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4. Combined Pre-Supernova Alert System with Kamland and Super-Kamiokande

Author

KamLAND, Collaborations, Super-Kamiokande, Abe, Seisho, Eizuka, Minori, Futagi, Sawako, Gando, Azusa, Gando, Yoshihito, Goto, Shun, Hachiya, Takahiko, Hata, Kazumi, Ichimura, Koichi, Ieki, Sei, Ikeda, Haruo, Inoue, Kunio, Ishidoshiro, Koji, Kamei, Yuto, Kawada, Nanami, Kishimoto, Yasuhiro, Koga, Masayuki, Kurasawa, Maho, Mitsui, Tadao, Miyake, Haruhiko, Morita, Daisuke, Nakahata, Takeshi, Nakajima, Rika, Nakamura, Kengo, Nakamura, Rikuo, Nakamura, Ryo, Nakane, Jun, Ozaki, Hideyoshi, Saito, Keita, Sakai, Taichi, Shimizu, Itaru, Shirai, Junpei, Shiraishi, Kensuke, Shoji, Ryunosuke, Suzuki, Atsuto, Takeuchi, Atsuto, Tamae, Kyoko, Watanabe, Hiroko, Watanabe, Kazuho, Yoshida, Sei, Umehara, Saori, Fushimi, Ken-Ichi, Kotera, Kenta, Urano, Yusuke, Berger, Bruce E., Fujikawa, Brian K., Larned, John G., Maricic, Jelena, Fu, Zhenghao, Smolsky, Joseph, Winslow, Lindley A., Efremenko, Yuri, Karwowski, Hugon J., Markoff, Diane M., Tornow, Werner, Dell'Oro, Stefano, O'Donnell, Thomas, Detwiler, Jason A., Enomoto, Sanshiro, Decowski, Michal P., Weerman, Kelly M., Grant, Christopher, Song, Hasung, Li, Aobo, Axani, Spencer N., Garcia, Miles, Abe, Ko, Bronner, Christophe, Hayato, Yoshinari, Hiraide, Katsuki, Hosokawa, Keishi, Ieki, Kei, Ikeda, Motoyasu, Kameda, June, Kanemura, Yuki, Kaneshima, Ryota, Kashiwagi, Yuri, Kataoka, Yousuke, Miki, Shintaro, Mine, Shunichi, Miura, Makoto, Moriyama, Shigetaka, Nakahata, Masayuki, Nakano, Yuuki, Nakayama, Shoei, Noguchi, Yohei, Sato, Kazufumi, Sekiya, Hiroyuki, Shiba, Hayato, Shimizu, Kotaro, Shiozawa, Masato, Sonoda, Yutaro, Suzuki, Yoichiro, Takeda, Atsushi, Takemoto, Yasuhiro, Tanaka, Hidekazu K., Yano, Takatomi, Han, Seungho, Kajita, Takaaki, Okumura, Kimihiro, Tashiro, Takuya, Tomiya, Takuya, Wang, Xubin, Yoshida, Shunsuke, Fernandez, Pablo, Labarga, Luis, Ospina, Nataly, Zaldivar, Bryan, Pointon, Barry W., Kearns, Edward, Raaf, Jennifer L., Wan, Linyan, Wester, Thomas, Bian, Jianming, Griskevich, Jeff, Smy, Michael B., Sobel, Henry W., Takhistov, Volodymyr, Yankelevich, Alejandro, Hill, James, Jang, MinCheol, Lee, Seonghak, Moon, DongHo, Park, RyeongGyoon, Bodur, Baran, Scholberg, Kate, Walter, Chris W., Beauchêne, Antoine, Drapier, Olivier, Giampaolo, Alberto, Mueller, Thomas A., Santos, Andrew D., Paganini, Pascal, Quilain, Benjamin, Rogly, Rudolph, Nakamura, Taku, Jang, Jee-Seung, Machado, Lucas N., Learned, John G., Choi, Koun, Iovine, Nadege, Cao, Son V., Anthony, Lauren H. V., Martin, Daniel G. R., Prouse, Nick W., Scott, Mark, Uchida, Yoshi, Berardi, Vincenzo, Calabria, Nicola F., Catanesi, M. G., Radicioni, Emilio, Langella, Aurora, de Rosa, Gianfranca, Collazuol, Gianmaria, Feltre, Matteo, Iacob, Fabio, Mattiazzi, Marco, Ludovici, Lucio, Gonin, Michel, Périssé, Lorenzo, Pronost, Guillaume, Fujisawa, Chiori, Horiuchi, Shogo, Kobayashi, Misaki, Liu, Yu-Ming, Maekawa, Yuto, Nishimura, Yasuhiro, Okazaki, Reo, Akutsu, Ryosuke, Friend, Megan, Hasegawa, Takuya, Ishida, Taku, Kobayashi, Takashi, Jakkapu, Mahesh, Matsubara, Tsunayuki, Nakadaira, Takeshi, Nakamura, Kenzo, Oyama, Yuichi, Sakashita, Ken, Sekiguchi, Tetsuro, Tsukamoto, Toshifumi, Yrey, Antoniosk Portocarrero, Bhuiyan, Nahid, Burton, George T., Di Lodovico, Francesca, Gao, Joanna, Goldsack, Alexander, Katori, Teppei, Migenda, Jost, Ramsden, Rory M., Xie, Zhenxiong, Zsoldos, Stephane, Suzuki, Atsumu T., Takagi, Yusuke, Takeuchi, Yasuo, Zhong, Haiwen, Feng, Jiahui, Feng, Li-Cheng, Hu, Jianrun, Hu, Zhuojun, Kawaue, Masaki, Kikawa, Tatsuya, Mori, Masamitsu, Nakaya, Tsuyoshi, Wendell, Roger A., Yasutome, Kenji, Jenkins, Sam J., McCauley, Neil K., Mehta, Pruthvi, Tarrant, Adam, Wilking, Mike J., Fukuda, Yoshiyuki, Itow, Yoshitaka, Menjo, Hiroaki, Ninomiya, Kotaro, Yoshioka, Yushi, Lagoda, Justyna, Mandal, Maitrayee, Mijakowski, Piotr, Prabhu, Yashwanth S., Zalipska, Joanna, Jia, Mo, Jiang, Junjie, Shi, Wei, Yanagisawa, Chiaki, Harada, Masayuki, Hino, Yota, Ishino, Hirokazu, Koshio, Yusuke, Nakanishi, Fumi, Sakai, Seiya, Tada, Tomoaki, Tano, Tomohiro, Ishizuka, Takeharu, Barr, Giles, Barrow, Daniel, Cook, Laurence, Samani, Soniya, Wark, David, Holin, Anna, Nova, Federico, Jung, Seunghyun, Yang, Byeongsu, Yang, JeongYeol, Yoo, Jonghee, Fannon, Jack E. P., Kneale, Liz, Malek, Matthew, McElwee, Jordan M., Thiesse, Matthew D., Thompson, Lee F., Wilson, Stephen T., Okazawa, Hiroko, Mohan, Lakshmi S., Kim, SooBong, Kwon, Eunhyang, Seo, Ji-Woong, Yu, Intae, Ichikawa, Atsuko K., Nakamura, Kiseki D., Tairafune, Seidai, Nishijima, Kyoshi, Eguchi, Aoi, Nakagiri, Kota, Nakajima, Yasuhiro, Shima, Shizuka, Taniuchi, Natsumi, Watanabe, Eiichiro, Yokoyama, Masashi, de Perio, Patrick, Fujita, Saki, Jesus-Valls, Cesar, Martens, Kai, Tsui, Ka M., Vagins, Mark R., Xia, Junjie, Izumiyama, Shota, Kuze, Masahiro, Matsumoto, Ryo, Terada, Kotaro, Asaka, Ryusei, Ishitsuka, Masaki, Ito, Hiroshi, Ommura, Yuga, Shigeta, Natsuki, Shinoki, Masataka, Yamauchi, Koki, Yoshida, Tsukasa, Gaur, Rhea, Gousy-Leblan, Vincent, Hartz, Mark, Konaka, Akira, Li, Xiaoyue, Chen, Shaomin, Xu, Benda, Zhang, Aiqiang, Zhang, Bin, Posiadala-Zezula, Magdalena, Boyd, Steven B., Edwards, Rory, Hadley, David, Nicholson, Matthew, O'Flaherty, Marcus, Richards, Benjamin, Ali, Ajmi, Jamieson, Blair, Amanai, Shogo, Marti-Magro, Lluis, Minamino, Akihiro, Shibayama, Ryo, and Suzuki, Serina

Subjects
High Energy Physics - Experiment, Astrophysics - High Energy Astrophysical Phenomena, Physics - Instrumentation and Detectors
Abstract

Preceding a core-collapse supernova, various processes produce an increasing amount of neutrinos of all flavors characterized by mounting energies from the interior of massive stars. Among them, the electron antineutrinos are potentially detectable by terrestrial neutrino experiments such as KamLAND and Super-Kamiokande via inverse beta decay interactions. Once these pre-supernova neutrinos are observed, an early warning of the upcoming core-collapse supernova can be provided. In light of this, KamLAND and Super-Kamiokande, both located in the Kamioka mine in Japan, have been monitoring pre-supernova neutrinos since 2015 and 2021, respectively. Recently, we performed a joint study between KamLAND and Super-Kamiokande on pre-supernova neutrino detection. A pre-supernova alert system combining the KamLAND detector and the Super-Kamiokande detector was developed and put into operation, which can provide a supernova alert to the astrophysics community. Fully leveraging the complementary properties of these two detectors, the combined alert is expected to resolve a pre-supernova neutrino signal from a 15 M$_{\odot}$ star within 510 pc of the Earth, at a significance level corresponding to a false alarm rate of no more than 1 per century. For a Betelgeuse-like model with optimistic parameters, it can provide early warnings up to 12 hours in advance., Comment: Resubmitted to ApJ. 22 pages, 16 figures, for more information about the combined pre-supernova alert system, see https://www.lowbg.org/presnalarm/

Published
2024
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5. Integrative multi-omics analyses to identify the genetic and functional mechanisms underlying ovarian cancer risk regions.

Author

Dareng, Eileen, Coetzee, Simon, Tyrer, Jonathan, Peng, Pei-Chen, Rosenow, Will, Chen, Stephanie, Davis, Brian, Dezem, Felipe, Seo, Ji-Heui, Nameki, Robbin, Reyes, Alberto, Aben, Katja, Anton-Culver, Hoda, Antonenkova, Natalia, Aravantinos, Gerasimos, Bandera, Elisa, Beane Freeman, Laura, Beckmann, Matthias, Beeghly-Fadiel, Alicia, Benitez, Javier, Bernardini, Marcus, Bjorge, Line, Black, Amanda, Bogdanova, Natalia, Bolton, Kelly, Brenton, James, Budzilowska, Agnieszka, Butzow, Ralf, Cai, Hui, Campbell, Ian, Cannioto, Rikki, Chang-Claude, Jenny, Chanock, Stephen, Chen, Kexin, Chenevix-Trench, Georgia, Chiew, Yoke-Eng, Cook, Linda, DeFazio, Anna, Dennis, Joe, Doherty, Jennifer, Dörk, Thilo, du Bois, Andreas, Dürst, Matthias, Eccles, Diana, Ene, Gabrielle, Fasching, Peter, Flanagan, James, Fortner, Renée, Fostira, Florentia, Gentry-Maharaj, Aleksandra, Giles, Graham, Goodman, Marc, Gronwald, Jacek, Haiman, Christopher, Håkansson, Niclas, Heitz, Florian, Hildebrandt, Michelle, Høgdall, Estrid, Høgdall, Claus, Huang, Ruea-Yea, Jensen, Allan, Jones, Michael, Kang, Daehee, Karlan, Beth, Karnezis, Anthony, Kelemen, Linda, Kennedy, Catherine, Khusnutdinova, Elza, Kiemeney, Lambertus, Kjaer, Susanne, Kupryjanczyk, Jolanta, Labrie, Marilyne, Lambrechts, Diether, Larson, Melissa, Le, Nhu, Lester, Jenny, Li, Lian, Lubiński, Jan, Lush, Michael, Marks, Jeffrey, Matsuo, Keitaro, May, Taymaa, McLaughlin, John, McNeish, Iain, Menon, Usha, Missmer, Stacey, Modugno, Francesmary, Moffitt, Melissa, Monteiro, Alvaro, Moysich, Kirsten, Narod, Steven, Nguyen-Dumont, Tu, Odunsi, Kunle, Olsson, Håkan, Onland-Moret, N, Park, Sue, Pejovic, Tanja, Permuth, Jennifer, Piskorz, Anna, and Prokofyeva, Darya

Subjects
GWAS, epithelial ovarian cancer risk, fine mapping, functional mechanisms, Humans, Female, Genome-Wide Association Study, Polymorphism, Single Nucleotide, Ovarian Neoplasms, Genetic Predisposition to Disease, Carcinoma, Ovarian Epithelial, Transcriptome, Risk Factors, Genomics, Case-Control Studies, Multiomics
Abstract

To identify credible causal risk variants (CCVs) associated with different histotypes of epithelial ovarian cancer (EOC), we performed genome-wide association analysis for 470,825 genotyped and 10,163,797 imputed SNPs in 25,981 EOC cases and 105,724 controls of European origin. We identified five histotype-specific EOC risk regions (p value

Published
2024

14. Evaluation of left ventricular filling pressure by echocardiography in patients with atrial fibrillation

Author

Khan, Faraz H., Zhao, Debbie, Ha, Jong-Won, Nagueh, Sherif F., Voigt, Jens-Uwe, Klein, Allan L., Gude, Einar, Broch, Kaspar, Chan, Nicholas, Quill, Gina M., Doughty, Robert N., Young, Alistair, Seo, Ji-Won, García-Izquierdo, Eusebio, Moñivas-Palomero, Vanessa, Mingo-Santos, Susana, Wang, Tom Kai Ming, Bezy, Stephanie, Ohte, Nobuyuki, Skulstad, Helge, Beladan, Carmen C., Popescu, Bogdan A., Kikuchi, Shohei, Panis, Vasileios, Donal, Erwan, Remme, Espen W., Nash, Martyn P., and Smiseth, Otto A.

Published
2024
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18. Nuclear RNA catabolism controls endogenous retroviruses, gene expression asymmetry, and dedifferentiation.

Author

Torre, Denis, Fstkchyan, Yesai, Ho, Jessica, Cheon, Youngseo, Patel, Roosheel, Degrace, Emma, Mzoughi, Slim, Schwarz, Megan, Mohammed, Kevin, Seo, Ji-Seon, Romero-Bueno, Raquel, Demircioglu, Deniz, Hasson, Dan, Tang, Weijing, Mahajani, Sameehan, Campisi, Laura, Zheng, Simin, Song, Won-Suk, Wang, Ying-Chih, Shah, Hardik, Francoeur, Nancy, Soto, Juan, Salfati, Zelda, Weirauch, Matthew, Warburton, Peter, Beaumont, Kristin, Smith, Melissa, Mulder, Lubbertus, Jang, Cholsoon, Lee, Daeyoup, De Rubeis, Silvia, Cobos, Inma, Tam, Oliver, Hammell, Molly, Seldin, Marcus, Sebra, Robert, Rosenberg, Brad, Benner, Chris, Guccione, Ernesto, Basu, Uttiya, Sebastiano, Vittorio, Shi, Yongsheng, Kessenbrock, Kai, Villalta, Sergio, Marazzi, Ivan, and Byun, Minji

Subjects
2CLC, Integrator, MERVL, RNA catabolism, elongation, endogenous retrovirus, non-coding RNA, stem cell, totipotent-like cells, transcription-associated RNA degradation, Endogenous Retroviruses, RNA, Nuclear, Epigenesis, Genetic, Heterochromatin, Gene Expression
Abstract

Endogenous retroviruses (ERVs) are remnants of ancient parasitic infections and comprise sizable portions of most genomes. Although epigenetic mechanisms silence most ERVs by generating a repressive environment that prevents their expression (heterochromatin), little is known about mechanisms silencing ERVs residing in open regions of the genome (euchromatin). This is particularly important during embryonic development, where induction and repression of distinct classes of ERVs occur in short temporal windows. Here, we demonstrate that transcription-associated RNA degradation by the nuclear RNA exosome and Integrator is a regulatory mechanism that controls the productive transcription of most genes and many ERVs involved in preimplantation development. Disrupting nuclear RNA catabolism promotes dedifferentiation to a totipotent-like state characterized by defects in RNAPII elongation and decreased expression of long genes (gene-length asymmetry). Our results indicate that RNA catabolism is a core regulatory module of gene networks that safeguards RNAPII activity, ERV expression, cell identity, and developmental potency.

Published
2023

21. Toll-like receptor 2-mediated ERK activation significantly upregulates interleukin-6 expression in M2-polarized macrophages

Author

Jo Wol Soon, Kim Sung Dae, Jeong Soo Kyung, Oh Su Jung, Baik Ji Sue, Seo Ji An, Baek Jeong-Hwa, Lee Chang Geun, Kang Young-Rok, Jeong Min Ho, and Park Moon-Taek

Subjects
tlr2, il-6, erk, m2 macrophage, Biochemistry, QD415-436
Abstract

M2-polarized macrophages and interleukin (IL)-6 significantly alter the tumor microenvironment and promote the malignant behaviors of tumor cells. This study aimed to establish M2-type macrophages from THP-1 cells, which are human leukemia monocytes, and investigate the significance of toll-like receptor 2 (TLR2) signaling in IL-6 production.

Published
2024
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22. College Students' Preferences on Principles for the Effective Instructional Video Design for Online General English Classes in Korea

Author

Seo, Ji-Young

Abstract

The present study investigates the preferences of students regarding the principles for the effective design of instructional videos to identify factors that influence engagement. A questionnaire was distributed to 232 students enrolled in online liberal arts classes at a private university in South Korea. Frequency analysis was conducted to determine preferences, whereas an independent sample t-test and one-way analysis of variance were administered to verify any differences in preferences according to gender and grade. The findings are as follows. First, out of the 12 principles that should be considered in the design of instructional videos, the students most preferred the review quiz principle. Moreover, this factor was found to exert the greatest influence on engagement. Second, incorporating real-life situation principles into instructional videos also had a significant impact on engagement. Third, female students expressed higher levels of preference than did male students in terms of the preview, course content on screen, and review quiz principles. Fourth, sophomores preferred the review quiz principle more than the freshmen did. The results of the present study are in line with those of previous research in that the effective instructional design of multimedia lessons requires reducing extraneous processing, managing essential processing, and fostering generative processing. Particularly, the study found that Korean students value video lectures with generative activities for meaningful learning. Based on the findings of the study, pedagogical considerations of the design of recorded lectures and its structure for active engagement, and suggestions for future studies are provided.

Published
2022

23. Generation of host-directed and virus-specific antivirals using targeted protein degradation promoted by small molecules and viral RNA mimics.

Author

Zhao, Nan, Ho, Jessica, Meng, Fanye, Zheng, Simin, Kurland, Andrew, Tian, Lu, Rea-Moreno, Martha, Song, Xiangyang, Seo, Ji-Seon, Kaniskan, H, Te Velthuis, Aartjan, Tortorella, Domenico, Chen, Ya-Wen, Johnson, Jeffrey, Jin, Jian, and Marazzi, Ivan

Subjects
CMV, GSPT1, PROTAC, SARS-CoV-2, antiviral therapeutics, influenza virus, oligonucleotide, small molecule, Humans, Antiviral Agents, Proteolysis, RNA, Viral, Ligands, Viruses, Ubiquitin-Protein Ligases, Viral Proteins, Carrier Proteins
Abstract

Targeted protein degradation (TPD), as exemplified by proteolysis-targeting chimera (PROTAC), is an emerging drug discovery platform. PROTAC molecules, which typically contain a target protein ligand linked to an E3 ligase ligand, recruit a target protein to the E3 ligase to induce its ubiquitination and degradation. Here, we applied PROTAC approaches to develop broad-spectrum antivirals targeting key host factors for many viruses and virus-specific antivirals targeting unique viral proteins. For host-directed antivirals, we identified a small-molecule degrader, FM-74-103, that elicits selective degradation of human GSPT1, a translation termination factor. FM-74-103-mediated GSPT1 degradation inhibits both RNA and DNA viruses. Among virus-specific antivirals, we developed viral RNA oligonucleotide-based bifunctional molecules (Destroyers). As a proof of principle, RNA mimics of viral promoter sequences were used as heterobifunctional molecules to recruit and target influenza viral polymerase for degradation. This work highlights the broad utility of TPD to rationally design and develop next-generation antivirals.

Published
2023

27. Computational Thinking Education Model Through Play-Type Software Teaching and Learning Model

Author

Joo, Kil Hong, Seo, Ji-Hoon, Park, Nam Hun, Angrisani, Leopoldo, Series Editor, Arteaga, Marco, Series Editor, Chakraborty, Samarjit, Series Editor, Chen, Shanben, Series Editor, Chen, Tan Kay, Series Editor, Dillmann, Rüdiger, Series Editor, Duan, Haibin, Series Editor, Ferrari, Gianluigi, Series Editor, Ferre, Manuel, Series Editor, Hirche, Sandra, Series Editor, Jabbari, Faryar, Series Editor, Jia, Limin, Series Editor, Kacprzyk, Janusz, Series Editor, Khamis, Alaa, Series Editor, Kroeger, Torsten, Series Editor, Li, Yong, Series Editor, Liang, Qilian, Series Editor, Martín, Ferran, Series Editor, Ming, Tan Cher, Series Editor, Minker, Wolfgang, Series Editor, Misra, Pradeep, Series Editor, Mukhopadhyay, Subhas, Series Editor, Ning, Cun-Zheng, Series Editor, Nishida, Toyoaki, Series Editor, Oneto, Luca, Series Editor, Panigrahi, Bijaya Ketan, Series Editor, Pascucci, Federica, Series Editor, Qin, Yong, Series Editor, Seng, Gan Woon, Series Editor, Speidel, Joachim, Series Editor, Veiga, Germano, Series Editor, Wu, Haitao, Series Editor, Zamboni, Walter, Series Editor, Tan, Kay Chen, Series Editor, Park, Ji Su, editor, Yang, Laurence T., editor, Pan, Yi, editor, and Park, James J., editor

Published
2024
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28. Comparative Analysis of Machine Learning Models for Menu Recommendation System

Author

Kim, Aleksandr, Seo, Ji-Yun, Jung, Sang-Joong, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Choi, Bong Jun, editor, Singh, Dhananjay, editor, Tiwary, Uma Shanker, editor, and Chung, Wan-Young, editor

Published
2024
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29. Development of LSTM-Based Sentence Generation Model to Improve Recognition Performance of OCR System

Author

Kim, Jae-Jung, Seo, Ji-Yun, Noh, Yun-Hong, Jung, Sang-Joong, Jeong, Do-Un, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Choi, Bong Jun, editor, Singh, Dhananjay, editor, Tiwary, Uma Shanker, editor, and Chung, Wan-Young, editor

Published
2024
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30. Development of IMU Sensor-Based XGBoost Model for Patients with Elbow Joint Damage

Author

Kim, Jae-Jung, Seo, Ji-Yun, Noh, Yun-Hong, Jung, Sang-Joong, Jeong, Do-Un, Goos, Gerhard, Founding Editor, Hartmanis, Juris, Founding Editor, Bertino, Elisa, Editorial Board Member, Gao, Wen, Editorial Board Member, Steffen, Bernhard, Editorial Board Member, Yung, Moti, Editorial Board Member, Choi, Bong Jun, editor, Singh, Dhananjay, editor, Tiwary, Uma Shanker, editor, and Chung, Wan-Young, editor

Published
2024
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32. Increased nuclear factor I-mediated chromatin access drives transition to androgen receptor splice variant dependence in prostate cancer

Author

Poluben, Larysa, Nouri, Mannan, Liang, Jiaqian, Chen, Shaoyong, Varkaris, Andreas, Ersoy-Fazlioglu, Betul, Voznesensky, Olga, Lee, Irene I., Qiu, Xintao, Cato, Laura, Seo, Ji-Heui, Freedman, Matthew L., Sowalsky, Adam G., Lack, Nathan A., Corey, Eva, Nelson, Peter S., Brown, Myles, Long, Henry W., Russo, Joshua W., and Balk, Steven P.

Published
2025
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39. Extensive androgen receptor enhancer heterogeneity in primary prostate cancers underlies transcriptional diversity and metastatic potential.

Author

Kneppers, Jeroen, Severson, Tesa, Siefert, Joseph, Schol, Pieter, Joosten, Stacey, Yu, Ivan, Huang, Chia-Chi, Morova, Tunç, Altıntaş, Umut, Giambartolomei, Claudia, Seo, Ji-Heui, Baca, Sylvan, Carneiro, Isa, Emberly, Eldon, Pasaniuc, Bogdan, Jerónimo, Carmen, Henrique, Rui, Freedman, Matthew, Wessels, Lodewyk, Lack, Nathan, Bergman, Andries, and Zwart, Wilbert

Subjects
Male, Humans, Receptors, Androgen, Regulatory Sequences, Nucleic Acid, Prostatic Neoplasms, Prostate, Chromatin
Abstract

Androgen receptor (AR) drives prostate cancer (PCa) development and progression. AR chromatin binding profiles are highly plastic and form recurrent programmatic changes that differentiate disease stages, subtypes and patient outcomes. While prior studies focused on concordance between patient subgroups, inter-tumor heterogeneity of AR enhancer selectivity remains unexplored. Here we report high levels of AR chromatin binding heterogeneity in human primary prostate tumors, that overlap with heterogeneity observed in healthy prostate epithelium. Such heterogeneity has functional consequences, as somatic mutations converge on commonly-shared AR sites in primary over metastatic tissues. In contrast, less-frequently shared AR sites associate strongly with AR-driven gene expression, while such heterogeneous AR enhancer usage also distinguishes patients outcome. These findings indicate that epigenetic heterogeneity in primary disease is directly informative for risk of biochemical relapse. Cumulatively, our results illustrate a high level of AR enhancer heterogeneity in primary PCa driving differential expression and clinical impact.

Published
2022

40. Drug-Induced Epigenomic Plasticity Reprograms Circadian Rhythm Regulation to Drive Prostate Cancer toward Androgen Independence.

Author

Linder, Simon, Hoogstraat, Marlous, Stelloo, Suzan, Eickhoff, Nils, Schuurman, Karianne, de Barros, Hilda, Alkemade, Maartje, Bekers, Elise M, Severson, Tesa M, Sanders, Joyce, Huang, Chia-Chi Flora, Morova, Tunc, Altintas, Umut Berkay, Hoekman, Liesbeth, Kim, Yongsoo, Baca, Sylvan C, Sjöström, Martin, Zaalberg, Anniek, Hintzen, Dorine C, de Jong, Jeroen, Kluin, Roelof JC, de Rink, Iris, Giambartolomei, Claudia, Seo, Ji-Heui, Pasaniuc, Bogdan, Altelaar, Maarten, Medema, René H, Feng, Felix Y, Zoubeidi, Amina, Freedman, Matthew L, Wessels, Lodewyk FA, Butler, Lisa M, Lack, Nathan A, van der Poel, Henk, Bergman, Andries M, and Zwart, Wilbert

Subjects
Biomedical and Clinical Sciences, Clinical Sciences, Oncology and Carcinogenesis, Prostate Cancer, Aging, Urologic Diseases, Biotechnology, Cancer, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 2.1 Biological and endogenous factors, Aetiology, ARNTL Transcription Factors, Androgens, Cell Line, Tumor, Circadian Rhythm, Drug Resistance, Neoplasm, Epigenomics, Humans, Male, Nitriles, Prostatic Neoplasms, Castration-Resistant, Receptors, Androgen, Biochemistry and cell biology, Oncology and carcinogenesis
Abstract

In prostate cancer, androgen receptor (AR)-targeting agents are very effective in various disease stages. However, therapy resistance inevitably occurs, and little is known about how tumor cells adapt to bypass AR suppression. Here, we performed integrative multiomics analyses on tissues isolated before and after 3 months of AR-targeting enzalutamide monotherapy from patients with high-risk prostate cancer enrolled in a neoadjuvant clinical trial. Transcriptomic analyses demonstrated that AR inhibition drove tumors toward a neuroendocrine-like disease state. Additionally, epigenomic profiling revealed massive enzalutamide-induced reprogramming of pioneer factor FOXA1 from inactive chromatin sites toward active cis-regulatory elements that dictate prosurvival signals. Notably, treatment-induced FOXA1 sites were enriched for the circadian clock component ARNTL. Posttreatment ARNTL levels were associated with patients' clinical outcomes, and ARNTL knockout strongly decreased prostate cancer cell growth. Our data highlight a remarkable cistromic plasticity of FOXA1 following AR-targeted therapy and revealed an acquired dependency on the circadian regulator ARNTL, a novel candidate therapeutic target.SignificanceUnderstanding how prostate cancers adapt to AR-targeted interventions is critical for identifying novel drug targets to improve the clinical management of treatment-resistant disease. Our study revealed an enzalutamide-induced epigenomic plasticity toward prosurvival signaling and uncovered the circadian regulator ARNTL as an acquired vulnerability after AR inhibition, presenting a novel lead for therapeutic development. See related commentary by Zhang et al., p. 2017. This article is highlighted in the In This Issue feature, p. 2007.

Published
2022

41. Genetic determinants of chromatin reveal prostate cancer risk mediated by context-dependent gene regulation

Author

Baca, Sylvan C, Singler, Cassandra, Zacharia, Soumya, Seo, Ji-Heui, Morova, Tunc, Hach, Faraz, Ding, Yi, Schwarz, Tommer, Huang, Chia-Chi Flora, Anderson, Jacob, Fay, André P, Kalita, Cynthia, Groha, Stefan, Pomerantz, Mark M, Wang, Victoria, Linder, Simon, Sweeney, Christopher J, Zwart, Wilbert, Lack, Nathan A, Pasaniuc, Bogdan, Takeda, David Y, Gusev, Alexander, and Freedman, Matthew L

Subjects
Biological Sciences, Genetics, Urologic Diseases, Cancer, Human Genome, Prevention, Aging, Cancer Genomics, Biotechnology, Prostate Cancer, 2.1 Biological and endogenous factors, Chromatin, Gene Expression Regulation, Genetic Predisposition to Disease, Genome-Wide Association Study, Humans, Male, Polymorphism, Single Nucleotide, Prostatic Neoplasms, Quantitative Trait Loci, Medical and Health Sciences, Developmental Biology, Agricultural biotechnology, Bioinformatics and computational biology
Abstract

Many genetic variants affect disease risk by altering context-dependent gene regulation. Such variants are difficult to study mechanistically using current methods that link genetic variation to steady-state gene expression levels, such as expression quantitative trait loci (eQTLs). To address this challenge, we developed the cistrome-wide association study (CWAS), a framework for identifying genotypic and allele-specific effects on chromatin that are also associated with disease. In prostate cancer, CWAS identified regulatory elements and androgen receptor-binding sites that explained the association at 52 of 98 known prostate cancer risk loci and discovered 17 additional risk loci. CWAS implicated key developmental transcription factors in prostate cancer risk that are overlooked by eQTL-based approaches due to context-dependent gene regulation. We experimentally validated associations and demonstrated the extensibility of CWAS to additional epigenomic datasets and phenotypes, including response to prostate cancer treatment. CWAS is a powerful and biologically interpretable paradigm for studying variants that influence traits by affecting transcriptional regulation.

Published
2022

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