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Start Over Author "Ginell Elliott" Topic 0302 clinical medicine
6 results on '"Ginell Elliott"'

1. The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma

Author

Matthew D. Shirley, Julie T. Chen, Ailing Li, Anthony Vattay, David A. Ruddy, Anka Bric, Kay X. Xiang, Simon Mathieu, Troy Smith, Julien Papillon, Deborah Castelletti, Rukundo Ntaganda, Kathleen Sprouffske, Hyo-eun C. Bhang, Yun Feng, Dorothee Abramowski, Ali Farsidjani, Audrey Kauffmann, Grainne Kerr, Aurore Desplat, Geoffrey Bushold, Katsumasa Nakajima, Henrik Möbitz, GiNell Elliott, Christopher D. Adair, Zainab Jagani, and Florencia Rago

Subjects
Uveal Neoplasms, 0301 basic medicine, Cancer Research, Chromosomal Proteins, Non-Histone, cells, genetic processes, macromolecular substances, Biology, Chromatin remodeling, Mice, 03 medical and health sciences, 0302 clinical medicine, Cell Line, Tumor, medicine, Animals, Humans, Melanoma, Transcription factor, GNA11, Cancer, Microphthalmia-associated transcription factor, medicine.disease, Chromatin, SWI/SNF, enzymes and coenzymes (carbohydrates), 030104 developmental biology, Oncology, 030220 oncology & carcinogenesis, Cancer research, biological phenomena, cell phenomena, and immunity, GNAQ, Transcription Factors
Abstract

Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context-specific roles for the mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) in various cancer lineages. Here, we find evidence that the SWI/SNF complex is essential through analysis of functional genomics screens and further validation in a panel of uveal melanoma cell lines using both genetic tools and small-molecule inhibitors of SWI/SNF. In addition, we describe a functional relationship between the SWI/SNF complex and the melanocyte lineage–specific transcription factor Microphthalmia-associated Transcription Factor, suggesting that these two factors cooperate to drive a transcriptional program essential for uveal melanoma cell survival. These studies highlight a critical role for SWI/SNF in uveal melanoma, and demonstrate a novel path toward the treatment of this cancer.

Published
2020
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2. A proof of concept for biomarker-guided targeted therapy against ovarian cancer based on patient-derived tumor xenografts

Author

Joshua M. Korn, Ronald Meyer, Juliet Williams, Colleen Kowal, Roberto Velazquez, Paul Fordjour, Esther Kurth, Adam C. Palmer, Hans Bitter, Xiamei Zhang, Deborah Plana, GiNell Elliott, Margaret E. McLaughlin, Alice Loo, Julie Muszynski, David A. Ruddy, William R. Sellers, Daniel P. Rakiec, Stacy Rivera, Guizhi Yang, Jeffrey A. Engelman, Caroline Bullock, Hui Gao, Peter K. Sorger, and John Green

Subjects
0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, medicine.medical_treatment, Antineoplastic Agents, Drug resistance, Kaplan-Meier Estimate, Carcinoma, Ovarian Epithelial, Proof of Concept Study, Article, Targeted therapy, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, Antineoplastic Combined Chemotherapy Protocols, medicine, Carcinoma, Biomarkers, Tumor, Distribution (pharmacology), Humans, Molecular Targeted Therapy, Precision Medicine, Ovarian Neoplasms, Chemotherapy, business.industry, medicine.disease, Precision medicine, Xenograft Model Antitumor Assays, Gene Expression Regulation, Neoplastic, 030104 developmental biology, Drug Resistance, Neoplasm, 030220 oncology & carcinogenesis, Biomarker (medicine), Female, Ovarian cancer, business
Abstract

Advanced ovarian cancers are a leading cause of cancer-related death in women and are currently treated with surgery and chemotherapy. This standard of care is often temporarily successful but exhibits a high rate of relapse, after which, treatment options are few. Here we investigate whether biomarker-guided use of multiple targeted therapies, including small molecules and antibody–drug conjugates, is a viable alternative. A panel of patient-derived ovarian cancer xenografts (PDX), similar in genetics and chemotherapy responsiveness to human tumors, was exposed to 21 monotherapies and combination therapies. Three monotherapies and one combination were found to be active in different subsets of PDX. Analysis of gene expression data identified biomarkers associated with responsiveness to each of the three targeted therapies, none of which directly inhibits an oncogenic driver. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. The distribution of biomarker positivity in The Cancer Genome Atlas data suggests the potential for a similar precision approach in human patients. Significance: This study exploits a panel of patient-derived xenografts to demonstrate that most ovarian tumors can be matched to effective biomarker-guided treatments.

Published
2020

3. Degron mediated BRM/SMARCA2 depletion uncovers novel combination partners for treatment of BRG1/SMARCA4-mutant cancers

Author

Florencia Rago, Sosathya Sovath, David A. Ruddy, Zainab Jagani, GiNell Elliott, Hyo-eun C. Bhang, Grainne Kerr, and Matthew T. DiMare

Subjects
0301 basic medicine, Lung Neoplasms, animal structures, Mutant, Biophysics, Mice, Nude, Antineoplastic Agents, Biochemistry, Oxidative Phosphorylation, Gene Knockout Techniques, Mice, 03 medical and health sciences, 0302 clinical medicine, Carcinoma, Non-Small-Cell Lung, Cell Line, Tumor, Animals, Humans, CRISPR, MCL1, Molecular Biology, Sulfonamides, Chemistry, Cell growth, DNA Helicases, Nuclear Proteins, Cell Biology, Isoquinolines, Xenograft Model Antitumor Assays, SWI/SNF, Cell biology, 030104 developmental biology, 030220 oncology & carcinogenesis, Mutation, Proteolysis, Cancer cell, SMARCA4, Myeloid Cell Leukemia Sequence 1 Protein, Female, CRISPR-Cas Systems, Degron, Transcription Factors
Abstract

Recent studies have highlighted that cancer cells with a loss of the SWI/SNF complex catalytic subunit BRG1 are dependent on the remaining ATPase, BRM, making it an attractive target for cancer therapy. However, an understanding of the extent of target inhibition required to arrest cell growth, necessary to develop an appropriate therapeutic strategy, remains unknown. Here, we utilize tunable depletion of endogenous BRM using the SMASh degron, and interestingly observe that BRG1-mutant lung cancer cells require near complete depletion of BRM to robustly inhibit growth both in vitro and in vivo. Therefore, to identify pathways that synergize with partial BRM depletion and afford a deeper response, we performed a genome-wide CRISPR screen and discovered a combinatorial effect between BRM depletion and the knockout of various genes of the oxidative phosphorylation pathway and the anti-apoptotic gene MCL1. Together these studies provide an important framework to elucidate the requirements of BRM inhibition in the BRG1-mutant state with implications on the feasibility of targeting BRM alone, as well as reveal novel insights into pathways that can be exploited in combination toward deeper anti-tumor responses.

Published
2019
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4. Biomarker-guided treatment strategies for ovarian cancer identified from a heterogeneous panel of patient-derived tumor xenografts

Author

Deborah Plana, GiNell Elliott, David A. Ruddy, Xiamei Zhang, Stacy Rivera, Joshua M. Korn, Jeffrey A. Engelman, Margaret E. McLaughlin, Ronald Meyer, John Green, Paul Fordjour, Hui Gao, Esther Kurth, Adam C. Palmer, Julie Goldovitz, Guizhi Yang, Caroline Bullock, William R. Sellers, Roberto Velazquez, Daniel P. Rakiec, Colleen Kowal, Peter K. Sorger, Juliet Williams, Hans Bitter, and Alice Loo

Subjects
Oncology, Response rate (survey), 0303 health sciences, medicine.medical_specialty, Chemotherapy, business.industry, medicine.medical_treatment, Disease, medicine.disease, 3. Good health, Targeted therapy, 03 medical and health sciences, Therapeutic approach, 0302 clinical medicine, 030220 oncology & carcinogenesis, Internal medicine, medicine, Biomarker (medicine), Distribution (pharmacology), business, Ovarian cancer, 030304 developmental biology
Abstract

Advanced ovarian cancers are a leading cause of cancer-related death in women. Such cancers are currently treated with surgery and chemotherapy which is often temporarily successful but exhibits a high rate of relapse after which treatment options are few. Here we assess the responses of a panel of patient-derived ovarian cancer xenografts (PDXs) to 19 mono and combination therapies, including small molecules and antibody-drug conjugates. The PDX panel aimed to mimic the heterogeneity of disease observed in patients, and exhibited a distribution of responsiveness to standard of care chemotherapy similar to human clinical data. Three monotherapies and one drug combination were found to be active in different subsets of PDXs. By analyzing gene expression data we identified gene expression biomarkers predictive of responsiveness to each of three novel targeted therapy regimens. While no single treatment had as high a response rate as chemotherapy, nearly 90% of PDXs were eligible for and responded to at least one biomarker-guided treatment, including tumors resistant to standard chemotherapy. Biomarker frequency was similar in human patients, suggesting the possibility of a new therapeutic approach to ovarian cancer and demonstrating the potential power of PDX-based trials in broadening the reach of precision cancer medicine.

Published
2020
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5. Drosophila Muller F Elements Maintain a Distinct Set of Genomic Properties Over 40 Million Years of Evolution

Author

Raechel Harnoto, Morgan C. Anderson, Amy Z. Xu, Heather Hedeen, Arnaldo J. Santiago-Sanabria, Brandy L. Hammond, Kenneth Saville, Ross D. Kooienga, Christopher Chesley, Robert W. Morris, Aubree T. Gillis, Brittney Offenbacker, Katherine C. Palozola, Trisha Tomkins, Nicole Yu, Matthew Kwong, Megan E. Aldrup, Jordan E. Kus, Chelsey Friedrichs, Kenneth Stapleton, Carly E. Pelchen, Norma Chamma, Joshua F. Machone, Danielle Kulich, Andre Kennedy, Matt J. Crowley, Daniel Broomfield, Adeola Adebayo, Nicolas Ragland, Shady Messiah, Jonathan Misch, Meghan B. Rooney, Eva N. Rubio-Marrero, Will Sherrill, Joyce Stamm, Rachel R. Leads, Lindsey Shantzer, Alexis J. Scott, Andrew W. Waggoner, Kristen M. Cooper, Adam Haberman, Carmen A. Watchinski, Marcos A. Perez, Lisa Kadlec, Kiara N. Medina-Ortega, Kayla Chapman, Cheryl Bailey, Nicholas Fazzio, Insun Chong, Lasse Schmidt, Darla M. Balthaser, Megan DeShetler, Jien Shim, Anna Rogers, Chris Uitvlugt, Bryan Yarrington, Ruth A. Howe, Andrea Ochoa, Gregory J. Mullen, Young Lu Kim, Olivia L Knowles, Kevin M. Levine, Matthew M. Villerot, Thomas J. Rose, Jonathan E. Smith, Sukhjit Kaur, Roshni Patel, Olivia Plante, Tenzin Choeying, Jennifer R. Ramthun, Tiffany Y. Y. Choi, Michael Rahimi, Guzal Khayrullina, Lauren R. Boudreaux, James E. J. Bedard, Brian A. Dow, Christopher A. Louie, Kenneth S. Smith, Joannee Zumkehr, Marcus Gostelow, Melissa A. Tache, Tiffany Dai, Joan D. Zambrana-Burgos, Lauren R. Meyer, Carter Brown, Adam Brown, Travis Lamb, Carissa Belella, Hannah Gilman, David DuPuis, Ramón E. Rivera-Vicéns, Priyanka Naik, Anna L. Shipman, Jad El-Adaimi, Eric Spencer, Jonathan D. Marra, Melissa D. Patao, Sharon Ibarra, Jiayu Zhang, Ashley Vetor, Bobbi Botsford, Jenifer Winters, Nelson A. Valentín-Feliciano, Lauren M. Robinson, Christopher R. Macchi, Jennifer Hernández-Muñiz, E. Gloria C. Regisford, Jaelyn L. Johnson, Cory M. Dauphin, Tezin A. Walji, Matthew A. Zaborowicz, Stacey Winkler, Shannon M. Lowell, Marly R. McCracken, Andrew Adams, Lindsay A. Spaeder, Matthew W. Wolski, Adrese Kandahari, Fabiola Robles-Juarbe, Bryce A. Turner, Ángel L. Laboy-Corales, David T. Watson, Elaine J. Durchholz, Vanessa Rodriguez, Emily J. Teepe, Alaina C. Conturso, Eric Nyabeta Onsarigo, Tijana Martinov, Rohit Venkat, Charles R. Hauser, Priya Srikanth, Marwan Ibrahem, Karl E. Smith, Jessica M. Tucci, Ethan J. Brock, Aparna Sreenivasan, Jasmine Hales, Brianna K. Barnard, Andrew P. Stein, Jessica G. Thomas, Mallory Perella, Lorraine Rodriguez-Bonilla, Shekerah Primus, Zachary D. Moore, Caitlin M. Ament, Amber N. Hare, Brad Pamnani, Eugenia A. Soliterman, Christina Paluskievicz, Yashira M. Valentín-Feliciano, Alexandra K. Eckardt, Anya Goodman, Joseph W. Noynaert, Ashlee G. Johnson, Tyneshia C. P. Henry, Camille D. Ratliff, Ian O. Chase, Michel A. Conn, Jessica Koehler, Daniela Martiniuc, Allison J. Schepers, Megan B. Vylonis, Chrystel Dol, William Dirkes, Michelle S. Rivera-Llovet, Susana Rodríguez-Santiago, Heather L. Eisler, Mary L. Preuss, Daymon Peterson, Martin G. Burg, Aaditya Khatri, John R. Woytanowski, Holly Schiedermayer, Dara Cohn, Leah E Waldman, William M. Morris, Sharon C. Ehret, Marianna Defendini-Ávila, Jessica Fese, Suzette M. Arias-Mejias, Anna Kammrath, William D. Barshop, Edwin G. Ramírez-Aponte, Luis A. Jimenez, Carolina Marques dos Santos Vieira, Cody D. Kern, Francheska M. Delgado-Peraza, Tiffany Wan, Janice L. Krumm, Osagie Ighile, Eric D. Sassu, Jess M. Darusz, Laura Rodela, Daniel S. Nicolas, Shubha Govind, Mary Miller, Joseph E Marcus, Jason Pollack, Rostislav Castillo, Daniel Coomes, Matthew J. Borr, Diana Pérez-Afanador, Lucas A. Watson, Hannah C. Koaches, Amber Quintana, Faith H. Kung, Cameron B. Harris, Bridget M. Janssen, Cristina Zambrana-Echevarría, Jennifer K. Jones, Ian Dobbe, Benjamin M. Lewis, Lena N. Lupey, Julia A. Hilbrands, Cristina Montero Diez, Jorge L. Santiago-Ortiz, Dustin S. Woyski, Sandy D. Mach, Joseph Perez-Otero, Karim A. Sharif, Carlos Mendoza, John D. Fitzgibbons, Nelson H. Knudsen, Christy MacKinnon, Hayley M. Faber, Kwabea Agbley, Michelle Heslop, Olivia Cyrankowski, Priscilla Rodriguez, Melissa Jones, Jean M. Strelitz, Ryan A. Grove, Rachel A Greenstein, Michael Murillo, Elizabeth Greiner-Sosanko, Ciani Jean Sparks, Darryl McFarland, Franca G. Rossi, Heran Gebreyesus, Chris Kay, Danielle Ladzekpo, Chris Harward, Jordan S. Christie, Consuelo J. Alvarez, Elaine V. Morlock, Geoff Scott, Kelsey Hockenberger, Sepo Musokotwane, Adam Fearnow, Lauren J. Keny, Alaina J. Grantham, Evangelina Reza, Mike Colgan, Melanie K. Regan, Stephanie J. Potocny, Sasha L. Dorsett, Tara Skorupa, Valerie M. Gónzalez-Pérez, Vinayak S. Nikam, Anne C. Meier, Varun Sundaram, Helen B. Rankin, Andrew B. Nylander, Mariela Gines-Rosario, Laurell MacMillian, Jeannette M. Osterloh, Robert H. Allen, Melanie A. Smith, Sarah J. Spencer, Cheri M. Ackerman, Jeffrey L. Poet, Amanda J. Hay, Isaac O. Armistead, Laura K. Reed, Don W. Paetkau, Bib Yang, Enid M. Quintana-Torres, Kathryn L. Golden, Lauren A. DiLorenzo, Alen Ramic, Mark T. LeBlanc, Carl J. Minniti, Robert J. Bailey, Kristen M. Thomsen, Ashley L. Adams, Chad A. Koplinsky, Eliezer O. Perez-Colomba, Nicole A. Howey, Katie A. TerMeer, Stephanie Intriago, Christina N. Kufel, Mary Waters, Bo Liu, Thomas J. Bahr, Ashley R. Miller, Claire Pattison, Morgan R. Light, Amy T. Hark, Jennifer S. Doty, Catherine M. Mageeney, Adam J. Ronk, Nadezhda Fefelova, Andrew R. Armstrong, Maida Chen, Elizabeth Macias, Kim M. Chau, Paul Bilinski, Trevor G. Floyd, Cassidy T. Lee, Jenna C. Tenney, Bob Gardner, Patricia Ortiz-Ortiz, Elizabeth S. Jewell, Gabi Lucas, Brandon Lee, Jenifer N. Jarrell, Jimmy Hsiang-Chun Chang, Lorraine Malkowitz, Ulises Marrero-Llerena, Gabriel Stancu, Matthew R. Unzicker, Andrea P. Burgos-Bula, Michelle L. Miller, Elisandra Rivera, Kate Bagaeva, Jessica W. Polk, Jordan E. Carney, Maureen Corrielus, Jana Nietmann, Jeff Howenstein, Elizabeth Kiernan, Sabya A. Rauf, Brandon M. Katz, Elizabeth C. Nordman, Devon Shallman, Eric M. Clark, Lenin Lopez, Karen J. Kraftmann, Leslie Guadron, Julia Kuhn, Allison R. Schneiter, Satish C. Bhalla, Emily J. Howell, Blair Undem, Jeffrey S. Thompson, Arelys Flores-Vazquez, John Kiley, Cody M. Morrow, Joseline Serrano-González, John Mark Knepper, Christopher Beck, Calise Debow, Anna L. Smith, Angelica Garcia, Shelbi Christgen, Shadie Emiah, Tammy Mazur, Rachel E. VanDyken, Frank R. Soto delValle, Zachary Nichols, William R. Kennedy, Ameer Zidan, Douglas A. Herrick, Thomas Q. Xu, Elizabeth Shoop, Jessica A. Kampmeier, John M. Kerber, Caitlin Pozmanter, Emily L. Hong, Frederic J. Deuschle, Allyson B. Rivard, William Neutzling, Joseph V. Moran, Benjamin K. Johnson, Jacob Jipp, Shannon R. McCartha, Abby Vrable, Z. Goodwin, Suchita Rastogi, Alyssa M. Newman, Lionel Ortiz-Fuentes, Arjun A. Anilkumar, Bryan M. Hennessy, Hui-Min Chung, Katie L. Goeller, Carlos E. Santos-Ramos, Adam Dillman, Christine D. Wilson, Sarah J. Peacock, Andrew J. Kim, Carol I. Morales-Caraballo, Briana Brinkley, Justin Alldredge, Rebecca Krock, Kristen C. Davis, David Dunbar, Joshua L. Manghelli, Erica K. Earl, Katherine Gavinski, Sheryl T. Smith, Portia Mason, Lindsay J. Hoogenboom, Jessen T. Havill, Sonya G. Méndez-Castellanos, Darrin T. Schultz, Katherine J. Faber, Allison O’Rouke, Emily G. Miller, Yara Ashrawi, Curtiss E. Lane, Saryleine Ortiz-DeChoudens, Michael W. Sandusky, Andrew Montgomery, Rita Kabaso, Todd Aronhalt, Jonathan D. Foust, Jorge Ruiz, Eric Helmreich, Todd T. Eckdahl, Charlotte Lea, Kevin Coulson, Kristin M. French, Kate A. Woodard, Brandon J. Burkhart, Kylie McNeil, Curtis R. Edwards, Jimmy Ma, Darcie D. Elder, Tia DiTommaso, Nicholaus Monsma, Sarah A. Jelgerhuis, Stephanie J. Adams, Nichole Rigby, Heather L. Holderness, Charlotte Williams, Megan Donegan, Taylor S. Harding, Javier O. Martinez-Rodriguez, Sandeep Venkataram, Tiffany Wong, Anika Toorie, Jenny L. Rose, Ashley S. Brown, Sarah A. Popelka, Matthew Williams, Julie Bryant, Sarah C. R. Elgin, Sonali Kumar, Joshua Burkhardt, William J. Puetz, Erica L. Alvendia, Richard A. Tumminello, Kesley Parry, Joshua R. Smith, Ashley F. Custer, Carlos E. Ortiz, Yedda Li, April E. Bednarski, Simon Ng, Max Mandelbaum, Arlene J. Hoogewerf, Chelsea A. Walker, Ryan S. Lee, Jeannette Wong, Isabella Theresa Felzer-Kim, Harrison Friedman, Megan Bourland, Luis R. Colón-Cruz, Lucy Liu, Nicole C. Olson, Yi Ren, Adam P Lousararian, José M. Cruz-García, Charlie Manchee, Kyle Zoll, Kristina M. Stemler, Juliana Belén-Rodríguez, Ashley S. Timko, Jane Lopilato, England Raimey, Amy D. Melton, Joshua D. Forsyth, Christopher D. Savell, Himabindu Reddy, Alica B. Allen, Amanda Maffa, Daniel W. Cassidy, Luciann Bracero-Quiñones, Eric Lemmon, Justina R. Bartling, Bradley J. Ogden, Petros Svoronos, Mary Spratt, Lisa Sudmeier, Héctor A. Martell-Martínez, James F. Geary, Bridget J. Sessions, Christopher Campana, Kaitlyn A. Downey, Seth G. Dawson, Daniella Menillo, Casey Hanson, James M. Bellush, Justin A. Gonzales, Roy Song, Karvyn Torchon, Betsy Hoover, Michael Closser, Lacey Neufeld, Micah Shelton, Benjamin R. Does, Juan Carlos Martínez-Cruzado, Jordan S. Baumgardner, Nicole Chichearo, Mary T. Reilly, Colleen V. Kelley, Monica Yalamanchili, Dawn Lau, Abbie Morgan, Alyssa Cifelli, Milton R. Herrold, Ambreen Khan, James Messler, Kyle Westphal, James L. Kehoe, Juliana A. Wurzler, Garrett Salzman, Tracy Wang, Charlene Emerson, Lyndsey A. Reynolds, Alysha Moretti, Marita K. Abrams, Mara G. Cole, Michael B. Schultz, Samantha Cruz, Natalie Ngai, Nadia Safa, Vicente Velasquez, Ashley Townsend, Jonathan L. Crooke-Rosado, Amber M. Gygi, Ishwar S. Gill, Christopher McLaughlin, Dorianmarie Vargas-Franco, Alissa Beckett, Samantha Vue, Nadine L. Rossi, Justina Chinwong, Ryan Michael Rempe, Trip Freeburg, Amy J. Johnson, Omolara Glenn, Jade Lea Rekai, Hashini Gunasinghe, Vivienne Echendu, Marshall Strother, Morgan Baker, Christopher D. Smith, Paolo A. DaSilva, Noelle Delacruz, Tiara Tirasawasdichai, Yakov Shevin, Wilfried Guiblet, Shane M. Patao, Peterson R. Cullimore, Giancarlo F. Garbagnati, Adam E. Musick, Sarah C. Butzler, Jonathan D. Presley, Ana I. Correa-Muller, Christopher D. Shaffer, Chunguang Du, Ryan D. Mitchell, Jonathan P. Rennhack, Barbara L. Hopkins, Mary E. Shaw, Jessica E. Hill, Jeremy N. Wong, Anna Kim, Christopher B. Khoury, Julia Chapman, Amanda T. Mercer, Jessica A. Shuen, Joyce H. Lau, I.N. Falk, Sunil Rathore, Christopher J. Jones, Laura Simone Bisogno, Nighat P. Kokan, Paul Yenerall, Amber L. Price, Kelsey T. Bushhouse, Stephen L. McDaniel, Andrew P. Drake, Johnathan D. English, Sampson K. Boham, Robert A. Herbstsomer, Daniel S. Fosselman, Kevin Babilonia-Figueroa, Matthew Simon, Anne G. Rosenwald, Bryan J. Rupley, Heather Cohen, Victoria Scala, Avery B. Cromwell, Christopher E. Blunden, Yelena P. Davis, William B. Armstrong, Kristine Ostby, Joanna Haye, Lauren M. Wysocki, Lena Christiansen, Allison A. Throm, Sarah Flohr, Matthew Wawersik, Rebecca J. Cotteleer, Kristen R Ramirez, Dontae A. Jacobs, Sarah Woehlke, Gregory S. Messenger, Soham Aso, Nicole Clarke-Medley, Bryant R. Swanson, Lindsay K. Brouwer, S. Catherine Silver Key, Stephanie Zarrasola, Michael S. Salgado, Dong K. Rhee, Mai Abdelnabi, Eve VanEck, Jeremy Buhler, Sarah Kong, Turner Conrad, Jennifer Roecklein-Canfield, Marykathryn Tynon, Brian J. Maniaci, Alexa M. McDonough, Ivan G. Llavona-Cartagena, J. Devin Spencer, Todd D. Johnson, Azita Bashiri, Kimberley Ramsey, Mike Polen, Hien P Nguyen, Seantay D. Patterson, Lucia Wande, Nicholas U. Schwartz, Han Yuan, Albeliz Santiago-Colón, Joseph Medina, Samuel Thomas Crowley, Emma Shoemaker, Alex J. Feliciano-Cancela, Alexander J. Kujawski, Lillyann Asencio-Zayas, Gentry L. Pickett, Matt J. Randazzo, Erica Stagaard, Kristin M. LaForge, Gabriela A. Llaurador-Caraballo, Anastasia K. Yemelyanova, Alan Tseng, Erika E. Menyes, Julie Azarewicz, Christa Burke, Samuel I. Smith, Nazanin Ghavam, Carolina Gomez, Cameron Fick, Anthony Pinto, Lindsay Rios, Gary A Kuleck, Ashley Rich, Kayla A. Florian, Martin N. Cheramie, Yuki Kwan Wa Shum, Atlee Baker, LaJerald Augustine, Alyson Greenwell, Rasleen K. Saluja, Jason S. Macias, Wesley W. Winn, Samantha M. Schmuecker, Michelle E. M. Eisen, Pedro Benitez, Jeanette Hauke, Nora C. Goscinski, Justin R. DiAngelo, Carter T. Docking, David D. Xiong, Brittany D. Pasierb, Matt Van Camp, Yin Zheng, Nikie L. McCabe, Emily Reed, Katie Homa, Kimberly S. Kolibas, Elizabeth A. Karaska, Grace A. Dougherty, John P. Fanning, Michael Fasano, Joseph E. Sable, Robert W. Schulz, San Francisco Nguyen, Michael L. Rojas-Vargas, Kierstin L. Naylor, Emily Peoples, Jessica Neely, Lejla Cesko, Brionna D. Davis-Reyes, Roxanne Banker, Amanda K. Tilot, Jordan P. Brand, William H. Newhart, Lauriaun Johnson, Michelle M. Giddens, Nicole B. Clark, Anant Agarwalla, Thomas F. Minton, Dana W. Brooks, Amanda D. Garrett, Bethany M. Klett, Kristin M. Starkey, Antoinette E. Fafara-Thompson, Michael R. Rubin, Jonathon M. Benson, Erica Enoch, Amanda M. Damsteegt, Zackary W. Scott, Elisabeth A. Kelly, Jason M. Barnett, Wilson Leung, Luke J. Rodriguez-Giron, Krishna C. Mudumbi, Francis J. May, Nadyan M. Vargas-Barreto, Geeta Statton, José L. Torres-Castillo, Sarah Hirsch, Rachel M. Reem, Linghui Li, Deirdre Robinett, Jason Caronna, Abneris E. Rodríguez-Laboy, Samantha Lawrence, Katherine R. Reynolds, Corinne Weeks, Allison M. Sterling, Chun Leung Ng, Roman E. Ramirez, Daron C. Barnard, Leming Zhou, Eric P. Spana, John A. Toth, Alvin Lu, Krizia C. Menéndez-Serrano, Jonathan M. Heckman, Ben Chlebina, Matthew C. Fadus, Helmet T. Karim, Shailly Gaur, Timothy R. Jelsema, Nicholas Keysock, Thomas J. Carr, Zach Fusco, Evan M. Verbofsky, Monal Naik, Amanda H. Flores, Kristin A. Knouse, Olga R. Kopp, Elizabeth Feenstra, Edward P. Sweeney, Christen Johnson, Justin Crawford, Damian Urick, Victor W. Mullen, Carrie A. Dunham, Gabriella A. DeMichele, Mengyang Sun, William Harrington, Jessica M. Bodenberg, Xavier A. Collado-Méndez, T. Aaron Wiles, Michelle K. Powers, Phillip J. Minnick, Lourdes N. Irizarry-González, Valeria Silva, Steven Ovu, Nik Kolba, Peter Lindbeck, Jerome M. Molleston, Ifeanyi Obiorah, David Carranza, Lauren R. Beck, Alina M. Tamayo-Figueroa, Elaine R. Mardis, Rachel N. Lippert, Ingrid T. Rivera-Pagán, Mahdi Soos, Trung T. Nguyen, Megan Martinez, Van Kim, Benjamin L. Danner, Randall J. DeJong, Melissa M. Trieu, Andrea M. Senquiz-Gonzalez, Mary Grace Schueler, Emily E. Magnuson, Lesley E. Jackson, Hendrick Pagán-Torres, Fareed Sanusi, Dana Koenig, Vidya Chandrasekaran, Chinmoy I. Bhatiya, Dongyeon Kim, Paul J. Overvoorde, Reece Watson, Jennifer Schottler, Devry Lin, Jim Youngblom, Taylor Schauder, Nigel Madden, Isabel Valdez, Thomas John Reynolds, Kelly M. Deranek, Anne A. Welker, Jackie X. White, Nicole C. Riddle, Jacob Pfeil, Aldo Heredia-Negrón, Christine Langner, Tao Jian He, Jonathan P. Mecoli, Lissett Mayorga, Scott Chiang, Rishi Singhal, Julia C. Peairs, Michael Quach, Anne M. Eime, GiNell Elliott, Meleah J. Gross, Melissa Drewry, Julia A. Emerson, Anthony K. Lambright, Isaac Appiah, Gregory M. Robertson, Nathaniel Regenold, Philip Pham, George Odisho, Alexi Archambault, Matthew Dothager, Shana M. Baldassari, Paul J. Lee, Callie R. Merry, Jesse R. Farek, Archana Tare, Srebrenka Robic, William Vernon, Tam Vuong, Bethany Grace Bonifield, Katrina Thistle, Rose M. Dowd, Noor Tazudeen, Jennifer Weaver, Manpreet Kaur, Nicole M. Caesar, Yi Zhang, Michael C. Cristostomo, Albert Tzeng, Kayla Vondy, Emily Perling, Ramiro A. Chavez, Lanor S. Horton, Matt Kroll, Levent H. Beken, Justin R. Starcher, Sam Asinof, Nathalia M. Cruz, Eunice George, Adam T. Morrow, Heather Milnthorp, Cheryl Mazzeo, Kristen R. Hatfield, Anna L. Boudoures, Ashley A. Tewilliager, Edna P. Tascón-Peñaranda, Vilma F. Huerta, Sarah Tuberty, Mallory A. Williams, Rachel E. Weber, Sarah Spencer, Emily C. Leatherman, Yuying Gosser, Steve DeFazio, Patrick Ng, Jeri Sparks, Pavan Bhat, Mindy E. Bower, Jordan E. Matthews, Cyrus E. Kuschner, Anne Bertolet, Matt Kusner, Thomas C. Giarla, Jessica Penn, Gerard P. McNeil, Mariam Meghdari, Michael J. Wolyniak, Matthew Juergens, Karla I. Velázquez-Soto, Maria Kaisler, Jeanine Schibler, Alexis Nagengast, Susan Parrish, Frances Marín-Maldonado, Shiv Mohini, Jessica King, Danny Mammo, Katherine S. Harker, Allyson P. Hawkins, Kelly Drumm, Jennifer A. Lammers, Allyson P Mallya, Ashley Bryant, Katie Weihbrecht, Pete Wendland, Gabriela V. Bernal-Vega, Nestor A. Gutierrez, Armando G. Bermudez-Capo, Luke R. Salbert, Kirk Haltaufderhyde, Michelle L. Kappes, Mary A. Smith, York Chen, Miguel Vélez-Vázquez, Brittany E. Plescher, Francis D. Beauchamp-Pérez, Alyssa Ward, Andrea N. Clary, Don Foret, Mitchell J McDonald, Mariela Colon-Vazquez, Amanda L. Blaker, Hao Yang, James Z. Liu, Austin B. Limle, Henry Huang, Luis Vilanova-Velez, Edgar Garibay, Philip J. Freda, Laura L. Mays Hoopes, Maureen S. Hammond, Marian M. Kaehler, Rebecca Shuford, Ray Sunjed, Cynthia K. Hanson, Marielle VanderVennen, Idaliz M. Martínez-Traverso, Jack Y. Yu, Spencer L. Franchi, Michael Snavely, John E. Anderson, Lainey S. Rubin, Kelly K. Jones, Stephanie F. Mel, Stacey Lytle, Danny L. Tran, Chelsea R. Barberi, Max Mian Liu, Eric A. Nollet, Sarah E. Muller, Diana Norton, John M. Braverman, Thu A. Phan, Nelson Membreno, Colin Khoshabian, John Gooch, Cassandra Kubricky, Priscila M. Rodríguez-García, Anna Wylie, Diana L. E. Johnson, Anna K. Unruh, Deborah Hammett, Jon Sarezky, Marie Brown, Carolina Riascos-Cuero, Emily J. Diekema, Emmy E. Ogawa, Miranda Chavez, Zuzana Kocsisova, Dennis Revie, Anniken M. Lydon, Peter A. Cognetti, Ashley A. Collins, Tariq Abusheikh, Erin K. Luippold, Kevin Myirski, Brian O. Rodríguez-Echevarría, Haley J. Plasman, Lara Baatenburg, Jesse Hendriksma, Christopher R. Knob, Max Semon, Cassandra Farrar, Xiao Zhu, Ali Dobbe, Marie-Isabelle B. Seydoux, Griffin Sadovsky, Shreya Prasad, Victoria Newcomb, Chad Gier, Dmitri Serjanov, Jules Wellinghoff, Maxwell T. Smith-Gee, and Alexandra H. Scoma

Subjects
Transposable element, Codon Adaptation Index, Euchromatin, Heterochromatin, transposons, evolution of heterochromatin, Investigations, Genome, Evolution, Molecular, 03 medical and health sciences, gene size, 0302 clinical medicine, melting characteristics, Species Specificity, codon bias, Genetics, Animals, Drosophila Proteins, Selection, Genetic, Codon, Molecular Biology, Genetics (clinical), 030304 developmental biology, Polytene Chromosomes, Repetitive Sequences, Nucleic Acid, Gene Rearrangement, 0303 health sciences, biology, Computational Biology, Molecular Sequence Annotation, Gene rearrangement, Exons, Genomics, biology.organism_classification, Introns, Drosophila melanogaster, Codon usage bias, DNA Transposable Elements, Drosophila, 030217 neurology & neurosurgery
Abstract

The Muller F element (4.2 Mb, ~80 protein-coding genes) is an unusual autosome of Drosophila melanogaster; it is mostly heterochromatic with a low recombination rate. To investigate how these properties impact the evolution of repeats and genes, we manually improved the sequence and annotated the genes on the D. erecta, D. mojavensis, and D. grimshawi F elements and euchromatic domains from the Muller D element. We find that F elements have greater transposon density (25–50%) than euchromatic reference regions (3–11%). Among the F elements, D. grimshawi has the lowest transposon density (particularly DINE-1: 2% vs. 11–27%). F element genes have larger coding spans, more coding exons, larger introns, and lower codon bias. Comparison of the Effective Number of Codons with the Codon Adaptation Index shows that, in contrast to the other species, codon bias in D. grimshawi F element genes can be attributed primarily to selection instead of mutational biases, suggesting that density and types of transposons affect the degree of local heterochromatin formation. F element genes have lower estimated DNA melting temperatures than D element genes, potentially facilitating transcription through heterochromatin. Most F element genes (~90%) have remained on that element, but the F element has smaller syntenic blocks than genome averages (3.4–3.6 vs. 8.4–8.8 genes per block), indicating greater rates of inversion despite lower rates of recombination. Overall, the F element has maintained characteristics that are distinct from other autosomes in the Drosophila lineage, illuminating the constraints imposed by a heterochromatic milieu.

Published
2015

6. Intermediate DNA methylation is a conserved signature of genome regulation

Author

Keith L. Ligon, Philippe Gascard, Peggy J. Farnham, Cristian Coarfa, Ting Wang, Jonathan Mill, Xin Zhou, Chibo Hong, Mahvash Sigaroudinia, Misha Bilenky, Gary D. Stormo, Manolis Kellis, Joseph F. Costello, Ginell Elliott, Aleksandar Milosavljevic, Marco A. Marra, Thea D. Tlsty, Martin Hirst, Xiaoyun Xing, R. Alan Harris, Cecile L. Maire, Daofeng Li, Leonard C. Schalkwyk, Robert J.A. Bell, Massachusetts Institute of Technology. Department of Electrical Engineering and Computer Science, and Kellis, Manolis

Subjects
Epigenomics, General Physics and Astronomy, Biology, Synteny, Article, General Biochemistry, Genetics and Molecular Biology, Evolution, Molecular, Mice, 03 medical and health sciences, 0302 clinical medicine, Epigenetics of physical exercise, Histone methylation, Animals, Humans, RNA-Directed DNA Methylation, 030304 developmental biology, Genetics, 0303 health sciences, Multidisciplinary, Genome, Human, General Chemistry, Methylation, DNA Methylation, Molecular biology, Histone Code, Gene Expression Regulation, Histone methyltransferase, DNA methylation, Illumina Methylation Assay, 030217 neurology & neurosurgery
Abstract

The role of intermediate methylation states in DNA is unclear. Here, to comprehensively identify regions of intermediate methylation and their quantitative relationship with gene activity, we apply integrative and comparative epigenomics to 25 human primary cell and tissue samples. We report 18,452 intermediate methylation regions located near 36% of genes and enriched at enhancers, exons and DNase I hypersensitivity sites. Intermediate methylation regions average 57% methylation, are predominantly allele-independent and are conserved across individuals and between mouse and human, suggesting a conserved function. These regions have an intermediate level of active chromatin marks and their associated genes have intermediate transcriptional activity. Exonic intermediate methylation correlates with exon inclusion at a level between that of fully methylated and unmethylated exons, highlighting gene context-dependent functions. We conclude that intermediate DNA methylation is a conserved signature of gene regulation and exon usage., Many loci in the mammalian genome are intermediately methylated. Here, by comprehensively identifying these loci and quantifying their relationship with gene activity, the authors show that intermediate methylation is an evolutionarily conserved epigenomic signature of gene regulation.

Published
2014

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