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2. Escargot maintains stemness and suppresses differentiation in Drosophila intestinal stem cells

Author

Korzelius, Jerome, Naumann, Svenja K, Loza-Coll, Mariano A, Chan, Jessica SK, Dutta, Devanjali, Oberheim, Jessica, Gläßer, Christine, Southall, Tony D, Brand, Andrea H, Jones, D Leanne, and Edgar, Bruce A

Subjects
Stem Cell Research - Nonembryonic - Non-Human, Genetics, Stem Cell Research, Stem Cell Research - Nonembryonic - Human, Regenerative Medicine, Animals, Cell Differentiation, Drosophila, Drosophila Proteins, Gastrointestinal Tract, Gene Deletion, Gene Expression, Gene Expression Profiling, Stem Cells, Drosophila midgut, enterocyte differentiation, intestinal stem cells, Pdm1, Snail transcription factors, Biological Sciences, Information and Computing Sciences, Medical and Health Sciences, Developmental Biology
Abstract

Snail family transcription factors are expressed in various stem cell types, but their function in maintaining stem cell identity is unclear. In the adult Drosophila midgut, the Snail homolog Esg is expressed in intestinal stem cells (ISCs) and their transient undifferentiated daughters, termed enteroblasts (EB). We demonstrate here that loss of esg in these progenitor cells causes their rapid differentiation into enterocytes (EC) or entero-endocrine cells (EE). Conversely, forced expression of Esg in intestinal progenitor cells blocks differentiation, locking ISCs in a stem cell state. Cell type-specific transcriptome analysis combined with Dam-ID binding studies identified Esg as a major repressor of differentiation genes in stem and progenitor cells. One critical target of Esg was found to be the POU-domain transcription factor, Pdm1, which is normally expressed specifically in differentiated ECs. Ectopic expression of Pdm1 in progenitor cells was sufficient to drive their differentiation into ECs. Hence, Esg is a critical stem cell determinant that maintains stemness by repressing differentiation-promoting factors, such as Pdm1.

Published
2014

10. Age-related changes in polycomb gene regulation disrupt lineage fidelity in intestinal stem cells

Author

Tauc, Helen M, Rodriguez-Fernandez, Imilce A., Hackney, Jason, Pawlak, Michal, Ronnen-Oron, Tal, Korzelius, Jerome, Moussa, Hagar F, Chaudhuri, Subhra, Modrusan, Zora, Edgar, Bruce A., Jasper, Heinrich, Tauc, Helen M, Rodriguez-Fernandez, Imilce A., Hackney, Jason, Pawlak, Michal, Ronnen-Oron, Tal, Korzelius, Jerome, Moussa, Hagar F, Chaudhuri, Subhra, Modrusan, Zora, Edgar, Bruce A., and Jasper, Heinrich

Abstract

Tissue homeostasis requires long-term lineage fidelity of somatic stem cells. Whether and how age-related changes in somatic stem cells impact the faithful execution of lineage decisions remains largely unknown. Here, we address this question using genome-wide chromatin accessibility and transcriptome analysis as well as single-cell RNA-seq to explore stem-cell-intrinsic changes in the aging Drosophila intestine. These studies indicate that in stem cells of old flies, promoters of Polycomb (Pc) target genes become differentially accessible, resulting in the increased expression of enteroendocrine (EE) cell specification genes. Consistently, we find age-related changes in the composition of the EE progenitor cell population in aging intestines, as well as a significant increase in the proportion of EE-specified intestinal stem cells (ISCs) and progenitors in aging flies. We further confirm that Pc-mediated chromatin regulation is a critical determinant of EE cell specification in the Drosophila intestine. Pc is required to maintain expression of stem cell genes while ensuring repression of differentiation and specification genes. Our results identify Pc group proteins as central regulators of lineage identity in the intestinal epithelium and highlight the impact of age-related decline in chromatin regulation on tissue homeostasis.

Published
2021

11. Publisher Correction: The mutational impact of culturing human pluripotent and adult stem cells

Author

CMM Groep Cuppen, Cancer, CMM Groep De Ridder, Epi Infectieziekten Team 2, Infection & Immunity, CMM USEQ Facility, CMM, Kuijk, Ewart, Jager, Myrthe, van der Roest, Bastiaan, Locati, Mauro D, Van Hoeck, Arne, Korzelius, Jerome, Janssen, Roel, Besselink, Nicolle, Boymans, Sander, van Boxtel, Ruben, Cuppen, Edwin, CMM Groep Cuppen, Cancer, CMM Groep De Ridder, Epi Infectieziekten Team 2, Infection & Immunity, CMM USEQ Facility, CMM, Kuijk, Ewart, Jager, Myrthe, van der Roest, Bastiaan, Locati, Mauro D, Van Hoeck, Arne, Korzelius, Jerome, Janssen, Roel, Besselink, Nicolle, Boymans, Sander, van Boxtel, Ruben, and Cuppen, Edwin

Published
2020

12. The mutational impact of culturing human pluripotent and adult stem cells

Author

CMM Groep Cuppen, Cancer, CMM Groep De Ridder, Epi Infectieziekten Team 2, Infection & Immunity, CMM USEQ Facility, Genetica Klinische Genetica, CMM, Kuijk, Ewart, Jager, Myrthe, van der Roest, Bastiaan, Locati, Mauro D, Van Hoeck, Arne, Korzelius, Jerome, Janssen, Roel, Besselink, Nicolle, Boymans, Sander, van Boxtel, Ruben, Cuppen, Edwin, CMM Groep Cuppen, Cancer, CMM Groep De Ridder, Epi Infectieziekten Team 2, Infection & Immunity, CMM USEQ Facility, Genetica Klinische Genetica, CMM, Kuijk, Ewart, Jager, Myrthe, van der Roest, Bastiaan, Locati, Mauro D, Van Hoeck, Arne, Korzelius, Jerome, Janssen, Roel, Besselink, Nicolle, Boymans, Sander, van Boxtel, Ruben, and Cuppen, Edwin

Published
2020

14. Author response: Age-related changes in polycomb gene regulation disrupt lineage fidelity in intestinal stem cells

Author

Tauc, Helen M, primary, Rodriguez-Fernandez, Imilce A, additional, Hackney, Jason A, additional, Pawlak, Michal, additional, Ronnen Oron, Tal, additional, Korzelius, Jerome, additional, Moussa, Hagar F, additional, Chaudhuri, Subhra, additional, Modrusan, Zora, additional, Edgar, Bruce A, additional, and Jasper, Heinrich, additional

Published
2021
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16. MOESM2 of Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Author

Middelkamp, Sjors, Vlaar, Judith, Giltay, Jacques, Korzelius, Jerome, Besselink, Nicolle, Boymans, Sander, Janssen, Roel, Fonteijne, Lisanne De La, Binsbergen, Ellen Van, Roosmalen, Markus Van, Hochstenbach, Ron, Giachino, Daniela, Talkowski, Michael, Wigard Kloosterman, and Cuppen, Edwin

Abstract

Additional file 2. Figure S1 to S8, including figure legends and supplemental references.

Published
2019
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17. Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Author

Cancer, CMM Groep Cuppen, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Kloosterman, Brain, CMM Groep De Ridder, CMM, Middelkamp, Sjors, Vlaar, Judith M, Giltay, Jacques, Korzelius, Jerome, Besselink, Nicolle, Boymans, Sander, Janssen, Roel, de la Fonteijne, Lisanne, van Binsbergen, Ellen, van Roosmalen, Markus J, Hochstenbach, Ron, Giachino, Daniela, Talkowski, Michael E, Kloosterman, Wigard P, Cuppen, Edwin, Cancer, CMM Groep Cuppen, Genetica Klinische Genetica, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Kloosterman, Brain, CMM Groep De Ridder, CMM, Middelkamp, Sjors, Vlaar, Judith M, Giltay, Jacques, Korzelius, Jerome, Besselink, Nicolle, Boymans, Sander, Janssen, Roel, de la Fonteijne, Lisanne, van Binsbergen, Ellen, van Roosmalen, Markus J, Hochstenbach, Ron, Giachino, Daniela, Talkowski, Michael E, Kloosterman, Wigard P, and Cuppen, Edwin

Published
2019

18. Prioritization of genes driving congenital phenotypes of patients with de novo genomic structural variants

Author

Middelkamp, Sjors, primary, Vlaar, Judith M., additional, Giltay, Jacques, additional, Korzelius, Jerome, additional, Besselink, Nicolle, additional, Boymans, Sander, additional, Janssen, Roel, additional, de la Fonteijne, Lisanne, additional, van Binsbergen, Ellen, additional, van Roosmalen, Markus J., additional, Hochstenbach, Ron, additional, Giachino, Daniela, additional, Talkowski, Michael E., additional, Kloosterman, Wigard P., additional, and Cuppen, Edwin, additional

Published
2019
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20. Mutational impact of culturing human pluripotent and adult stem cells

Author

Kuijk, Ewart, primary, Jager, Myrthe, additional, Roest, Bastiaan van der, additional, Locati, Mauro, additional, Hoeck, Arne Van, additional, Korzelius, Jerome, additional, Janssen, Roel, additional, Besselink, Nicolle, additional, Boymans, Sander, additional, Boxtel, Ruben van, additional, and Cuppen, Edwin, additional

Published
2018
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21. Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Author

Cretu Stancu, Mircea, van Roosmalen, Markus J, Renkens, Ivo, Nieboer, Marleen M, Middelkamp, Sjors, de Ligt, Joep, Pregno, Giulia, Giachino, Daniela, Mandrile, Giorgia, Espejo Valle-Inclan, Jose, Korzelius, Jerome, de Bruijn, Ewart, Cuppen, Edwin, Talkowski, Michael E., Marschall, Tobias, de Ridder, Jeroen, Kloosterman, Wigard P, Cretu Stancu, Mircea, van Roosmalen, Markus J, Renkens, Ivo, Nieboer, Marleen M, Middelkamp, Sjors, de Ligt, Joep, Pregno, Giulia, Giachino, Daniela, Mandrile, Giorgia, Espejo Valle-Inclan, Jose, Korzelius, Jerome, de Bruijn, Ewart, Cuppen, Edwin, Talkowski, Michael E., Marschall, Tobias, de Ridder, Jeroen, and Kloosterman, Wigard P

Published
2017

22. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E

Published
2017

23. Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Author

CMM Groep Kaaij, Circulatory Health, CMM Groep Kloosterman, Genetica, CMM Groep De Ridder, CMM Groep Cuppen, Cancer, CMM, CMM Sectie Genomics and Bioinformatics, Child Health, Cretu Stancu, Mircea, van Roosmalen, Markus J, Renkens, Ivo, Nieboer, Marleen M, Middelkamp, Sjors, de Ligt, Joep, Pregno, Giulia, Giachino, Daniela, Mandrile, Giorgia, Espejo Valle-Inclan, Jose, Korzelius, Jerome, de Bruijn, Ewart, Cuppen, Edwin, Talkowski, Michael E., Marschall, Tobias, de Ridder, Jeroen, Kloosterman, Wigard P, CMM Groep Kaaij, Circulatory Health, CMM Groep Kloosterman, Genetica, CMM Groep De Ridder, CMM Groep Cuppen, Cancer, CMM, CMM Sectie Genomics and Bioinformatics, Child Health, Cretu Stancu, Mircea, van Roosmalen, Markus J, Renkens, Ivo, Nieboer, Marleen M, Middelkamp, Sjors, de Ligt, Joep, Pregno, Giulia, Giachino, Daniela, Mandrile, Giorgia, Espejo Valle-Inclan, Jose, Korzelius, Jerome, de Bruijn, Ewart, Cuppen, Edwin, Talkowski, Michael E., Marschall, Tobias, de Ridder, Jeroen, and Kloosterman, Wigard P

Published
2017

24. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, Talkowski, Michael E, Genetica Klinische Genetica, Brain, CMM, Circulatory Health, Cancer, Child Health, Genetica Sectie Genoomdiagnostiek, CMM Groep Cuppen, Genetica, CMM Groep Kloosterman, Redin, Claire, Brand, Harrison, Collins, Ryan L, Kammin, Tammy, Mitchell, Elyse, Hodge, Jennelle C, Hanscom, Carrie, Pillalamarri, Vamsee, Seabra, Catarina M, Abbott, Mary-Alice, Abdul-Rahman, Omar A, Aberg, Erika, Adley, Rhett, Alcaraz-Estrada, Sofia L, Alkuraya, Fowzan S, An, Yu, Anderson, Mary-Anne, Antolik, Caroline, Anyane-Yeboa, Kwame, Atkin, Joan F, Bartell, Tina, Bernstein, Jonathan A, Beyer, Elizabeth, Blumenthal, Ian, Bongers, Ernie M H F, Brilstra, Eva H, Brown, Chester W, Brüggenwirth, Hennie T, Callewaert, Bert, Chiang, Colby, Corning, Ken, Cox, Helen, Cuppen, Edwin, Currall, Benjamin B, Cushing, Tom, David, Dezso, Deardorff, Matthew A, Dheedene, Annelies, D'Hooghe, Marc, de Vries, Bert B A, Earl, Dawn L, Ferguson, Heather L, Fisher, Heather, FitzPatrick, David R, Gerrol, Pamela, Giachino, Daniela, Glessner, Joseph T, Gliem, Troy, Grady, Margo, Graham, Brett H, Griffis, Cristin, Gripp, Karen W, Gropman, Andrea L, Hanson-Kahn, Andrea, Harris, David J, Hayden, Mark A, Hill, Rosamund, Hochstenbach, Ron, Hoffman, Jodi D, Hopkin, Robert J, Hubshman, Monika W, Innes, A Micheil, Irons, Mira, Irving, Melita, Jacobsen, Jessie C, Janssens, Sandra, Jewett, Tamison, Johnson, John P, Jongmans, Marjolijn C, Kahler, Stephen G, Koolen, David A, Korzelius, Jerome, Kroisel, Peter M, Lacassie, Yves, Lawless, William, Lemyre, Emmanuelle, Leppig, Kathleen, Levin, Alex V, Li, Haibo, Li, Hong, Liao, Eric C, Lim, Cynthia, Lose, Edward J, Lucente, Diane, Macera, Michael J, Manavalan, Poornima, Mandrile, Giorgia, Marcelis, Carlo L, Margolin, Lauren, Mason, Tamara, Masser-Frye, Diane, McClellan, Michael W, Mendoza, Cinthya J Zepeda, Menten, Björn, Middelkamp, Sjors, Mikami, Liya R, Moe, Emily, Mohammed, Shehla, Mononen, Tarja, Mortenson, Megan E, Moya, Graciela, Nieuwint, Aggie W, Ordulu, Zehra, Parkash, Sandhya, Pauker, Susan P, Pereira, Shahrin, Perrin, Danielle, Phelan, Katy, Aguilar, Raul E Piña, Poddighe, Pino J, Pregno, Giulia, Raskin, Salmo, Reis, Linda, Rhead, William, Rita, Debra, Renkens, Ivo, Roelens, Filip, Ruliera, Jayla, Rump, Patrick, Schilit, Samantha L P, Shaheen, Ranad, Sparkes, Rebecca, Spiegel, Erica, Stevens, Blair, Stone, Matthew R, Tagoe, Julia, Thakuria, Joseph V, van Bon, Bregje W, van de Kamp, Jiddeke, van Der Burgt, Ineke, van Essen, Ton, van Ravenswaaij-Arts, Conny M, van Roosmalen, Markus J, Vergult, Sarah, Volker-Touw, Catharina M L, Warburton, Dorothy P, Waterman, Matthew J, Wiley, Susan, Wilson, Anna, Yerena-de Vega, Maria de la Concepcion A, Zori, Roberto T, Levy, Brynn, Brunner, Han G, de Leeuw, Nicole, Kloosterman, Wigard P, Thorland, Erik C, Morton, Cynthia C, Gusella, James F, and Talkowski, Michael E

Published
2017

25. Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Author

Cretu Stancu, Mircea, primary, van Roosmalen, Markus J., additional, Renkens, Ivo, additional, Nieboer, Marleen M., additional, Middelkamp, Sjors, additional, de Ligt, Joep, additional, Pregno, Giulia, additional, Giachino, Daniela, additional, Mandrile, Giorgia, additional, Espejo Valle-Inclan, Jose, additional, Korzelius, Jerome, additional, de Bruijn, Ewart, additional, Cuppen, Edwin, additional, Talkowski, Michael E., additional, Marschall, Tobias, additional, de Ridder, Jeroen, additional, and Kloosterman, Wigard P., additional

Published
2017
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26. Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Author

Stancu, Mircea Cretu, primary, van Roosmalen, Markus J., additional, Renkens, Ivo, additional, Nieboer, Marleen, additional, Middelkamp, Sjors, additional, Ligt, Joep de, additional, Pregno, Giulia, additional, Giachino, Daniela, additional, Mandrile, Giorgia, additional, Valle-Inclan, Jose Espejo, additional, Korzelius, Jerome, additional, Bruijn, Ewart de, additional, Cuppen, Edwin, additional, Talkowski, Michael E., additional, Marschall, Tobias, additional, Ridder, Jeroen de, additional, and Kloosterman, Wigard P., additional

Published
2017
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27. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies

Author

Redin, Claire, primary, Brand, Harrison, additional, Collins, Ryan L, additional, Kammin, Tammy, additional, Mitchell, Elyse, additional, Hodge, Jennelle C, additional, Hanscom, Carrie, additional, Pillalamarri, Vamsee, additional, Seabra, Catarina M, additional, Abbott, Mary-Alice, additional, Abdul-Rahman, Omar A, additional, Aberg, Erika, additional, Adley, Rhett, additional, Alcaraz-Estrada, Sofia L, additional, Alkuraya, Fowzan S, additional, An, Yu, additional, Anderson, Mary-Anne, additional, Antolik, Caroline, additional, Anyane-Yeboa, Kwame, additional, Atkin, Joan F, additional, Bartell, Tina, additional, Bernstein, Jonathan A, additional, Beyer, Elizabeth, additional, Blumenthal, Ian, additional, Bongers, Ernie M H F, additional, Brilstra, Eva H, additional, Brown, Chester W, additional, Brüggenwirth, Hennie T, additional, Callewaert, Bert, additional, Chiang, Colby, additional, Corning, Ken, additional, Cox, Helen, additional, Cuppen, Edwin, additional, Currall, Benjamin B, additional, Cushing, Tom, additional, David, Dezso, additional, Deardorff, Matthew A, additional, Dheedene, Annelies, additional, D'Hooghe, Marc, additional, de Vries, Bert B A, additional, Earl, Dawn L, additional, Ferguson, Heather L, additional, Fisher, Heather, additional, FitzPatrick, David R, additional, Gerrol, Pamela, additional, Giachino, Daniela, additional, Glessner, Joseph T, additional, Gliem, Troy, additional, Grady, Margo, additional, Graham, Brett H, additional, Griffis, Cristin, additional, Gripp, Karen W, additional, Gropman, Andrea L, additional, Hanson-Kahn, Andrea, additional, Harris, David J, additional, Hayden, Mark A, additional, Hill, Rosamund, additional, Hochstenbach, Ron, additional, Hoffman, Jodi D, additional, Hopkin, Robert J, additional, Hubshman, Monika W, additional, Innes, A Micheil, additional, Irons, Mira, additional, Irving, Melita, additional, Jacobsen, Jessie C, additional, Janssens, Sandra, additional, Jewett, Tamison, additional, Johnson, John P, additional, Jongmans, Marjolijn C, additional, Kahler, Stephen G, additional, Koolen, David A, additional, Korzelius, Jerome, additional, Kroisel, Peter M, additional, Lacassie, Yves, additional, Lawless, William, additional, Lemyre, Emmanuelle, additional, Leppig, Kathleen, additional, Levin, Alex V, additional, Li, Haibo, additional, Li, Hong, additional, Liao, Eric C, additional, Lim, Cynthia, additional, Lose, Edward J, additional, Lucente, Diane, additional, Macera, Michael J, additional, Manavalan, Poornima, additional, Mandrile, Giorgia, additional, Marcelis, Carlo L, additional, Margolin, Lauren, additional, Mason, Tamara, additional, Masser-Frye, Diane, additional, McClellan, Michael W, additional, Mendoza, Cinthya J Zepeda, additional, Menten, Björn, additional, Middelkamp, Sjors, additional, Mikami, Liya R, additional, Moe, Emily, additional, Mohammed, Shehla, additional, Mononen, Tarja, additional, Mortenson, Megan E, additional, Moya, Graciela, additional, Nieuwint, Aggie W, additional, Ordulu, Zehra, additional, Parkash, Sandhya, additional, Pauker, Susan P, additional, Pereira, Shahrin, additional, Perrin, Danielle, additional, Phelan, Katy, additional, Aguilar, Raul E Piña, additional, Poddighe, Pino J, additional, Pregno, Giulia, additional, Raskin, Salmo, additional, Reis, Linda, additional, Rhead, William, additional, Rita, Debra, additional, Renkens, Ivo, additional, Roelens, Filip, additional, Ruliera, Jayla, additional, Rump, Patrick, additional, Schilit, Samantha L P, additional, Shaheen, Ranad, additional, Sparkes, Rebecca, additional, Spiegel, Erica, additional, Stevens, Blair, additional, Stone, Matthew R, additional, Tagoe, Julia, additional, Thakuria, Joseph V, additional, van Bon, Bregje W, additional, van de Kamp, Jiddeke, additional, van Der Burgt, Ineke, additional, van Essen, Ton, additional, van Ravenswaaij-Arts, Conny M, additional, van Roosmalen, Markus J, additional, Vergult, Sarah, additional, Volker-Touw, Catharina M L, additional, Warburton, Dorothy P, additional, Waterman, Matthew J, additional, Wiley, Susan, additional, Wilson, Anna, additional, Yerena-de Vega, Maria de la Concepcion A, additional, Zori, Roberto T, additional, Levy, Brynn, additional, Brunner, Han G, additional, de Leeuw, Nicole, additional, Kloosterman, Wigard P, additional, Thorland, Erik C, additional, Morton, Cynthia C, additional, Gusella, James F, additional, and Talkowski, Michael E, additional

Published
2016
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29. C. elegans MCM-4 is a general DNA replication and checkpoint component with an epidermis-specific requirement for growth and viability

Author

Massachusetts Institute of Technology. Department of Biology, Horvitz, H. Robert, Korzelius, Jerome, The, Inge, Ruijtenberg, Suzan, Portegijs, Vincent, Xu, Huihong, van den Heuvel, Sander, Horvitz, Howard Robert, Massachusetts Institute of Technology. Department of Biology, Horvitz, H. Robert, Korzelius, Jerome, The, Inge, Ruijtenberg, Suzan, Portegijs, Vincent, Xu, Huihong, van den Heuvel, Sander, and Horvitz, Howard Robert

Abstract

DNA replication and its connection to M phase restraint are studied extensively at the level of single cells but rarely in the context of a developing animal. C. elegans lin-6 mutants lack DNA synthesis in postembryonic somatic cell lineages, while entry into mitosis continues. These mutants grow slowly and either die during larval development or develop into sterile adults. We found that lin-6 corresponds to mcm-4 and encodes an evolutionarily conserved component of the MCM2-7 pre-RC and replicative helicase complex. The MCM-4 protein is expressed in all dividing cells during embryonic and postembryonic development and associates with chromatin in late anaphase. Induction of cell cycle entry and differentiation continues in developing mcm-4 larvae, even in cells that went through abortive division. In contrast to somatic cells in mcm-4 mutants, the gonad continues DNA replication and cell division until late larval development. Expression of MCM-4 in the epidermis (also known as hypodermis) is sufficient to rescue the growth retardation and lethality of mcm-4 mutants. While the somatic gonad and germline show substantial ability to cope with lack of zygotic mcm-4 function, mcm-4 is specifically required in the epidermis for growth and survival of the whole organism. Thus, C. elegans mcm-4 has conserved functions in DNA replication and replication checkpoint control but also shows unexpected tissue-specific requirements.

Published
2014

30. Fly-FUCCI: A versatile tool for studying cell proliferation in complex tissues

Author

Zielke, Norman, Korzelius, Jerome, van Straaten, Monique, Bender, Katharina, Schuhknecht, Gregor F P, Dutta, Devanjali, Xiang, Jinyi, Edgar, Bruce A, Zielke, Norman, Korzelius, Jerome, van Straaten, Monique, Bender, Katharina, Schuhknecht, Gregor F P, Dutta, Devanjali, Xiang, Jinyi, and Edgar, Bruce A

Abstract

One promising approach for in vivo studies of cell proliferation is the FUCCI system (fluorescent ubiquitination-based cell cycle indicator). Here, we report the development of a Drosophila-specific FUCCI system (Fly-FUCCI) that allows one to distinguish G1, S, and G2 phases of interphase. Fly-FUCCI relies on fluorochrome-tagged degrons from the Cyclin B and E2F1 proteins, which are degraded by the ubiquitin E3-ligases APC/C and CRL4Cdt2, during mitosis or the onset of S phase, respectively. These probes can track cell-cycle patterns in cultured Drosophila cells, eye and wing imaginal discs, salivary glands, the adult midgut, and probably other tissues. To support a broad range of experimental applications, we have generated a toolkit of transgenic Drosophila lines that express the Fly-FUCCI probes under control of the UASt, UASp, QUAS, and ubiquitin promoters. The Fly-FUCCI system should be a valuable tool for visualizing cell-cycle activity during development, tissue homeostasis, and neoplastic growth.

Published
2014

31. Mapping and phasing of structural variation in patient genomes using nanopore sequencing.

Author

Stancu, Mircea Cretu, van Roosmalen, Markus J., Renkens, Ivo, Nieboer, Marleen M., Middelkamp, Sjors, de Ligt, Joep, Pregno, Giulia, Giachino, Daniela, Mandrile, Giorgia, Valle-Inclan, Jose Espejo, Korzelius, Jerome, de Bruijn, Ewart, Cuppen, Edwin, Talkowski, Michael E., Marschall, Tobias, de Ridder, Jeroen, and Kloosterman, Wigard P.

Subjects
GENOMES, HUMAN abnormalities, NUCLEOTIDE sequencing
Abstract

Despite improvements in genomics technology, the detection of structural variants (SVs) from short-read sequencing still poses challenges, particularly for complex variation. Here we analyse the genomes of two patients with congenital abnormalities using the MinION nanopore sequencer and a novel computational pipeline—NanoSV. We demonstrate that nanopore long reads are superior to short reads with regard to detection of de novo chromothripsis rearrangements. The long reads also enable efficient phasing of genetic variations, which we leveraged to determine the parental origin of all de novo chromothripsis breakpoints and to resolve the structure of these complex rearrangements. Additionally, genome-wide surveillance of inherited SVs reveals novel variants, missed in short-read data sets, a large proportion of which are retrotransposon insertions. We provide a first exploration of patient genome sequencing with a nanopore sequencer and demonstrate the value of long-read sequencing in mapping and phasing of SVs for both clinical and research applications [ABSTRACT FROM AUTHOR]

Published
2017
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33. Caenorhabditis elegans Cyclin D/CDK4 and Cyclin E/CDK2 Induce Distinct Cell Cycle Re-Entry Programs in Differentiated Muscle Cells

Author

Korzelius, Jerome, primary, The, Inge, additional, Ruijtenberg, Suzan, additional, Prinsen, Martine B. W., additional, Portegijs, Vincent, additional, Middelkoop, Teije C., additional, Groot Koerkamp, Marian J., additional, Holstege, Frank C. P., additional, Boxem, Mike, additional, and van den Heuvel, Sander, additional

Published
2011
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36. Caenorhabditis elegans Cyclin D/CDK4 and Cyclin E/ CDK2 Induce Distinct Cell Cycle Re-Entry Programs in Differentiated Muscle Cells.

Author

Korzelius, Jerome, The, Inge, Ruijtenberg, Suzan, Prinsen, Martine B. W., Portegijs, Vincent, Middelkoop, Teije C., Koerkamp, Marian J. Groot, Holstege, Frank C. P., Boxem, Mike, and Van den Heuvel, Sander

Subjects
*CELL proliferation, *CELL differentiation, *HOMEOSTASIS, *CAENORHABDITIS elegans, *MUSCLE cells
Abstract

Cell proliferation and differentiation are regulated in a highly coordinated and inverse manner during development and tissue homeostasis. Terminal differentiation usually coincides with cell cycle exit and is thought to engage stable transcriptional repression of cell cycle genes. Here, we examine the robustness of the post-mitotic state, using Caenorhabditis elegans muscle cells as a model. We found that expression of a G1 Cyclin and CDK initiates cell cycle re-entry in muscle cells without interfering with the differentiated state. Cyclin D/CDK4 (CYD-1/CDK-4) expression was sufficient to induce DNA synthesis in muscle cells, in contrast to Cyclin E/CDK2 (CYE-1/CDK-2), which triggered mitotic events. Tissue- specific gene-expression profiling and single molecule FISH experiments revealed that Cyclin D and E kinases activate an extensive and overlapping set of cell cycle genes in muscle, yet failed to induce some key activators of G1/S progression. Surprisingly, CYD-1/CDK-4 also induced an additional set of genes primarily associated with growth and metabolism, which were not activated by CYE-1/CDK-2. Moreover, CYD-1/CDK-4 expression also down-regulated a large number of genes enriched for catabolic functions. These results highlight distinct functions for the two G1 Cyclin/CDK complexes and reveal a previously unknown activity of Cyclin D/CDK-4 in regulating metabolic gene expression. Furthermore, our data demonstrate that many cell cycle genes can still be transcriptionally induced in post-mitotic muscle cells, while maintenance of the post-mitotic state might depend on stable repression of a limited number of critical cell cycle regulators. [ABSTRACT FROM AUTHOR]

Published
2011
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37. Herbivore-Induced Resistance against Microbial Pathogens in Arabidopsis.1.

Author

Vos, Martin De, Zaanen, Wendy Van, Koornneef, Annemart, Korzelius, Jerome P., Dicke, Marcel, Van Loon, L.C., and Pieterse, Come M.J.

Subjects
PATHOGENIC microorganisms, MICROBIAL physiology, HERBIVORES, ARABIDOPSIS, JASMONIC acid, CATERPILLARS
Abstract

Caterpillars of the herbivore Pieris rapae stimulate the production of jasmonic acid (JA) and ethylene (ET) in Arabidopsis (Arabidopsis thaliana) and trigger a defense response that affects insect performance on systemic tissues. To investigate the spectrum of effectiveness of P. rapae-induced resistance, we examined the level of resistance against different pathogens. Although the necrotrophic fungus Alternaria brassicicola is sensitive to JA-dependent defenses, herbivore-induced resistance was not effective against this pathogen. By contrast, caterpillar feeding significantly reduced disease caused by the bacterial pathogens Pseudomonas syringae pv tomato and Xanthomonas cam pestris pv armoraciae. However, this effect was apparent only locally in caterpillar-damaged tissue. Arabidopsis mutants jan, coil, ein2, sid2, eds5, and npr1 showed wild-type levels of P. rapae-induced protection against P. syringae pv tomato, suggesting that this local, herbivore-induced defense response does not depend exclusively on either JA, ET, or salicylic acid (SA). Resistance against the biotroph Turnip crinkle virus (TCV) requires SA, but not JA and ET. Nevertheless, herbivore feeding strongly affected TCV multiplication and TCV lesion formation, also in systemic tissues. Wounding alone was not effective, but application of P. rapae regurgitate onto the wounds induced a similar level of protection. Analysis of SA-induced PATHOGENESIS RELATED-1 (PR-1) expression revealed that P. rapae grazing primed Arabidopsis leaves for augmented expression of SA-dependent defenses. Pharmacological experiments showed that ET acts synergistically on SA-induced PR-1, suggesting that the increased production of FT upon herbivore feeding sensitizes the tissue to respond faster to SA, thereby contributing to an enhanced defensive capacity toward pathogens, such as TCV, that trigger SA-dependent defenses upon infection. [ABSTRACT FROM AUTHOR]

Published
2006
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38. Mapping and phasing of structural variation in patient genomes using nanopore sequencing

Author

Cretu Stancu, Mircea, Van Roosmalen, Markus J, Renkens, Ivo, Nieboer, Marleen M, Middelkamp, Sjors, De Ligt, Joep, Pregno, Giulia, Giachino, Daniela, Mandrile, Giorgia, Espejo Valle-Inclan, Jose, Korzelius, Jerome, De Bruijn, Ewart, Cuppen, Edwin, Talkowski, Michael E, Marschall, Tobias, De Ridder, Jeroen, and Kloosterman, Wigard P

Subjects
3. Good health

39. Herbivore-Induced Resistance against Microbial Pathogens in Arabidopsis.1.

Author

Vos, Martin De, Zaanen, Wendy Van, Koornneef, Annemart, Korzelius, Jerome P., Dicke, Marcel, Van Loon, L.C., and Pieterse, Come M.J.

Subjects
*PATHOGENIC microorganisms, *MICROBIAL physiology, *HERBIVORES, *ARABIDOPSIS, *JASMONIC acid, *CATERPILLARS
Abstract

Caterpillars of the herbivore Pieris rapae stimulate the production of jasmonic acid (JA) and ethylene (ET) in Arabidopsis (Arabidopsis thaliana) and trigger a defense response that affects insect performance on systemic tissues. To investigate the spectrum of effectiveness of P. rapae-induced resistance, we examined the level of resistance against different pathogens. Although the necrotrophic fungus Alternaria brassicicola is sensitive to JA-dependent defenses, herbivore-induced resistance was not effective against this pathogen. By contrast, caterpillar feeding significantly reduced disease caused by the bacterial pathogens Pseudomonas syringae pv tomato and Xanthomonas cam pestris pv armoraciae. However, this effect was apparent only locally in caterpillar-damaged tissue. Arabidopsis mutants jan, coil, ein2, sid2, eds5, and npr1 showed wild-type levels of P. rapae-induced protection against P. syringae pv tomato, suggesting that this local, herbivore-induced defense response does not depend exclusively on either JA, ET, or salicylic acid (SA). Resistance against the biotroph Turnip crinkle virus (TCV) requires SA, but not JA and ET. Nevertheless, herbivore feeding strongly affected TCV multiplication and TCV lesion formation, also in systemic tissues. Wounding alone was not effective, but application of P. rapae regurgitate onto the wounds induced a similar level of protection. Analysis of SA-induced PATHOGENESIS RELATED-1 (PR-1) expression revealed that P. rapae grazing primed Arabidopsis leaves for augmented expression of SA-dependent defenses. Pharmacological experiments showed that ET acts synergistically on SA-induced PR-1, suggesting that the increased production of FT upon herbivore feeding sensitizes the tissue to respond faster to SA, thereby contributing to an enhanced defensive capacity toward pathogens, such as TCV, that trigger SA-dependent defenses upon infection. [ABSTRACT FROM AUTHOR]

Published
2006
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40. The genomic landscape of balanced cytogenetic abnormalities associated with human congenital anomalies.

Author

Redin C, Brand H, Collins RL, Kammin T, Mitchell E, Hodge JC, Hanscom C, Pillalamarri V, Seabra CM, Abbott MA, Abdul-Rahman OA, Aberg E, Adley R, Alcaraz-Estrada SL, Alkuraya FS, An Y, Anderson MA, Antolik C, Anyane-Yeboa K, Atkin JF, Bartell T, Bernstein JA, Beyer E, Blumenthal I, Bongers EM, Brilstra EH, Brown CW, Brüggenwirth HT, Callewaert B, Chiang C, Corning K, Cox H, Cuppen E, Currall BB, Cushing T, David D, Deardorff MA, Dheedene A, D'Hooghe M, de Vries BB, Earl DL, Ferguson HL, Fisher H, FitzPatrick DR, Gerrol P, Giachino D, Glessner JT, Gliem T, Grady M, Graham BH, Griffis C, Gripp KW, Gropman AL, Hanson-Kahn A, Harris DJ, Hayden MA, Hill R, Hochstenbach R, Hoffman JD, Hopkin RJ, Hubshman MW, Innes AM, Irons M, Irving M, Jacobsen JC, Janssens S, Jewett T, Johnson JP, Jongmans MC, Kahler SG, Koolen DA, Korzelius J, Kroisel PM, Lacassie Y, Lawless W, Lemyre E, Leppig K, Levin AV, Li H, Li H, Liao EC, Lim C, Lose EJ, Lucente D, Macera MJ, Manavalan P, Mandrile G, Marcelis CL, Margolin L, Mason T, Masser-Frye D, McClellan MW, Mendoza CJ, Menten B, Middelkamp S, Mikami LR, Moe E, Mohammed S, Mononen T, Mortenson ME, Moya G, Nieuwint AW, Ordulu Z, Parkash S, Pauker SP, Pereira S, Perrin D, Phelan K, Aguilar RE, Poddighe PJ, Pregno G, Raskin S, Reis L, Rhead W, Rita D, Renkens I, Roelens F, Ruliera J, Rump P, Schilit SL, Shaheen R, Sparkes R, Spiegel E, Stevens B, Stone MR, Tagoe J, Thakuria JV, van Bon BW, van de Kamp J, van Der Burgt I, van Essen T, van Ravenswaaij-Arts CM, van Roosmalen MJ, Vergult S, Volker-Touw CM, Warburton DP, Waterman MJ, Wiley S, Wilson A, Yerena-de Vega MC, Zori RT, Levy B, Brunner HG, de Leeuw N, Kloosterman WP, Thorland EC, Morton CC, Gusella JF, and Talkowski ME

Subjects
Female, Humans, Male, Chromosome Aberrations, Congenital Abnormalities genetics, Gene Rearrangement, Genetic Markers genetics, Genetic Predisposition to Disease, Genome-Wide Association Study
Abstract

Despite the clinical significance of balanced chromosomal abnormalities (BCAs), their characterization has largely been restricted to cytogenetic resolution. We explored the landscape of BCAs at nucleotide resolution in 273 subjects with a spectrum of congenital anomalies. Whole-genome sequencing revised 93% of karyotypes and demonstrated complexity that was cryptic to karyotyping in 21% of BCAs, highlighting the limitations of conventional cytogenetic approaches. At least 33.9% of BCAs resulted in gene disruption that likely contributed to the developmental phenotype, 5.2% were associated with pathogenic genomic imbalances, and 7.3% disrupted topologically associated domains (TADs) encompassing known syndromic loci. Remarkably, BCA breakpoints in eight subjects altered a single TAD encompassing MEF2C, a known driver of 5q14.3 microdeletion syndrome, resulting in decreased MEF2C expression. We propose that sequence-level resolution dramatically improves prediction of clinical outcomes for balanced rearrangements and provides insight into new pathogenic mechanisms, such as altered regulation due to changes in chromosome topology., Competing Interests: The authors have none to declare.

Published
2017
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