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3. 7.344 Treating Infertility-- From Bench to Bedside and Bedside to Bench, Spring 2015

Author

Hersch, Jana, Carmell, Michelle, Hersch, Jana, and Carmell, Michelle

Abstract

In the western world, approximately 10–15% of couples suffer from subfertility. Consequently, over 5 million babies have been born thanks to assisted reproductive technologies, and more than half of those have been born in the past six years alone. This class will cover the basic biology behind fertility and explore the etiology of infertility. We will highlight open questions in reproductive biology, familiarize students with both tried-and-true and emerging reproductive technologies, and explore the advantages and pitfalls of each. This course is one of many Advanced Undergraduate Seminars offered by the Biology Department at MIT. These seminars are tailored for students with an interest in using primary research literature to discuss and learn about current biological research in a highly interactive setting. Many instructors of the Advanced Undergraduate Seminars are postdoctoral scientists with a strong interest in teaching.

Published
2023

5. GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability

Author

Dokshin, Gregoriy A., Davis, Gregory M., Sawle, Ashley D., Eldridge, Matthew D., Nicholls, Peter K., Gourley, Taylin E., Romer, Katherine A., Molesworth, Luke W., Tatnell, Hannah R., Ozturk, Ahmet R., De Rooij, Dirk G., Hannon, Gregory J., Page, David C., Mello, Craig C., Carmell, Michelle A., Dokshin, Gregoriy A., Davis, Gregory M., Sawle, Ashley D., Eldridge, Matthew D., Nicholls, Peter K., Gourley, Taylin E., Romer, Katherine A., Molesworth, Luke W., Tatnell, Hannah R., Ozturk, Ahmet R., De Rooij, Dirk G., Hannon, Gregory J., Page, David C., Mello, Craig C., and Carmell, Michelle A.

Abstract

GCNA proteins are expressed across eukarya in pluripotent cells and have conserved functions in fertility. GCNA homologs Spartan (DVC-1) and Wss1 resolve DNA-protein crosslinks (DPCs), including Topoisomerase-DNA adducts, during DNA replication. Here, we show that GCNA mutants in mouse and C. elegans display defects in genome maintenance including DNA damage, aberrant chromosome condensation, and crossover defects in mouse spermatocytes and spontaneous genomic rearrangements in C. elegans. We show that GCNA and topoisomerase II (TOP2) physically interact in both mice and worms and colocalize on condensed chromosomes during mitosis in C. elegans embryos. Moreover, C. elegans gcna-1 mutants are hypersensitive to TOP2 poison. Together, our findings support a model in which GCNA provides genome maintenance functions in the germline and may do so, in part, by promoting the resolution of TOP2 DPCs.

Published
2020

6. GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability

Author

Developmental Biology, Sub Developmental Biology, Dokshin, Gregoriy A., Davis, Gregory M., Sawle, Ashley D., Eldridge, Matthew D., Nicholls, Peter K., Gourley, Taylin E., Romer, Katherine A., Molesworth, Luke W., Tatnell, Hannah R., Ozturk, Ahmet R., De Rooij, Dirk G., Hannon, Gregory J., Page, David C., Mello, Craig C., Carmell, Michelle A., Developmental Biology, Sub Developmental Biology, Dokshin, Gregoriy A., Davis, Gregory M., Sawle, Ashley D., Eldridge, Matthew D., Nicholls, Peter K., Gourley, Taylin E., Romer, Katherine A., Molesworth, Luke W., Tatnell, Hannah R., Ozturk, Ahmet R., De Rooij, Dirk G., Hannon, Gregory J., Page, David C., Mello, Craig C., and Carmell, Michelle A.

Published
2020

7. Mammalian germ cells are determined after PGC colonization of the nascent gonad

Author

Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Nicholls, Peter K., Schorle, Hubert, Naqvi, Sahin, Hu, Yueh-Chiang, Fan, Yuting, Carmell, Michelle A., Page, David C., Whitehead Institute for Biomedical Research, Massachusetts Institute of Technology. Department of Biology, Nicholls, Peter K., Schorle, Hubert, Naqvi, Sahin, Hu, Yueh-Chiang, Fan, Yuting, Carmell, Michelle A., and Page, David C.

Abstract

Mammalian primordial germ cells (PGCs) are induced in the embryonic epiblast, before migrating to the nascent gonads. In fish, frogs, and birds, the germline segregates even earlier, through the action of maternally inherited germ plasm. Across vertebrates, migrating PGCs retain a broad developmental potential, regardless of whether they were induced or maternally segregated. In mammals, this potential is indicated by expression of pluripotency factors, and the ability to generate teratomas and pluripotent cell lines. How the germline loses this developmental potential remains unknown. Our genome-wide analyses of embryonic human and mouse germlines reveal a conserved transcriptional program, initiated in PGCs after gonadal colonization, that differentiates germ cells from their germline precursors and from somatic lineages. Through genetic studies in mice and pigs, we demonstrate that one such gonad-induced factor, the RNA-binding protein DAZL, is necessary in vivo to restrict the developmental potential of the germline; DAZL’s absence prolongs expression of a Nanog pluripotency reporter, facilitates derivation of pluripotent cell lines, and causes spontaneous gonadal teratomas. Based on these observations in humans, mice, and pigs, we propose that germ cells are determined after gonadal colonization in mammals. We suggest that germ cell determination was induced late in embryogenesis—after organogenesis has begun—in the common ancestor of all vertebrates, as in modern mammals, where this transition is induced by somatic cells of the gonad. We suggest that failure of this process of germ cell determination likely accounts for the origin of human testis cancer., Hope Funds for Cancer Research Fellow (Grant HFCR-15-06-06), National Health and Medical Research Council (Australia) (Early Career Fellowship Grant GNT1053776), German Research Council (Grant Scho 503 13-1), National Natural Science Foundation of China (Grant 81471507)

Published
2020

8. GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability

Author

Whitehead Institute for Biomedical Research, Romer, Katherine A., De Rooij, Dirk G., Page, David C., Carmell, Michelle A., Whitehead Institute for Biomedical Research, Romer, Katherine A., De Rooij, Dirk G., Page, David C., and Carmell, Michelle A.

Abstract

GCNA proteins are expressed across eukarya in pluripotent cells and have conserved functions in fertility. GCNA homologs Spartan (DVC-1) and Wss1 resolve DNA-protein crosslinks (DPCs), including Topoisomerase-DNA adducts, during DNA replication. Here, we show that GCNA mutants in mouse and C. elegans display defects in genome maintenance including DNA damage, aberrant chromosome condensation, and crossover defects in mouse spermatocytes and spontaneous genomic rearrangements in C. elegans. We show that GCNA and topoisomerase II (TOP2) physically interact in both mice and worms and colocalize on condensed chromosomes during mitosis in C. elegans embryos. Moreover, C. elegans gcna-1 mutants are hypersensitive to TOP2 poison. Together, our findings support a model in which GCNA provides genome maintenance functions in the germline and may do so, in part, by promoting the resolution of TOP2 DPCs. DNA topoisomerases help unwind DNA but occasionally get trapped, resulting in DNA-protein crosslinks (DPCs). DPCs damage DNA and threaten genomic integrity. Dokshin et al. find that GCNA protein family complements standard DPC processing machinery in resolving topoisomerase II DPCs to ensure heritable genome stability and germline immortality., National Institutes of Health (U.S.) (Grant P40 OD010440)

Published
2020

9. GCNA Interacts with Spartan and Topoisomerase II to Regulate Genome Stability

Author

Dokshin, Gregoriy A., primary, Davis, Gregory M., additional, Sawle, Ashley D., additional, Eldridge, Matthew D., additional, Nicholls, Peter K., additional, Gourley, Taylin E., additional, Romer, Katherine A., additional, Molesworth, Luke W., additional, Tatnell, Hannah R., additional, Ozturk, Ahmet R., additional, de Rooij, Dirk G., additional, Hannon, Gregory J., additional, Page, David C., additional, Mello, Craig C., additional, and Carmell, Michelle A., additional

Published
2020
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10. GCNA Preserves Genome Integrity and Fertility Across Species

Author

Bhargava, Varsha, primary, Goldstein, Courtney D., additional, Russell, Logan, additional, Xu, Lin, additional, Ahmed, Murtaza, additional, Li, Wei, additional, Casey, Amanda, additional, Servage, Kelly, additional, Kollipara, Rahul, additional, Picciarelli, Zachary, additional, Kittler, Ralf, additional, Yatsenko, Alexander, additional, Carmell, Michelle, additional, Orth, Kim, additional, Amatruda, James F., additional, Yanowitz, Judith L., additional, and Buszczak, Michael, additional

Published
2020
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12. GCNA preserves genome integrity and fertility across species

Author

Bhargava, Varsha, primary, Goldstein, Courtney D., additional, Russell, Logan, additional, Xu, Lin, additional, Ahmed, Murtaza, additional, Li, Wei, additional, Casey, Amanda, additional, Servage, Kelly, additional, Kollipara, Rahul, additional, Picciarelli, Zachary, additional, Kittler, Ralf, additional, Yatsenko, Alexander, additional, Carmell, Michelle, additional, Orth, Kim, additional, Amatruda, James F., additional, Yanowitz, Judith L., additional, and Buszczak, Michael, additional

Published
2019
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13. GCNA interacts with Spartan and Topoisomerase II to regulate genome stability

Author

Davis, Gregory M., primary, Dokshin, Gregoriy A., additional, Sawle, Ashley D., additional, Eldridge, Matthew D., additional, Romer, Katherine A., additional, Gourley, Taylin E., additional, Molesworth, Luke W., additional, Tatnell, Hannah R., additional, Ozturk, Ahmet R., additional, de Rooij, Dirk G., additional, Hannon, Gregory J., additional, Page, David C., additional, Mello, Craig C., additional, and Carmell, Michelle A., additional

Published
2019
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16. A widely employed germ cell marker is an ancient disordered protein with reproductive functions in diverse eukaryotes

Author

Massachusetts Institute of Technology. Department of Biology, Reddien, Peter, Page, David C, Carmell, Michelle A, Dokshin, Gregoriy A, Skaletsky, Helen, Hu, Yueh-Chiang, van Wolfswinkel, Josien C, Igarashi, Kyomi J, Bellott, Daniel W, Nefedov, Michael, Enders, George C, Uversky, Vladimir N, Mello, Craig C, Massachusetts Institute of Technology. Department of Biology, Reddien, Peter, Page, David C, Carmell, Michelle A, Dokshin, Gregoriy A, Skaletsky, Helen, Hu, Yueh-Chiang, van Wolfswinkel, Josien C, Igarashi, Kyomi J, Bellott, Daniel W, Nefedov, Michael, Enders, George C, Uversky, Vladimir N, and Mello, Craig C

Abstract

The advent of sexual reproduction and the evolution of a dedicated germline in multicellular organisms are critical landmarks in eukaryotic evolution. We report an ancient family of GCNA (germ cell nuclear antigen) proteins that arose in the earliest eukaryotes, and feature a rapidly evolving intrinsically disordered region (IDR). Phylogenetic analysis reveals that GCNA proteins emerged before the major eukaryotic lineages diverged; GCNA predates the origin of a dedicated germline by a billion years. Gcna gene expression is enriched in reproductive cells across eukarya – either just prior to or during meiosis in single-celled eukaryotes, and in stem cells and germ cells of diverse multicellular animals. Studies of Gcna-mutant C. elegans and mice indicate that GCNA has functioned in reproduction for at least 600 million years. Homology to IDR-containing proteins implicated in DNA damage repair suggests that GCNA proteins may protect the genomic integrity of cells carrying a heritable genome., Life Sciences Research Foundation, Howard Hughes Medical Institute

Published
2017

17. The Molecular Taxonomy of Primary Prostate Cancer

Author

Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Bradley, Robert K, Carmell, Michelle, Carter, Scott, Chin, Lynda, Cibulskis, Kristian, Getz, Gad Asher, Heiman, David, Lander, Eric Steven, Lin, Pei, Loda, Massimo, Meyerson, Matthew L, Park, Peter J, Seidman, Jonathan, Sougnez, Carrie L, Verhaak, Roel, Voet, Douglas, Abeshouse, Adam, Ahn, Jaeil, Akbani, Rehan, Ally, Adrian, Amin, Samirkumar, Andry, Christopher D., Annala, Matti, Aprikian, Armen, Armenia, Joshua, Arora, Arshi, Auman, J. Todd, Balasundaram, Miruna, Balu, Saianand, Barbieri, Christopher E., Bauer, Thomas, Benz, Christopher C., Bergeron, Alain, Beroukhim, Rameen, Berrios, Mario, Bivol, Adrian, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S., dos Reis, Rodolfo Borges, Boutros, Paul C., Bowen, Jay, Bowlby, Reanne, Boyd, Jeffrey, Breggia, Anne, Brimo, Fadi, Brooks, Denise, Broom, Bradley M., Bryce, Alan H., Bubley, Glenn, Burks, Eric, Butterfield, Yaron S.N., Button, Michael, Canes, David, Carlotti, Carlos G., Carlsen, Rebecca, Carroll, Peter R., Cartun, Richard, Carver, Brett S., Chan, June M., Chang, Matthew T., Chen, Yu, Costello, Anthony J., Cherniack, Andrew D., Chevalier, Simone, Cho, Juok, Chu, Andy, Chuah, Eric, Chudamani, Sudha, Ciriello, Giovanni, Clarke, Amanda, Cooperberg, Matthew R., Corcoran, Niall M., Cowan, Janet, Crain, Daniel, Curley, Erin, David, Kerstin, Demchok, John A., Demichelis, Francesca, Dhalla, Noreen, Dhir, Rajiv, Doueik, Alexandre, Drake, Bettina, Dvinge, Heidi, Dyakova, Natalya, Felau, Ina, Ferguson, Martin L., Frazer, Scott, Freedland, Stephen, Fu, Yao, Bristow, Christopher A., Gao, Jianjiong, Gardner, Johanna, Gastier-Foster, Julie M., Gehlenborg, Nils, Gerken, Mark, Gerstein, Mark B., Godwin, Andrew K., Gopalan, Anuradha, Graefen, Markus, Graim, Kiley, Gribbin, Thomas, Guin, Ranabir, Gupta, Manaswi, Hadjipanayis, Angela, Haider, Syed, Hamel, Lucie, Hayes, D. Neil, Hess, Julian, Hoadley, Katherine A., Holbrook, Andrea H., Holt, Robert A., Holway, Antonia, Hovens, Christopher M., Hoyle, Alan P., Huang, Mei, Hutter, Carolyn M., Ittmann, Michael, Iype, Lisa, Jefferys, Stuart R., Jones, Corbin D., Jones, Steven J.M., Juhl, Hartmut, Kahles, Andre, Kane, Christopher J., Kasaian, Katayoon, Kerger, Michael, Khurana, Ekta, Kim, Jaegil, Klein, Robert J., Kucherlapati, Raju, Lacombe, Louis, Ladanyi, Marc, Lai, Phillip H., Laird, Peter W., Latour, Mathieu, Lawrence, Michael S., Lau, Kevin, LeBien, Tucker, Lee, Darlene, Lee, Semin, Lehmann, Kjong-Van, Leraas, Kristen M., Leshchiner, Ignaty, Leung, Robert, Libertino, John A., Lichtenberg, Tara M., Linehan, W. Marston, Ling, Shiyun, Lippman, Scott M., Liu, Jia, Liu, Wenbin, Lochovsky, Lucas, Logothetis, Christopher, Lolla, Laxmi, Longacre, Teri, Lu, Yiling, Luo, Jianhua, Ma, Yussanne, Mahadeshwar, Harshad S., Mallery, David, Mariamidze, Armaz, Marra, Marco A., Mayo, Michael, McCall, Shannon, McKercher, Ginette, Meng, Shaowu, Mes-Masson, Anne-Marie, Merino, Maria J., Mieczkowski, Piotr A., Mills, Gordon B., Mills Shaw, Kenna R., Minner, Sarah, Moinzadeh, Alireza, Moore, Richard A., Morris, Scott, Morrison, Carl, Mose, Lisle E., Mungall, Andrew J., Murray, Bradley A., Myers, Jerome B., Naresh, Rashi, Nelson, Joel, Nelson, Mark A., Nelson, Peter S., Newton, Yulia, Noble, Michael S., Noushmehr, Houtan, Nykter, Matti, Pantazi, Angeliki, Parfenov, Michael, Parker, Joel S., Paulauskis, Joseph, Penny, Robert, Perou, Charles M., Piche, Alain, Pihl, Todd, Pinto, Peter A., Prandi, Davide, Protopopov, Alexei, Ramirez, Nilsa C., Rao, Arvind, Rathmell, W. Kimryn, Ratsch, Gunnar, Ren, Xiaojia, Reuter, Victor E., Reynolds, Sheila M., Rhie, Suhn K., Rieger-Christ, Kimberly, Roach, Jeffrey, Robertson, A. Gordon, Robinson, Brian, Rubin, Mark A., Saad, Fred, Sadeghi, Sara, Saksena, Gordon, Saller, Charles, Salner, Andrew, Sanchez-Vega, Francisco, Sander, Chris, Sandusky, George, Sauter, Guido, Sboner, Andrea, Scardino, Peter T., Scarlata, Eleonora, Schein, Jacqueline E., Schlomm, Thorsten, Schmidt, Laura S., Schultz, Nikolaus, Schumacher, Steven E., Neder, Luciano, Seth, Sahil, Sharp, Alexis, Shelton, Candace, Shelton, Troy, Shen, Hui, Shen, Ronglai, Sherman, Mark, Sheth, Margi, Shi, Yan, Shih, Juliann, Shmulevich, Ilya, Simko, Jeffry, Simon, Ronald, Simons, Janae V., Sipahimalani, Payal, Skelly, Tara, Sofia, Heidi J., Soloway, Matthew G., Song, Xingzhi, Sorcini, Andrea, Stepa, Serghei, Stewart, Chip, Stewart, John, Stuart, Joshua M., Sullivan, Travis B., Sun, Charlie, Sun, Huandong, Tam, Angela, Tan, Donghui, Tang, Jiabin, Tarnuzzer, Roy, Tarvin, Katherine, Taylor, Barry S., Teebagy, Patrick, Tenggara, Imelda, Tetu, Bernard, Tewari, Ashutosh, Thiessen, Nina, Thompson, Timothy, Thorne, Leigh B., Tirapelli, Daniela P., Tomlins, Scott A., Trevisan, Felipe Amstalden, Troncoso, Patricia, True, Lawrence D., Tsourlakis, Maria Christina, Tyekucheva, Svitlana, Van Allen, Eliezer, Van Den Berg, David J., Veluvolu, Umadevi, Vocke, Cathy D., Wan, Yunhu, Wang, Qingguo, Wang, Wenyi, Wang, Zhining, Weinhold, Nils, Weinstein, John N., Weisenberger, Daniel J., Wilkerson, Matthew D., Wise, Lisa, Witte, John, Wu, Chia-Chin, Wu, Junyuan, Wu, Ye, Xu, Andrew W., Yadav, Shalini S., Yang, Liming, Yang, Lixing, Yau, Christina, Ye, Huihui, Yena, Peggy, Zeng, Thomas, Zenklusen, Jean C., Zhang, Hailei, Zhang, Jiashan, Zhang, Wei, Zhong, Yi, Zhu, Kelsey, Zmuda, Erik, Cancer Genome Atlas Research Network, Bradley, Robert K., Meyerson, Matthew L., Park, Peter J., Massachusetts Institute of Technology. Institute for Medical Engineering & Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Bradley, Robert K, Carmell, Michelle, Carter, Scott, Chin, Lynda, Cibulskis, Kristian, Getz, Gad Asher, Heiman, David, Lander, Eric Steven, Lin, Pei, Loda, Massimo, Meyerson, Matthew L, Park, Peter J, Seidman, Jonathan, Sougnez, Carrie L, Verhaak, Roel, Voet, Douglas, Abeshouse, Adam, Ahn, Jaeil, Akbani, Rehan, Ally, Adrian, Amin, Samirkumar, Andry, Christopher D., Annala, Matti, Aprikian, Armen, Armenia, Joshua, Arora, Arshi, Auman, J. Todd, Balasundaram, Miruna, Balu, Saianand, Barbieri, Christopher E., Bauer, Thomas, Benz, Christopher C., Bergeron, Alain, Beroukhim, Rameen, Berrios, Mario, Bivol, Adrian, Bodenheimer, Tom, Boice, Lori, Bootwalla, Moiz S., dos Reis, Rodolfo Borges, Boutros, Paul C., Bowen, Jay, Bowlby, Reanne, Boyd, Jeffrey, Breggia, Anne, Brimo, Fadi, Brooks, Denise, Broom, Bradley M., Bryce, Alan H., Bubley, Glenn, Burks, Eric, Butterfield, Yaron S.N., Button, Michael, Canes, David, Carlotti, Carlos G., Carlsen, Rebecca, Carroll, Peter R., Cartun, Richard, Carver, Brett S., Chan, June M., Chang, Matthew T., Chen, Yu, Costello, Anthony J., Cherniack, Andrew D., Chevalier, Simone, Cho, Juok, Chu, Andy, Chuah, Eric, Chudamani, Sudha, Ciriello, Giovanni, Clarke, Amanda, Cooperberg, Matthew R., Corcoran, Niall M., Cowan, Janet, Crain, Daniel, Curley, Erin, David, Kerstin, Demchok, John A., Demichelis, Francesca, Dhalla, Noreen, Dhir, Rajiv, Doueik, Alexandre, Drake, Bettina, Dvinge, Heidi, Dyakova, Natalya, Felau, Ina, Ferguson, Martin L., Frazer, Scott, Freedland, Stephen, Fu, Yao, Bristow, Christopher A., Gao, Jianjiong, Gardner, Johanna, Gastier-Foster, Julie M., Gehlenborg, Nils, Gerken, Mark, Gerstein, Mark B., Godwin, Andrew K., Gopalan, Anuradha, Graefen, Markus, Graim, Kiley, Gribbin, Thomas, Guin, Ranabir, Gupta, Manaswi, Hadjipanayis, Angela, Haider, Syed, Hamel, Lucie, Hayes, D. Neil, Hess, Julian, Hoadley, Katherine A., Holbrook, Andrea H., Holt, Robert A., Holway, Antonia, Hovens, Christopher M., Hoyle, Alan P., Huang, Mei, Hutter, Carolyn M., Ittmann, Michael, Iype, Lisa, Jefferys, Stuart R., Jones, Corbin D., Jones, Steven J.M., Juhl, Hartmut, Kahles, Andre, Kane, Christopher J., Kasaian, Katayoon, Kerger, Michael, Khurana, Ekta, Kim, Jaegil, Klein, Robert J., Kucherlapati, Raju, Lacombe, Louis, Ladanyi, Marc, Lai, Phillip H., Laird, Peter W., Latour, Mathieu, Lawrence, Michael S., Lau, Kevin, LeBien, Tucker, Lee, Darlene, Lee, Semin, Lehmann, Kjong-Van, Leraas, Kristen M., Leshchiner, Ignaty, Leung, Robert, Libertino, John A., Lichtenberg, Tara M., Linehan, W. Marston, Ling, Shiyun, Lippman, Scott M., Liu, Jia, Liu, Wenbin, Lochovsky, Lucas, Logothetis, Christopher, Lolla, Laxmi, Longacre, Teri, Lu, Yiling, Luo, Jianhua, Ma, Yussanne, Mahadeshwar, Harshad S., Mallery, David, Mariamidze, Armaz, Marra, Marco A., Mayo, Michael, McCall, Shannon, McKercher, Ginette, Meng, Shaowu, Mes-Masson, Anne-Marie, Merino, Maria J., Mieczkowski, Piotr A., Mills, Gordon B., Mills Shaw, Kenna R., Minner, Sarah, Moinzadeh, Alireza, Moore, Richard A., Morris, Scott, Morrison, Carl, Mose, Lisle E., Mungall, Andrew J., Murray, Bradley A., Myers, Jerome B., Naresh, Rashi, Nelson, Joel, Nelson, Mark A., Nelson, Peter S., Newton, Yulia, Noble, Michael S., Noushmehr, Houtan, Nykter, Matti, Pantazi, Angeliki, Parfenov, Michael, Parker, Joel S., Paulauskis, Joseph, Penny, Robert, Perou, Charles M., Piche, Alain, Pihl, Todd, Pinto, Peter A., Prandi, Davide, Protopopov, Alexei, Ramirez, Nilsa C., Rao, Arvind, Rathmell, W. Kimryn, Ratsch, Gunnar, Ren, Xiaojia, Reuter, Victor E., Reynolds, Sheila M., Rhie, Suhn K., Rieger-Christ, Kimberly, Roach, Jeffrey, Robertson, A. Gordon, Robinson, Brian, Rubin, Mark A., Saad, Fred, Sadeghi, Sara, Saksena, Gordon, Saller, Charles, Salner, Andrew, Sanchez-Vega, Francisco, Sander, Chris, Sandusky, George, Sauter, Guido, Sboner, Andrea, Scardino, Peter T., Scarlata, Eleonora, Schein, Jacqueline E., Schlomm, Thorsten, Schmidt, Laura S., Schultz, Nikolaus, Schumacher, Steven E., Neder, Luciano, Seth, Sahil, Sharp, Alexis, Shelton, Candace, Shelton, Troy, Shen, Hui, Shen, Ronglai, Sherman, Mark, Sheth, Margi, Shi, Yan, Shih, Juliann, Shmulevich, Ilya, Simko, Jeffry, Simon, Ronald, Simons, Janae V., Sipahimalani, Payal, Skelly, Tara, Sofia, Heidi J., Soloway, Matthew G., Song, Xingzhi, Sorcini, Andrea, Stepa, Serghei, Stewart, Chip, Stewart, John, Stuart, Joshua M., Sullivan, Travis B., Sun, Charlie, Sun, Huandong, Tam, Angela, Tan, Donghui, Tang, Jiabin, Tarnuzzer, Roy, Tarvin, Katherine, Taylor, Barry S., Teebagy, Patrick, Tenggara, Imelda, Tetu, Bernard, Tewari, Ashutosh, Thiessen, Nina, Thompson, Timothy, Thorne, Leigh B., Tirapelli, Daniela P., Tomlins, Scott A., Trevisan, Felipe Amstalden, Troncoso, Patricia, True, Lawrence D., Tsourlakis, Maria Christina, Tyekucheva, Svitlana, Van Allen, Eliezer, Van Den Berg, David J., Veluvolu, Umadevi, Vocke, Cathy D., Wan, Yunhu, Wang, Qingguo, Wang, Wenyi, Wang, Zhining, Weinhold, Nils, Weinstein, John N., Weisenberger, Daniel J., Wilkerson, Matthew D., Wise, Lisa, Witte, John, Wu, Chia-Chin, Wu, Junyuan, Wu, Ye, Xu, Andrew W., Yadav, Shalini S., Yang, Liming, Yang, Lixing, Yau, Christina, Ye, Huihui, Yena, Peggy, Zeng, Thomas, Zenklusen, Jean C., Zhang, Hailei, Zhang, Jiashan, Zhang, Wei, Zhong, Yi, Zhu, Kelsey, Zmuda, Erik, Cancer Genome Atlas Research Network, Bradley, Robert K., Meyerson, Matthew L., and Park, Peter J.

Abstract

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects., National Institutes of Health (U.S.). (grant 5U24CA143799), National Institutes of Health (U.S.). (grant 5U24CA143835), National Institutes of Health (U.S.). (grant 5U24CA143840), National Institutes of Health (U.S.). (grant 5U24CA143843), National Institutes of Health (U.S.). (grant 5U24CA143845), National Institutes of Health (U.S.). (grant 5U24CA143848), National Institutes of Health (U.S.). (grant 5U24CA143858), National Institutes of Health (U.S.). (grant 5U24CA143866), National Institutes of Health (U.S.). (grant 5U24CA143867), National Institutes of Health (U.S.). (grant 5U24CA143882), National Institutes of Health (U.S.). (grant 5U24CA143883), National Institutes of Health (U.S.). (grant 5U24CA144025), National Institutes of Health (U.S.). (grant U54HG003067), National Institutes of Health (U.S.). (grant U54HG003079), National Institutes of Health (U.S.). (grant U54HG003273), National Institutes of Health (U.S.). (grant P30CA16672)

Published
2017

18. A widely employed germ cell marker is an ancient disordered protein with reproductive functions in diverse eukaryotes

Author

Carmell, Michelle A, primary, Dokshin, Gregoriy A, additional, Skaletsky, Helen, additional, Hu, Yueh-Chiang, additional, van Wolfswinkel, Josien C, additional, Igarashi, Kyomi J, additional, Bellott, Daniel W, additional, Nefedov, Michael, additional, Reddien, Peter W, additional, Enders, George C, additional, Uversky, Vladimir N, additional, Mello, Craig C, additional, and Page, David C, additional

Published
2016
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19. Author response: A widely employed germ cell marker is an ancient disordered protein with reproductive functions in diverse eukaryotes

Author

Carmell, Michelle A, primary, Dokshin, Gregoriy A, additional, Skaletsky, Helen, additional, Hu, Yueh-Chiang, additional, van Wolfswinkel, Josien C, additional, Igarashi, Kyomi J, additional, Bellott, Daniel W, additional, Nefedov, Michael, additional, Reddien, Peter W, additional, Enders, George C, additional, Uversky, Vladimir N, additional, Mello, Craig C, additional, and Page, David C, additional

Published
2016
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21. Whole Genome Epigenetics

Author

COLD SPRING HARBOR LAB NY, Carmell, Michelle A., Hannon, Gregory J., COLD SPRING HARBOR LAB NY, Carmell, Michelle A., and Hannon, Gregory J.

Abstract

An understanding of the cancer cell begins with knowledge of the genetic alterations that lead to neoplastic transformation. Much progress has been made in identifying areas of deletion, amplification and mutation in tumors. However, this is only part of the picture. Increasingly, we are learning that epigenetic changes, that is, changes in chromatin structure, are critically important in regulation cellular gene expression. Recently, several labs have published manuscripts identifying RNA interference as being crucial for the establishment of such epigenetic changes in species as diverse as Drosphilia, plants, and the fission yeast S. pombe. This knowledge presented a fantastic opportunity not only to study epigenetic changes, but to actually selectively create epigenetic changes by creating germline transgenic mice in which a target gene has been silenced by RNAi. After the demonstration that RNAi in mammalian cells can be mediated by vectors encoding short, hairpin RNAs (shRNAs), we sought to develop a system by which to create tranagenic mice using this technology. we demonstrate that a stable, heritable RNAi trigger in the form of a short hairpin was successfully passed through the mouse germline. As well as demonstrating a technique that can be applied to any gene of interest, we have created gene knock-down mouse models for the Neil-l DNA glycosylase involved in DNA repair pathways, and for p53. These observations open the way to the use of RNAi as a complement to standard knock-out methodologies and provides a means to rapidly assess the consequences of suppressing a gene of interest in a living animal. The vision driving the creation of this technology was one of eventual RNAi-based therapeutics. One could particularly imagine silencing oncogenes in cancer cells to attenuate their tumorgenic tendencies.

Published
2003

25. Dicer is essential for mouse development

Author

Bernstein, Emily, primary, Kim, Sang Yong, additional, Carmell, Michelle A, additional, Murchison, Elizabeth P, additional, Alcorn, Heather, additional, Li, Mamie Z, additional, Mills, Alea A, additional, Elledge, Stephen J, additional, Anderson, Kathryn V, additional, and Hannon, Gregory J, additional

Published
2003
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28. The molecular taxonomy of primary prostate cancer

Author

Piotr A. Mieczkowski, Jianhua Zhang, Saianand Balu, Marc Ladanyi, Victor E. Reuter, Johanna Gardner, Junyuan Wu, Troy Shelton, Simone Chevalier, Marco A. Marra, Anuradha Gopalan, Roy Tarnuzzer, Pei Lin, Joel S. Parker, Umadevi Veluvolu, Lisle E. Mose, Rebecca Carlsen, Michel Carmel, Shalini S. Yadav, Joseph Paulauskis, Fadi Brimo, Sheila Reynolds, Scott Frazer, Natalya Dyakova, Christopher A. Bristow, Brian D. Robinson, Lucie Hamel, Yaron S.N. Butterfield, Yao Fu, Syed Haider, Christopher J. Logothetis, Michael Parfenov, Jeff Boyd, Katherine Tarvin, Kjong-Van Lehmann, Stuart R. Jefferys, Alan P. Hoyle, Arshi Arora, A. Gordon Robertson, Matti Annala, Thomas L. Bauer, Jianhua Luo, Rodolfo Borges Dos Reis, Louis Lacombe, Andrew Salner, Matti Nykter, Alexandre Doueik, Mei Huang, Alireza Moinzadeh, Joshua Armenia, Andre Kahles, Rehan Akbani, Todd Pihl, Gordon Saksena, Robert A. Holt, Felipe Amstalden Trevisan, Mario Berrios, Nina Thiessen, Ronglai Shen, Carrie Sougnez, Xiaojia Ren, Matthew G. Soloway, Lixing Yang, W. Marston Linehan, Chip Stewart, Angeliki Pantazi, Alain Bergeron, Andrea Sboner, Angela Hadjipanayis, Xingzhi Song, Carlos Gilberto Carlotti, Manaswi Gupta, Rashi Naresh, Yiling Lu, Hartmut Juhl, Mark Gerstein, Robert Leung, Sahil Seth, Teri A. Longacre, Ignaty Leshchiner, Chris Sander, Andrew Wei Xu, Anne Marie Mes-Masson, Patrick Teebagy, Julian M. Hess, Matthew Meyerson, Adrian Ally, Jiabin Tang, Ye Wu, Janae V. Simons, David Van Den Berg, Kenna R. Mills Shaw, Patricia Troncoso, Thomas Gribbin, Shannon J. McCall, Andrew K. Godwin, Daniel J. Weisenberger, Kimberly Rieger-Christ, Nilsa C. Ramirez, Peter J. Park, Margi Sheth, Mark E. Sherman, Eric S. Lander, Yunhu Wan, Lisa Iype, Robert Penny, J. Todd Auman, Ekta Khurana, Stephen J. Freedland, Jeffry Simko, Nils Weinhold, Bradley M. Broom, Angela Tam, Nikolaus Schultz, Erik Zmuda, Wei Zhang, Wenyi Wang, Jeffrey Roach, Christopher E. Barbieri, Alan H. Bryce, Qingguo Wang, Lawrence D. True, Christopher C. Benz, Mathieu Latour, Richard A. Moore, Michael Mayo, Yi Zhong, Tara M. Lichtenberg, Jacqueline E. Schein, Svitlana Tyekucheva, Ranabir Guin, Scott L. Carter, Michael Kerger, David Canes, Scott M. Lippman, Alexei Protopopov, Katayoon Kasaian, Peter A. Pinto, Peter S. Nelson, W. Kimryn Rathmell, David Mallery, Brett S. Carver, David I. Heiman, Juok Cho, Doug Voet, Thorsten Schlomm, Janet E. Cowan, Heidi J. Sofia, Peggy Yena, Matthew D. Wilkerson, Glenn Bubley, Tucker W. LeBien, Yan Shi, Lucas Lochovsky, Gordon B. Mills, Hailei Zhang, Andrea Holbrook, Christopher M. Hovens, Christina Yau, Jonathan G. Seidman, Samirkumar B. Amin, Corbin D. Jones, Andrew D. Cherniack, Lori Boice, Laxmi Lolla, Kristen M. Leraas, Denise Brooks, Francesca Demichelis, Maria Christina Tsourlakis, Katherine A. Hoadley, Charles Saller, Leigh B. Thorne, Julie M. Gastier-Foster, Jaegil Kim, Rameen Beroukhim, Peter R. Carroll, John A. Demchok, Christopher J. Kane, Jay Bowen, Massimo Loda, Richard Cartun, Ina Felau, Carl Morrison, Kerstin David, Eliezer M. Van Allen, Laura S. Schmidt, D. Neil Hayes, Adrian Bivol, Michael S. Lawrence, Raju Kucherlapati, Kelsey Zhu, Wen-Bin Liu, Matthew R. Cooperberg, Houtan Noushmehr, Daniel Crain, Luciano Neder, Lynda Chin, Barry S. Taylor, Jiashan Zhang, Bradley A. Murray, Ginette McKercher, Miruna Balasundaram, Chia Chin Wu, Peter T. Scardino, Suhn K. Rhie, Mark A. Rubin, Jean C. Zenklusen, Ronald Simon, Jaeil Ahn, Markus Graefen, Phillip H. Lai, Michael Ittmann, June M. Chan, Maria J. Merino, Andy Chu, Liming Yang, Charles M. Perou, Steven J.M. Jones, Gad Getz, Stacey Gabriel, Martin L. Ferguson, Jianjiong Gao, Payal Sipahimalani, Lisa Wise, Serghei Stepa, Arvind Rao, Bettina F. Drake, Antonia H. Holway, Armaz Mariamidze, Kiley Graim, Juliann Shih, Guido Sauter, Sarah Minner, Amanda Clarke, Harshad S. Mahadeshwar, Andrew J. Mungall, Alain Piché, Cathy D. Vocke, Sudha Chudamani, Yulia Newton, Davide Prandi, Roeland Verhaak, Ilya Shmulevich, Matthew T. Chang, Sara Sadeghi, Michael Button, Joshua M. Stuart, Anne Breggia, Kristian Cibulskis, Giovanni Ciriello, Paul C. Boutros, Yu Chen, Zhining Wang, Jerome Myers, Heidi Dvinge, Ashutosh Tewari, Scott Morris, Andrea Sorcini, Tara Skelly, Niall M. Corcoran, Michael S. Noble, Anthony J. Costello, Timothy C. Thompson, Eric Chuah, Carolyn M. Hutter, Robert K. Bradley, Fred Saad, John A. Libertino, Reanne Bowlby, John A. Stewart, Shiyun Ling, Gunnar Rätsch, George E. Sandusky, Alexis Sharp, Eric J. Burks, Thomas Zeng, Erin Curley, Charlie Sun, Rajiv Dhir, Yussanne Ma, Huihui Ye, Hui Shen, Nils Gehlenborg, Imelda Tenggara, Travis Sullivan, Tom Bodenheimer, Jia Liu, Christopher D. Andry, Adam Abeshouse, Daniela P. Tirapelli, John N. Weinstein, Kevin Lau, Francisco Sanchez-Vega, Armen Aprikian, Peter W. Laird, Noreen Dhalla, Candace Shelton, Joel Nelson, Bernard Têtu, Darlene Lee, Eleonora Scarlata, Mark Nelson, Steven E. Schumacher, Robert J. Klein, Mark Gerken, Donghui Tan, Semin Lee, John S. Witte, Shaowu Meng, Huandong Sun, Moiz S. Bootwalla, Scott A. Tomlins, Institute for Medical Engineering and Science, Broad Institute of MIT and Harvard, Massachusetts Institute of Technology. Department of Biology, Bradley, Robert K, Carmell, Michelle, Carter, Scott, Chin, Lynda, Cibulskis, Kristian, Getz, Gad Asher, Heiman, David, Lander, Eric Steven, Lin, Pei, Loda, Massimo, Meyerson, Matthew L, Park, Peter J, Seidman, Jonathan, Sougnez, Carrie L, Verhaak, Roel, and Voet, Douglas

Subjects
0301 basic medicine, Oncology, Male, medicine.medical_specialty, DNA Repair, DNA repair, Urology, MEDLINE, Biology, SPOP, Bioinformatics, Molecular taxonomy, General Biochemistry, Genetics and Molecular Biology, Article, Epigenesis, Genetic, Fusion gene, 03 medical and health sciences, Prostate cancer, Phosphatidylinositol 3-Kinases, 0302 clinical medicine, Prostate, Internal medicine, medicine, Humans, Neoplasm Metastasis, Gene, 030304 developmental biology, Gynecology, 0303 health sciences, Primary (chemistry), business.industry, Prostatic Neoplasms, medicine.disease, 3. Good health, Androgen receptor, Gene Expression Regulation, Neoplastic, GENÉTICA, 030104 developmental biology, medicine.anatomical_structure, Receptors, Androgen, 030220 oncology & carcinogenesis, DNA methylation, Mutation, Cancer research, ras Proteins, Gene Fusion, business, Signal Transduction
Abstract

There is substantial heterogeneity among primary prostate cancers, evident in the spectrum of molecular abnormalities and its variable clinical course. As part of The Cancer Genome Atlas (TCGA), we present a comprehensive molecular analysis of 333 primary prostate carcinomas. Our results revealed a molecular taxonomy in which 74% of these tumors fell into one of seven subtypes defined by specific gene fusions (ERG, ETV1/4, and FLI1) or mutations (SPOP, FOXA1, and IDH1). Epigenetic profiles showed substantial heterogeneity, including an IDH1 mutant subset with a methylator phenotype. Androgen receptor (AR) activity varied widely and in a subtype-specific manner, with SPOP and FOXA1 mutant tumors having the highest levels of AR-induced transcripts. 25% of the prostate cancers had a presumed actionable lesion in the PI3K or MAPK signaling pathways, and DNA repair genes were inactivated in 19%. Our analysis reveals molecular heterogeneity among primary prostate cancers, as well as potentially actionable molecular defects., National Institutes of Health (U.S.). (grant 5U24CA143799), National Institutes of Health (U.S.). (grant 5U24CA143835), National Institutes of Health (U.S.). (grant 5U24CA143840), National Institutes of Health (U.S.). (grant 5U24CA143843), National Institutes of Health (U.S.). (grant 5U24CA143845), National Institutes of Health (U.S.). (grant 5U24CA143848), National Institutes of Health (U.S.). (grant 5U24CA143858), National Institutes of Health (U.S.). (grant 5U24CA143866), National Institutes of Health (U.S.). (grant 5U24CA143867), National Institutes of Health (U.S.). (grant 5U24CA143882), National Institutes of Health (U.S.). (grant 5U24CA143883), National Institutes of Health (U.S.). (grant 5U24CA144025), National Institutes of Health (U.S.). (grant U54HG003067), National Institutes of Health (U.S.). (grant U54HG003079), National Institutes of Health (U.S.). (grant U54HG003273), National Institutes of Health (U.S.). (grant P30CA16672)

Published
2015

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