, Mark James, Pinoli, Pietro, Hong, Chenyang, Yip, Kevin Y., Spence, Jefrey P., Batra, Sanjit Singh, Song, Yun S., Mahony, Shaun, Zhang, Zheng, Tan, Wuwei, Shen, Yang, Sun, Yuanfei, Shi, Minyi, Adrian, Jessika, Sandstrom, Richard S., Farrell, Nina P., Halow, Jessica M., Lee, Kristen, Jiang, Lixia, Yang, Xinqiong, Epstein, Charles B., Strattan, J. Seth, Bernstein, Bradley E., Snyder, Michael P., Kellis, Manolis, Noble, William S., and Kundaje, Anshul Bharat

Published
2023
Full Text
View/download PDF

13. Evaluation of SARS-CoV-2 serology assays reveals a range of test performance

Author

Whitman, Jeffrey D, Hiatt, Joseph, Mowery, Cody T, Shy, Brian R, Yu, Ruby, Yamamoto, Tori N, Rathore, Ujjwal, Goldgof, Gregory M, Whitty, Caroline, Woo, Jonathan M, Gallman, Antonia E, Miller, Tyler E, Levine, Andrew G, Nguyen, David N, Bapat, Sagar P, Balcerek, Joanna, Bylsma, Sophia A, Lyons, Ana M, Li, Stacy, Wong, Allison Wai-yi, Gillis-Buck, Eva Mae, Steinhart, Zachary B, Lee, Youjin, Apathy, Ryan, Lipke, Mitchell J, Smith, Jennifer Anne, Zheng, Tina, Boothby, Ian C, Isaza, Erin, Chan, Jackie, Acenas, Dante D, Lee, Jinwoo, Macrae, Trisha A, Kyaw, Than S, Wu, David, Ng, Dianna L, Gu, Wei, York, Vanessa A, Eskandarian, Haig Alexander, Callaway, Perri C, Warrier, Lakshmi, Moreno, Mary E, Levan, Justine, Torres, Leonel, Farrington, Lila A, Loudermilk, Rita P, Koshal, Kanishka, Zorn, Kelsey C, Garcia-Beltran, Wilfredo F, Yang, Diane, Astudillo, Michael G, Bernstein, Bradley E, Gelfand, Jeffrey A, Ryan, Edward T, Charles, Richelle C, Iafrate, A John, Lennerz, Jochen K, Miller, Steve, Chiu, Charles Y, Stramer, Susan L, Wilson, Michael R, Manglik, Aashish, Ye, Chun Jimmie, Krogan, Nevan J, Anderson, Mark S, Cyster, Jason G, Ernst, Joel D, Wu, Alan HB, Lynch, Kara L, Bern, Caryn, Hsu, Patrick D, and Marson, Alexander

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Coronaviruses, Infectious Diseases, 4.2 Evaluation of markers and technologies, Infection, Good Health and Well Being, Adult, Aged, Aged, 80 and over, Antibodies, Viral, Betacoronavirus, Biotechnology, COVID-19, COVID-19 Testing, Chromatography, Affinity, Clinical Laboratory Techniques, Coronavirus Infections, Enzyme-Linked Immunosorbent Assay, Female, Humans, Immunoglobulin G, Immunoglobulin M, Male, Middle Aged, Pandemics, Pneumonia, Viral, Point-of-Care Testing, Reverse Transcriptase Polymerase Chain Reaction, SARS-CoV-2, Sensitivity and Specificity, Young Adult
Abstract

Appropriate use and interpretation of serological tests for assessments of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) exposure, infection and potential immunity require accurate data on assay performance. We conducted a head-to-head evaluation of ten point-of-care-style lateral flow assays (LFAs) and two laboratory-based enzyme-linked immunosorbent assays to detect anti-SARS-CoV-2 IgM and IgG antibodies in 5-d time intervals from symptom onset and studied the specificity of each assay in pre-coronavirus disease 2019 specimens. The percent of seropositive individuals increased with time, peaking in the latest time interval tested (>20 d after symptom onset). Test specificity ranged from 84.3% to 100.0% and was predominantly affected by variability in IgM results. LFA specificity could be increased by considering weak bands as negative, but this decreased detection of antibodies (sensitivity) in a subset of SARS-CoV-2 real-time PCR-positive cases. Our results underline the importance of seropositivity threshold determination and reader training for reliable LFA deployment. Although there was no standout serological assay, four tests achieved more than 80% positivity at later time points tested and more than 95% specificity.

Published
2020

14. Perspectives on ENCODE

Author

Snyder, Michael P, Gingeras, Thomas R, Moore, Jill E, Weng, Zhiping, Gerstein, Mark B, Ren, Bing, Hardison, Ross C, Stamatoyannopoulos, John A, Graveley, Brenton R, Feingold, Elise A, Pazin, Michael J, Pagan, Michael, Gilchrist, Daniel A, Hitz, Benjamin C, Cherry, J Michael, Bernstein, Bradley E, Mendenhall, Eric M, Zerbino, Daniel R, Frankish, Adam, Flicek, Paul, and Myers, Richard M

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, Biotechnology, 1.1 Normal biological development and functioning, Animals, Binding Sites, Chromatin, DNA Methylation, Databases, Genetic, Gene Expression Regulation, Genome, Genome, Human, Genomics, Histones, Humans, Mice, Molecular Sequence Annotation, Quality Control, Regulatory Sequences, Nucleic Acid, Transcription Factors, ENCODE Project Consortium, General Science & Technology
Abstract

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

Published
2020

15. Expanded encyclopaedias of DNA elements in the human and mouse genomes

Author

Moore, Jill E, Purcaro, Michael J, Pratt, Henry E, Epstein, Charles B, Shoresh, Noam, Adrian, Jessika, Kawli, Trupti, Davis, Carrie A, Dobin, Alexander, Kaul, Rajinder, Halow, Jessica, Van Nostrand, Eric L, Freese, Peter, Gorkin, David U, Shen, Yin, He, Yupeng, Mackiewicz, Mark, Pauli-Behn, Florencia, Williams, Brian A, Mortazavi, Ali, Keller, Cheryl A, Zhang, Xiao-Ou, Elhajjajy, Shaimae I, Huey, Jack, Dickel, Diane E, Snetkova, Valentina, Wei, Xintao, Wang, Xiaofeng, Rivera-Mulia, Juan Carlos, Rozowsky, Joel, Zhang, Jing, Chhetri, Surya B, Zhang, Jialing, Victorsen, Alec, White, Kevin P, Visel, Axel, Yeo, Gene W, Burge, Christopher B, Lécuyer, Eric, Gilbert, David M, Dekker, Job, Rinn, John, Mendenhall, Eric M, Ecker, Joseph R, Kellis, Manolis, Klein, Robert J, Noble, William S, Kundaje, Anshul, Guigó, Roderic, Farnham, Peggy J, Cherry, J Michael, Myers, Richard M, Ren, Bing, Graveley, Brenton R, Gerstein, Mark B, Pennacchio, Len A, Snyder, Michael P, Bernstein, Bradley E, Wold, Barbara, Hardison, Ross C, Gingeras, Thomas R, Stamatoyannopoulos, John A, and Weng, Zhiping

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Genetics, Human Genome, 1.1 Normal biological development and functioning, Animals, Chromatin, DNA, DNA Footprinting, DNA Methylation, DNA Replication Timing, Databases, Genetic, Deoxyribonuclease I, Genome, Genome, Human, Genomics, Histones, Humans, Mice, Mice, Transgenic, Molecular Sequence Annotation, RNA-Binding Proteins, Registries, Regulatory Sequences, Nucleic Acid, Transcription, Genetic, Transposases, ENCODE Project Consortium, General Science & Technology
Abstract

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

Published
2020

16. Expanded encyclopaedias of DNA elements in the human and mouse genomes.

Author

ENCODE Project Consortium, Moore, Jill E, Purcaro, Michael J, Pratt, Henry E, Epstein, Charles B, Shoresh, Noam, Adrian, Jessika, Kawli, Trupti, Davis, Carrie A, Dobin, Alexander, Kaul, Rajinder, Halow, Jessica, Van Nostrand, Eric L, Freese, Peter, Gorkin, David U, Shen, Yin, He, Yupeng, Mackiewicz, Mark, Pauli-Behn, Florencia, Williams, Brian A, Mortazavi, Ali, Keller, Cheryl A, Zhang, Xiao-Ou, Elhajjajy, Shaimae I, Huey, Jack, Dickel, Diane E, Snetkova, Valentina, Wei, Xintao, Wang, Xiaofeng, Rivera-Mulia, Juan Carlos, Rozowsky, Joel, Zhang, Jing, Chhetri, Surya B, Zhang, Jialing, Victorsen, Alec, White, Kevin P, Visel, Axel, Yeo, Gene W, Burge, Christopher B, Lécuyer, Eric, Gilbert, David M, Dekker, Job, Rinn, John, Mendenhall, Eric M, Ecker, Joseph R, Kellis, Manolis, Klein, Robert J, Noble, William S, Kundaje, Anshul, Guigó, Roderic, Farnham, Peggy J, Cherry, J Michael, Myers, Richard M, Ren, Bing, Graveley, Brenton R, Gerstein, Mark B, Pennacchio, Len A, Snyder, Michael P, Bernstein, Bradley E, Wold, Barbara, Hardison, Ross C, Gingeras, Thomas R, Stamatoyannopoulos, John A, and Weng, Zhiping

Subjects
ENCODE Project Consortium, Chromatin, Animals, Mice, Transgenic, Humans, Mice, Deoxyribonuclease I, Transposases, RNA-Binding Proteins, Histones, DNA, Registries, DNA Footprinting, Genomics, DNA Methylation, DNA Replication Timing, Transcription, Genetic, Regulatory Sequences, Nucleic Acid, Genome, Genome, Human, Databases, Genetic, Molecular Sequence Annotation, Human Genome, HIV/AIDS, Vaccine Related, Biotechnology, Genetics, Immunization, Vaccine Related (AIDS), Prevention, 1.1 Normal biological development and functioning, Generic health relevance, General Science & Technology
Abstract

The human and mouse genomes contain instructions that specify RNAs and proteins and govern the timing, magnitude, and cellular context of their production. To better delineate these elements, phase III of the Encyclopedia of DNA Elements (ENCODE) Project has expanded analysis of the cell and tissue repertoires of RNA transcription, chromatin structure and modification, DNA methylation, chromatin looping, and occupancy by transcription factors and RNA-binding proteins. Here we summarize these efforts, which have produced 5,992 new experimental datasets, including systematic determinations across mouse fetal development. All data are available through the ENCODE data portal (https://www.encodeproject.org), including phase II ENCODE1 and Roadmap Epigenomics2 data. We have developed a registry of 926,535 human and 339,815 mouse candidate cis-regulatory elements, covering 7.9 and 3.4% of their respective genomes, by integrating selected datatypes associated with gene regulation, and constructed a web-based server (SCREEN; http://screen.encodeproject.org) to provide flexible, user-defined access to this resource. Collectively, the ENCODE data and registry provide an expansive resource for the scientific community to build a better understanding of the organization and function of the human and mouse genomes.

Published
2020

17. Perspectives on ENCODE.

Author

ENCODE Project Consortium, Snyder, Michael P, Gingeras, Thomas R, Moore, Jill E, Weng, Zhiping, Gerstein, Mark B, Ren, Bing, Hardison, Ross C, Stamatoyannopoulos, John A, Graveley, Brenton R, Feingold, Elise A, Pazin, Michael J, Pagan, Michael, Gilchrist, Daniel A, Hitz, Benjamin C, Cherry, J Michael, Bernstein, Bradley E, Mendenhall, Eric M, Zerbino, Daniel R, Frankish, Adam, Flicek, Paul, and Myers, Richard M

Subjects
ENCODE Project Consortium, Chromatin, Animals, Humans, Mice, Histones, Transcription Factors, Genomics, DNA Methylation, Gene Expression Regulation, Binding Sites, Regulatory Sequences, Nucleic Acid, Genome, Genome, Human, Quality Control, Databases, Genetic, Molecular Sequence Annotation, Human Genome, Vaccine Related, Biotechnology, Genetics, Immunization, Vaccine Related (AIDS), Prevention, 1.1 Normal biological development and functioning, Generic health relevance, General Science & Technology
Abstract

The Encylopedia of DNA Elements (ENCODE) Project launched in 2003 with the long-term goal of developing a comprehensive map of functional elements in the human genome. These included genes, biochemical regions associated with gene regulation (for example, transcription factor binding sites, open chromatin, and histone marks) and transcript isoforms. The marks serve as sites for candidate cis-regulatory elements (cCREs) that may serve functional roles in regulating gene expression1. The project has been extended to model organisms, particularly the mouse. In the third phase of ENCODE, nearly a million and more than 300,000 cCRE annotations have been generated for human and mouse, respectively, and these have provided a valuable resource for the scientific community.

Published
2020

18. Test performance evaluation of SARS-CoV-2 serological assays

Author

Whitman, Jeffrey D, Hiatt, Joseph, Mowery, Cody T, Shy, Brian R, Yu, Ruby, Yamamoto, Tori N, Rathore, Ujjwal, Goldgof, Gregory M, Whitty, Caroline, Woo, Jonathan M, Gallman, Antonia E, Miller, Tyler E, Levine, Andrew G, Nguyen, David N, Bapat, Sagar P, Balcerek, Joanna, Bylsma, Sophia A, Lyons, Ana M, Li, Stacy, Wong, Allison Wai-yi, Gillis-Buck, Eva Mae, Steinhart, Zachary B, Lee, Youjin, Apathy, Ryan, Lipke, Mitchell J, Smith, Jennifer Anne, Zheng, Tina, Boothby, Ian C, Isaza, Erin, Chan, Jackie, Acenas, Dante D, Lee, Jinwoo, Macrae, Trisha A, Kyaw, Than S, Wu, David, Ng, Dianna L, Gu, Wei, York, Vanessa A, Eskandarian, Haig Alexander, Callaway, Perri C, Warrier, Lakshmi, Moreno, Mary E, Levan, Justine, Torres, Leonel, Farrington, Lila A, Loudermilk, Rita, Koshal, Kanishka, Zorn, Kelsey C, Garcia-Beltran, Wilfredo F, Yang, Diane, Astudillo, Michael G, Bernstein, Bradley E, Gelfand, Jeffrey A, Ryan, Edward T, Charles, Richelle C, Iafrate, A John, Lennerz, Jochen K, Miller, Steve, Chiu, Charles Y, Stramer, Susan L, Wilson, Michael R, Manglik, Aashish, Ye, Chun Jimmie, Krogan, Nevan J, Anderson, Mark S, Cyster, Jason G, Ernst, Joel D, Wu, Alan HB, Lynch, Kara L, Bern, Caryn, Hsu, Patrick D, and Marson, Alexander

Subjects
Biological Sciences, Biomedical and Clinical Sciences, Clinical Sciences, Emerging Infectious Diseases, Infectious Diseases, Coronaviruses, Clinical Research, Coronaviruses Diagnostics and Prognostics, 4.2 Evaluation of markers and technologies, Infection, Good Health and Well Being
Abstract

Background:Serological tests are crucial tools for assessments of SARS-CoV-2 exposure, infection and potential immunity. Their appropriate use and interpretation require accurate assay performance data. Method:We conducted an evaluation of 10 lateral flow assays (LFAs) and two ELISAs to detect anti-SARS-CoV-2 antibodies. The specimen set comprised 128 plasma or serum samples from 79 symptomatic SARS-CoV-2 RT-PCR-positive individuals; 108 pre-COVID-19 negative controls; and 52 recent samples from individuals who underwent respiratory viral testing but were not diagnosed with Coronavirus Disease 2019 (COVID-19). Samples were blinded and LFA results were interpreted by two independent readers, using a standardized intensity scoring system. Results:Among specimens from SARS-CoV-2 RT-PCR-positive individuals, the percent seropositive increased with time interval, peaking at 81.8-100.0% in samples taken >20 days after symptom onset. Test specificity ranged from 84.3-100.0% in pre-COVID-19 specimens. Specificity was higher when weak LFA bands were considered negative, but this decreased sensitivity. IgM detection was more variable than IgG, and detection was highest when IgM and IgG results were combined. Agreement between ELISAs and LFAs ranged from 75.7-94.8%. No consistent cross-reactivity was observed. Conclusion:Our evaluation showed heterogeneous assay performance. Reader training is key to reliable LFA performance, and can be tailored for survey goals. Informed use of serology will require evaluations covering the full spectrum of SARS-CoV-2 infections, from asymptomatic and mild infection to severe disease, and later convalescence. Well-designed studies to elucidate the mechanisms and serological correlates of protective immunity will be crucial to guide rational clinical and public health policies.

Published
2020

22. Mitochondrial variant enrichment from high-throughput single-cell RNA sequencing resolves clonal populations

Author

Miller, Tyler E., Lareau, Caleb A., Verga, Julia A., DePasquale, Erica A. K., Liu, Vincent, Ssozi, Daniel, Sandor, Katalin, Yin, Yajie, Ludwig, Leif S., El Farran, Chadi A., Morgan, Duncan M., Satpathy, Ansuman T., Griffin, Gabriel K., Lane, Andrew A., Love, J. Christopher, Bernstein, Bradley E., Sankaran, Vijay G., and van Galen, Peter

Published
2022
Full Text
View/download PDF

24. Single-cell RNA-seq reveals developmental plasticity with coexisting oncogenic states and immune evasion programs in ETP-ALL

Author

Anand, Praveen, Guillaumet-Adkins, Amy, Dimitrova, Valeriya, Yun, Huiyoung, Drier, Yotam, Sotudeh, Noori, Rogers, Anna, Ouseph, Madhu M., Nair, Monica, Potdar, Sayalee, Isenhart, Randi, Kloeber, Jake A., Vijaykumar, Tushara, Niu, Leili, Vincent, Tiffaney, Guo, Guangwu, Frede, Julia, Harris, Marian H., Place, Andrew E., Silverman, Lewis B., Teachey, David T., Lane, Andrew A., DeAngelo, Daniel J., Aster, Jon C., Bernstein, Bradley E., Lohr, Jens G., and Knoechel, Birgit

Published
2021
Full Text
View/download PDF

26. Epigenetic silencing by SETDB1 suppresses tumour intrinsic immunogenicity

Author

Griffin, Gabriel K., Wu, Jingyi, Iracheta-Vellve, Arvin, Patti, James C., Hsu, Jeffrey, Davis, Thomas, Dele-Oni, Deborah, Du, Peter P., Halawi, Aya G., Ishizuka, Jeffrey J., Kim, Sarah Y., Klaeger, Susan, Knudsen, Nelson H., Miller, Brian C., Nguyen, Tung H., Olander, Kira E., Papanastasiou, Malvina, Rachimi, Suzanna, Robitschek, Emily J., Schneider, Emily M., Yeary, Mitchell D., Zimmer, Margaret D., Jaffe, Jacob D., Carr, Steven A., Doench, John G., Haining, W. Nicholas, Yates, Kathleen B., Manguso, Robert T., and Bernstein, Bradley E.

Published
2021
Full Text
View/download PDF

33. An Integrative Model of Cellular States, Plasticity, and Genetics for Glioblastoma

Author

Neftel, Cyril, Laffy, Julie, Filbin, Mariella G., Hara, Toshiro, Shore, Marni E., Rahme, Gilbert J., Richman, Alyssa R., Silverbush, Dana, Shaw, McKenzie L., Hebert, Christine M., Dewitt, John, Gritsch, Simon, Perez, Elizabeth M., Gonzalez Castro, L. Nicolas, Lan, Xiaoyang, Druck, Nicholas, Rodman, Christopher, Dionne, Danielle, Kaplan, Alexander, Bertalan, Mia S., Small, Julia, Pelton, Kristine, Becker, Sarah, Bonal, Dennis, Nguyen, Quang-De, Servis, Rachel L., Fung, Jeremy M., Mylvaganam, Ravindra, Mayr, Lisa, Gojo, Johannes, Haberler, Christine, Geyeregger, Rene, Czech, Thomas, Slavc, Irene, Nahed, Brian V., Curry, William T., Carter, Bob S., Wakimoto, Hiroaki, Brastianos, Priscilla K., Batchelor, Tracy T., Stemmer-Rachamimov, Anat, Martinez-Lage, Maria, Frosch, Matthew P., Stamenkovic, Ivan, Riggi, Nicolo, Rheinbay, Esther, Monje, Michelle, Rozenblatt-Rosen, Orit, Cahill, Daniel P., Patel, Anoop P., Hunter, Tony, Verma, Inder M., Ligon, Keith L., Louis, David N., Regev, Aviv, Bernstein, Bradley E., Tirosh, Itay, and Suvà, Mario L.

Published
2019
Full Text
View/download PDF

34. Genetic and epigenetic fine mapping of causal autoimmune disease variants

Author

Farh, Kyle Kai-How, Marson, Alexander, Zhu, Jiang, Kleinewietfeld, Markus, Housley, William J, Beik, Samantha, Shoresh, Noam, Whitton, Holly, Ryan, Russell JH, Shishkin, Alexander A, Hatan, Meital, Carrasco-Alfonso, Marlene J, Mayer, Dita, Luckey, C John, Patsopoulos, Nikolaos A, De Jager, Philip L, Kuchroo, Vijay K, Epstein, Charles B, Daly, Mark J, Hafler, David A, and Bernstein, Bradley E

Subjects
Immunization, Human Genome, Vaccine Related, Autoimmune Disease, Genetics, 1.1 Normal biological development and functioning, 2.1 Biological and endogenous factors, Aetiology, Underpinning research, Inflammatory and immune system, Autoimmune Diseases, Base Sequence, Chromatin, Consensus Sequence, Enhancer Elements, Genetic, Epigenesis, Genetic, Epigenomics, Genome-Wide Association Study, Humans, Nucleotide Motifs, Organ Specificity, Polymorphism, Single Nucleotide, T-Lymphocytes, Transcription Factors, General Science & Technology
Abstract

Genome-wide association studies have identified loci underlying human diseases, but the causal nucleotide changes and mechanisms remain largely unknown. Here we developed a fine-mapping algorithm to identify candidate causal variants for 21 autoimmune diseases from genotyping data. We integrated these predictions with transcription and cis-regulatory element annotations, derived by mapping RNA and chromatin in primary immune cells, including resting and stimulated CD4(+) T-cell subsets, regulatory T cells, CD8(+) T cells, B cells, and monocytes. We find that ∼90% of causal variants are non-coding, with ∼60% mapping to immune-cell enhancers, many of which gain histone acetylation and transcribe enhancer-associated RNA upon immune stimulation. Causal variants tend to occur near binding sites for master regulators of immune differentiation and stimulus-dependent gene activation, but only 10-20% directly alter recognizable transcription factor binding motifs. Rather, most non-coding risk variants, including those that alter gene expression, affect non-canonical sequence determinants not well-explained by current gene regulatory models.

Published
2015

36. Alzheimer's disease: early alterations in brain DNA methylation at ANK1, BIN1, RHBDF2 and other loci

Author

De Jager, Philip L, Srivastava, Gyan, Lunnon, Katie, Burgess, Jeremy, Schalkwyk, Leonard C, Yu, Lei, Eaton, Matthew L, Keenan, Brendan T, Ernst, Jason, McCabe, Cristin, Tang, Anna, Raj, Towfique, Replogle, Joseph, Brodeur, Wendy, Gabriel, Stacey, Chai, High S, Younkin, Curtis, Younkin, Steven G, Zou, Fanggeng, Szyf, Moshe, Epstein, Charles B, Schneider, Julie A, Bernstein, Bradley E, Meissner, Alex, Ertekin-Taner, Nilufer, Chibnik, Lori B, Kellis, Manolis, Mill, Jonathan, and Bennett, David A

Subjects
Neurosciences, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Brain Disorders, Alzheimer's Disease, Human Genome, Genetics, Dementia, Neurodegenerative, Acquired Cognitive Impairment, Aging, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adaptor Proteins, Signal Transducing, Aged, Aged, 80 and over, Alzheimer Disease, Amyloidosis, Ankyrins, Brain, Carrier Proteins, CpG Islands, DNA Methylation, Female, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Intracellular Signaling Peptides and Proteins, Male, Middle Aged, Nuclear Proteins, Protein Interaction Maps, Tumor Suppressor Proteins, Psychology, Cognitive Sciences, Neurology & Neurosurgery
Abstract

We used a collection of 708 prospectively collected autopsied brains to assess the methylation state of the brain's DNA in relation to Alzheimer's disease (AD). We found that the level of methylation at 71 of the 415,848 interrogated CpGs was significantly associated with the burden of AD pathology, including CpGs in the ABCA7 and BIN1 regions, which harbor known AD susceptibility variants. We validated 11 of the differentially methylated regions in an independent set of 117 subjects. Furthermore, we functionally validated these CpG associations and identified the nearby genes whose RNA expression was altered in AD: ANK1, CDH23, DIP2A, RHBDF2, RPL13, SERPINF1 and SERPINF2. Our analyses suggest that these DNA methylation changes may have a role in the onset of AD given that we observed them in presymptomatic subjects and that six of the validated genes connect to a known AD susceptibility gene network.

Published
2014

37. Comparative analysis of metazoan chromatin organization

Author

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

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

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

Published
2014

38. Tissue-specific SMARCA4 binding at active and repressed regulatory elements during embryogenesis.

Author

Attanasio, Catia, Nord, Alex S, Zhu, Yiwen, Blow, Matthew J, Biddie, Simon C, Mendenhall, Eric M, Dixon, Jesse, Wright, Crystal, Hosseini, Roya, Akiyama, Jennifer A, Holt, Amy, Plajzer-Frick, Ingrid, Shoukry, Malak, Afzal, Veena, Ren, Bing, Bernstein, Bradley E, Rubin, Edward M, Visel, Axel, and Pennacchio, Len A

Subjects
Extremities, Myocardium, Heart, Brain, Chromatin, Animals, Mice, DNA Helicases, Nuclear Proteins, Histones, Transcription Factors, Organ Specificity, Gene Expression Regulation, Developmental, Protein Binding, Genome, Regulatory Elements, Transcriptional, Human Genome, Stem Cell Research, Genetics, Underpinning research, 1.1 Normal biological development and functioning, Generic health relevance, Biological Sciences, Medical and Health Sciences, Bioinformatics
Abstract

The SMARCA4 (also known as BRG1 in humans) chromatin remodeling factor is critical for establishing lineage-specific chromatin states during early mammalian development. However, the role of SMARCA4 in tissue-specific gene regulation during embryogenesis remains poorly defined. To investigate the genome-wide binding landscape of SMARCA4 in differentiating tissues, we engineered a Smarca4(FLAG) knock-in mouse line. Using ChIP-seq, we identified ∼51,000 SMARCA4-associated regions across six embryonic mouse tissues (forebrain, hindbrain, neural tube, heart, limb, and face) at mid-gestation (E11.5). The majority of these regions was distal from promoters and showed dynamic occupancy, with most distal SMARCA4 sites (73%) confined to a single or limited subset of tissues. To further characterize these regions, we profiled active and repressive histone marks in the same tissues and examined the intersection of informative chromatin states and SMARCA4 binding. This revealed distinct classes of distal SMARCA4-associated elements characterized by activating and repressive chromatin signatures that were associated with tissue-specific up- or down-regulation of gene expression and relevant active/repressed biological pathways. We further demonstrate the predicted active regulatory properties of SMARCA4-associated elements by retrospective analysis of tissue-specific enhancers and direct testing of SMARCA4-bound regions in transgenic mouse assays. Our results indicate a dual active/repressive function of SMARCA4 at distal regulatory sequences in vivo and support its role in tissue-specific gene regulation during embryonic development.

Published
2014

39. Single-Cell RNA-Seq Reveals AML Hierarchies Relevant to Disease Progression and Immunity

Author

van Galen, Peter, Hovestadt, Volker, Wadsworth II, Marc H., Hughes, Travis K., Griffin, Gabriel K., Battaglia, Sofia, Verga, Julia A., Stephansky, Jason, Pastika, Timothy J., Lombardi Story, Jennifer, Pinkus, Geraldine S., Pozdnyakova, Olga, Galinsky, Ilene, Stone, Richard M., Graubert, Timothy A., Shalek, Alex K., Aster, Jon C., Lane, Andrew A., and Bernstein, Bradley E.

Published
2019
Full Text
View/download PDF

40. An autoimmune transcriptional circuit drives FOXP3+ regulatory T cell dysfunction.

Author

Sumida, Tomokazu S., Lincoln, Matthew R., He, Liang, Park, Yongjin, Ota, Mineto, Oguchi, Akiko, Son, Raku, Yi, Alice, Stillwell, Helen A., Leissa, Greta A., Fujio, Keishi, Murakawa, Yasuhiro, Kulminski, Alexander M., Epstein, Charles B., Bernstein, Bradley E., Kellis, Manolis, and Hafler, David A.

Subjects
INTERFERON regulatory factors, REGULATORY T cells, ZINC-finger proteins, AP-1 transcription factor, CENTRAL nervous system diseases, TRANSCRIPTION factors
Abstract

Autoimmune diseases, among the most common disorders of young adults, are mediated by genetic and environmental factors. Although CD4+FOXP3+ regulatory T cells (Tregs) play a central role in preventing autoimmunity, the molecular mechanism underlying their dysfunction is unknown. Here, we performed comprehensive transcriptomic and epigenomic profiling of Tregs in the autoimmune disease multiple sclerosis (MS) to identify critical transcriptional programs regulating human autoimmunity. We found that up-regulation of a primate-specific short isoform of PR domain zinc finger protein 1 (PRDM1-S) induces expression of serum and glucocorticoid-regulated kinase 1 (SGK1) independent from the evolutionarily conserved long PRDM1, which led to destabilization of forkhead box P3 (FOXP3) and Treg dysfunction. This aberrant PRDM1-S/SGK1 axis is shared among other autoimmune diseases. Furthermore, the chromatin landscape profiling in Tregs from individuals with MS revealed enriched activating protein–1 (AP-1)/interferon regulatory factor (IRF) transcription factor binding as candidate upstream regulators of PRDM1-S expression and Treg dysfunction. Our study uncovers a mechanistic model where the evolutionary emergence of PRDM1-S and epigenetic priming of AP-1/IRF may be key drivers of dysfunctional Tregs in autoimmune diseases. Editor's summary: Regulatory T cells (Tregs) are known to be dysfunctional in autoimmune diseases, but the cause of this dysfunction has not been fully elucidated. Here, Sumida et al. found that Tregs isolated from individuals with multiple sclerosis, an autoimmune disease of the central nervous system, had increased expression of the short isoform of PR domain zinc finger protein 1 (PRDM1-S), which destabilized expression of the essential Treg transcription factor FOXP3 and induced Treg dysfunction mediated through SGK1, a salt-sensing kinase. Upstream epigenetic analysis revealed a regulatory role for AP-1 and IRF transcription factors in this circuit. The authors detected similar up-regulation of PRDM1-S in other autoimmune diseases, suggesting that PRDM1-S overexpression may be a common feature of Treg dysfunction. —Courtney Malo [ABSTRACT FROM AUTHOR]

Published
2024
Full Text
View/download PDF

41. Developmental and oncogenic programs in H3K27M gliomas dissected by single-cell RNA-seq

Author

Filbin, Mariella G., Tirosh, Itay, Hovestadt, Volker, Shaw, McKenzie L., Escalante, Leah E., Mathewson, Nathan D., Neftel, Cyril, Frank, Nelli, Pelton, Kristine, Hebert, Christine M., Haberler, Christine, Yizhak, Keren, Gojo, Johannes, Egervari, Kristof, Mount, Christopher, van Galen, Peter, Bonal, Dennis M., Nguyen, Quang-De, Beck, Alexander, Sinai, Claire, Czech, Thomas, Dorfer, Christian, Goumnerova, Liliana, Lavarino, Cinzia, Carcaboso, Angel M., Mora, Jaume, Mylvaganam, Ravindra, Luo, Christina C., Peyr, Andreas, Popović, Mara, Azizi, Amedeo, Batchelor, Tracy. T., Frosch, Matthew P., Martinez-Lage, Maria, Kieran, Mark W., Bandopadhayay, Pratiti, Beroukhim, Rameen, Fritsch, Gerhard, Getz, Gad, Rozenblatt-Rosen, Orit, Wucherpfennig, Kai W., Louis, David N., Monje, Michelle, Slavc, Irene, Ligon, Keith L., Golub, Todd R., Regev, Aviv, Bernstein, Bradley E., and Suvà, Mario L.

Published
2018

42. Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma

Author

McBrayer, Samuel K., Mayers, Jared R., DiNatale, Gabriel J., Shi, Diana D., Khanal, Januka, Chakraborty, Abhishek A., Sarosiek, Kristopher A., Briggs, Kimberly J., Robbins, Alissa K., Sewastianik, Tomasz, Shareef, Sarah J., Olenchock, Benjamin A., Parker, Seth J., Tateishi, Kensuke, Spinelli, Jessica B., Islam, Mirazul, Haigis, Marcia C., Looper, Ryan E., Ligon, Keith L., Bernstein, Bradley E., Carrasco, Ruben D., Cahill, Daniel P., Asara, John M., Metallo, Christian M., Yennawar, Neela H., Vander Heiden, Matthew G., and Kaelin, William G., Jr.

Published
2018
Full Text
View/download PDF

44. Inducible histone K-to-M mutations are dynamic tools to probe the physiological role of site-specific histone methylation in vitro and in vivo

Author

Brumbaugh, Justin, Kim, Ik Soo, Ji, Fei, Huebner, Aaron J., Di Stefano, Bruno, Schwarz, Benjamin A., Charlton, Jocelyn, Coffey, Amy, Choi, Jiho, Walsh, Ryan M., Schindler, Jeffrey W., Anselmo, Anthony, Meissner, Alexander, Sadreyev, Ruslan I., Bernstein, Bradley E., Hock, Hanno, and Hochedlinger, Konrad

Published
2019
Full Text
View/download PDF

47. Enhancer signatures stratify and predict outcomes of non-functional pancreatic neuroendocrine tumors

Author

Cejas, Paloma, Drier, Yotam, Dreijerink, Koen M. A., Brosens, Lodewijk A. A., Deshpande, Vikram, Epstein, Charles B., Conemans, Elfi B., Morsink, Folkert H. M., Graham, Mindy K., Valk, Gerlof D., Vriens, Menno R., Castillo, Carlos Fernandez-del, Ferrone, Cristina R., Adar, Tomer, Bowden, Michaela, Whitton, Holly J., Da Silva, Annacarolina, Font-Tello, Alba, Long, Henry W., Gaskell, Elizabeth, Shoresh, Noam, Heaphy, Christopher M., Sicinska, Ewa, Kulke, Matthew H., Chung, Daniel C., Bernstein, Bradley E., and Shivdasani, Ramesh A.

Published
2019
Full Text
View/download PDF

48. Dual Targeting of Oncogenic Activation and Inflammatory Signaling Increases Therapeutic Efficacy in Myeloproliferative Neoplasms

Author

Kleppe, Maria, Koche, Richard, Zou, Lihua, van Galen, Peter, Hill, Corinne E., Dong, Lauren, De Groote, Sofie, Papalexi, Efthymia, Hanasoge Somasundara, Amritha V., Cordner, Keith, Keller, Matthew, Farnoud, Noushin, Medina, Juan, McGovern, Erin, Reyes, Jaime, Roberts, Justin, Witkin, Matthew, Rapaport, Franck, Teruya-Feldstein, Julie, Qi, Jun, Rampal, Raajit, Bernstein, Bradley E., Bradner, James E., and Levine, Ross L.

Published
2018
Full Text
View/download PDF

49. Mapping and analysis of chromatin state dynamics in nine human cell types

Author

Ernst, Jason, Kheradpour, Pouya, Mikkelsen, Tarjei S, Shoresh, Noam, Ward, Lucas D, Epstein, Charles B, Zhang, Xiaolan, Wang, Li, Issner, Robbyn, Coyne, Michael, Ku, Manching, Durham, Timothy, Kellis, Manolis, and Bernstein, Bradley E

Subjects
Genetics, Biotechnology, Cancer, Human Genome, 2.1 Biological and endogenous factors, Aetiology, Binding Sites, Cell Line, Cell Line, Tumor, Cell Physiological Phenomena, Cells, Cultured, Chromatin, Chromosome Mapping, Gene Expression Regulation, Genome, Human, Hep G2 Cells, Humans, Promoter Regions, Genetic, Reproducibility of Results, Transcription Factors, General Science & Technology
Abstract

Chromatin profiling has emerged as a powerful means of genome annotation and detection of regulatory activity. The approach is especially well suited to the characterization of non-coding portions of the genome, which critically contribute to cellular phenotypes yet remain largely uncharted. Here we map nine chromatin marks across nine cell types to systematically characterize regulatory elements, their cell-type specificities and their functional interactions. Focusing on cell-type-specific patterns of promoters and enhancers, we define multicell activity profiles for chromatin state, gene expression, regulatory motif enrichment and regulator expression. We use correlations between these profiles to link enhancers to putative target genes, and predict the cell-type-specific activators and repressors that modulate them. The resulting annotations and regulatory predictions have implications for the interpretation of genome-wide association studies. Top-scoring disease single nucleotide polymorphisms are frequently positioned within enhancer elements specifically active in relevant cell types, and in some cases affect a motif instance for a predicted regulator, thus suggesting a mechanism for the association. Our study presents a general framework for deciphering cis-regulatory connections and their roles in disease.

Published
2011

50. Comparison of sequencing-based methods to profile DNA methylation and identification of monoallelic epigenetic modifications

Author

Harris, R Alan, Wang, Ting, Coarfa, Cristian, Nagarajan, Raman P, Hong, Chibo, Downey, Sara L, Johnson, Brett E, Fouse, Shaun D, Delaney, Allen, Zhao, Yongjun, Olshen, Adam, Ballinger, Tracy, Zhou, Xin, Forsberg, Kevin J, Gu, Junchen, Echipare, Lorigail, O'Geen, Henriette, Lister, Ryan, Pelizzola, Mattia, Xi, Yuanxin, Epstein, Charles B, Bernstein, Bradley E, Hawkins, R David, Ren, Bing, Chung, Wen-Yu, Gu, Hongcang, Bock, Christoph, Gnirke, Andreas, Zhang, Michael Q, Haussler, David, Ecker, Joseph R, Li, Wei, Farnham, Peggy J, Waterland, Robert A, Meissner, Alexander, Marra, Marco A, Hirst, Martin, Milosavljevic, Aleksandar, and Costello, Joseph F

Subjects
Biological Sciences, Genetics, Human Genome, Cancer, Alleles, Cell Line, CpG Islands, Cytosine, DNA Methylation, Embryonic Stem Cells, Epigenesis, Genetic, Gene Expression Regulation, Humans, Sequence Analysis, DNA, Sulfites
Abstract

Analysis of DNA methylation patterns relies increasingly on sequencing-based profiling methods. The four most frequently used sequencing-based technologies are the bisulfite-based methods MethylC-seq and reduced representation bisulfite sequencing (RRBS), and the enrichment-based techniques methylated DNA immunoprecipitation sequencing (MeDIP-seq) and methylated DNA binding domain sequencing (MBD-seq). We applied all four methods to biological replicates of human embryonic stem cells to assess their genome-wide CpG coverage, resolution, cost, concordance and the influence of CpG density and genomic context. The methylation levels assessed by the two bisulfite methods were concordant (their difference did not exceed a given threshold) for 82% for CpGs and 99% of the non-CpG cytosines. Using binary methylation calls, the two enrichment methods were 99% concordant and regions assessed by all four methods were 97% concordant. We combined MeDIP-seq with methylation-sensitive restriction enzyme (MRE-seq) sequencing for comprehensive methylome coverage at lower cost. This, along with RNA-seq and ChIP-seq of the ES cells enabled us to detect regions with allele-specific epigenetic states, identifying most known imprinted regions and new loci with monoallelic epigenetic marks and monoallelic expression.

Published
2010

Catalog

Books, media, physical & digital resources
See catalog results