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1. Expression-Based Cell Lineage Analysis in Drosophila Through a Course-Based Research Experience for Early Undergraduates.

Author

Olson, John M, Evans, Cory J, Ngo, Kathy T, Kim, Hee Jong, Nguyen, Joseph Duy, Gurley, Kayla GH, Ta, Truc, Patel, Vijay, Han, Lisa, Truong-N, Khoa T, Liang, Letty, Chu, Maggie K, Lam, Hiu, Ahn, Hannah G, Banerjee, Abhik Kumar, Choi, In Young, Kelley, Ross G, Moridzadeh, Naseem, Khan, Awais M, Khan, Omair, Lee, Szuyao, Johnson, Elizabeth B, Tigranyan, Annie, Wang, Jay, Gandhi, Anand D, Padhiar, Manish M, Calvopina, Joseph Hargan, Sumra, Kirandeep, Ou, Kristy, Wu, Jessie C, Dickan, Joseph N, Ahmadi, Sabrena M, Allen, Donald N, Mai, Van Thanh, Ansari, Saif, Yeh, George, Yoon, Earl, Gon, Kimberly, Yu, John Y, He, Johnny, Zaretsky, Jesse M, Lee, Noemi E, Kuoy, Edward, Patananan, Alexander N, Sitz, Daniel, Tran, PhuongThao, Do, Minh-Tu, Akhave, Samira J, Alvarez, Silverio D, Asem, Bobby, Asem, Neda, Azarian, Nicole A, Babaesfahani, Arezou, Bahrami, Ahmad, Bhamra, Manjeet, Bhargava, Ragini, Bhatia, Rakesh, Bhatia, Subir, Bumacod, Nicholas, Caine, Jonathan J, Caldwell, Thomas A, Calica, Nicole A, Calonico, Elise M, Chan, Carman, Chan, Helen H-L, Chang, Albert, Chang, Chiaen, Chang, Daniel, Chang, Jennifer S, Charania, Nauman, Chen, Jasmine Y, Chen, Kevin, Chen, Lu, Chen, Yuyu, Cheung, Derek J, Cheung, Jesse J, Chew, Jessica J, Chew, Nicole B, Chien, Cheng-An Tony, Chin, Alana M, Chin, Chee Jia, Cho, Youngho, Chou, Man Ting, Chow, Ke-Huan K, Chu, Carolyn, Chu, Derrick M, Chu, Virginia, Chuang, Katherine, Chugh, Arunit Singh, Cubberly, Mark R, Daniel, Michael Guillermo, Datta, Sangita, Dhaliwal, Raj, Dinh, Jenny, Dixit, Dhaval, Dowling, Emmylou, Feng, Melinda, From, Christopher M, Furukawa, Daisuke, and Gaddipati, Himaja

Subjects
Eye, Brain, Lymphatic System, Animals, Drosophila, Gene Expression, Cell Lineage, Research, Students, Universities, Wings, Animal, CURE, G-TRACE, STEM, education, gene expression, Wings, Animal, Genetics
Abstract

A variety of genetic techniques have been devised to determine cell lineage relationships during tissue development. Some of these systems monitor cell lineages spatially and/or temporally without regard to gene expression by the cells, whereas others correlate gene expression with the lineage under study. The GAL4 Technique for Real-time and Clonal Expression (G-TRACE) system allows for rapid, fluorescent protein-based visualization of both current and past GAL4 expression patterns and is therefore amenable to genome-wide expression-based lineage screens. Here we describe the results from such a screen, performed by undergraduate students of the University of California, Los Angeles (UCLA) Undergraduate Research Consortium for Functional Genomics (URCFG) and high school summer scholars as part of a discovery-based education program. The results of the screen, which reveal novel expression-based lineage patterns within the brain, the imaginal disc epithelia, and the hematopoietic lymph gland, have been compiled into the G-TRACE Expression Database (GED), an online resource for use by the Drosophila research community. The impact of this discovery-based research experience on student learning gains was assessed independently and shown to be greater than that of similar programs conducted elsewhere. Furthermore, students participating in the URCFG showed considerably higher STEM retention rates than UCLA STEM students that did not participate in the URCFG, as well as STEM students nationwide.

Published
2019

3. Targeted demethylation at the CDKN1C/p57 locus induces human [beta] cell replication

Author

Ou, Kristy, Yu, Ming, Moss, Nicholas G., Wang, Yue J., Wang, Amber W., Nguyen, Son C., Jiang, Connie, Feleke, Eseye, Kameswaran, Vasumathi, Joyce, Eric F., Naji, Ali, Glaser, Benjamin, Avrahami, Dana, and Kaestner, Klaus H.

Subjects
Cell cycle -- Research, Pancreatic beta cells -- Research, Gene expression -- Research, Health care industry
Abstract

The loss of insulin-secreting [beta] cells is characteristic among type I and type II diabetes. Stimulating proliferation to expand sources of [beta] cells for transplantation remains a challenge because adult [beta] cells do not proliferate readily. The cell cycle inhibitor p57 has been shown to control cell division in human [beta] cells. Expression of p57 is regulated by the DNA methylation status of the imprinting control region 2 (ICR2), which is commonly hypomethylated in Beckwith-Wiedemann syndrome patients who exhibit massive [beta] cell proliferation. We hypothesized that targeted demethylation of the ICR2 using a transcription activator-like effector protein fused to the catalytic domain of TET1 (ICR2-TET1) would repress p57 expression and promote cell proliferation. We report here that overexpression of ICR2-TET1 in human fibroblasts reduces p57 expression levels and increases proliferation. Furthermore, human islets overexpressing ICR2-TET1 exhibit repression of p57 with concomitant upregulation of Ki-67 while maintaining glucose-sensing functionality. When transplanted into diabetic, immunodeficient mice, the epigenetically edited islets show increased [beta] cell replication compared with control islets. These findings demonstrate that epigenetic editing is a promising tool for inducing [beta] cell proliferation, which may one day alleviate the scarcity of transplantable [beta] cells for the treatment of diabetes., IntroductionIn 2014, 422 million people worldwide lived with diabetes (1). While patients with type I or severe forms of type II diabetes can manage extreme glucose excursions by administering insulin [...]

Published
2019
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4. The enhancer landscape predetermines the skeletal regeneration capacity of stromal cells

Author

Hochmann, Sarah, primary, Ou, Kristy, additional, Poupardin, Rodolphe, additional, Mittermeir, Michaela, additional, Textor, Martin, additional, Ali, Salaheddine, additional, Wolf, Martin, additional, Ellinghaus, Agnes, additional, Jacobi, Dorit, additional, Elmiger, Juri A. J., additional, Donsante, Samantha, additional, Riminucci, Mara, additional, Schäfer, Richard, additional, Kornak, Uwe, additional, Klein, Oliver, additional, Schallmoser, Katharina, additional, Schmidt-Bleek, Katharina, additional, Duda, Georg N., additional, Polansky, Julia K., additional, Geissler, Sven, additional, and Strunk, Dirk, additional

Published
2023
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6. Scripts used for: THE ENHANCER LANDSCAPE PREDETERMINES THE SKELETAL REGENERATION CAPACITY OF STROMAL CELLS

Author

Hochmann Sarah, Ou Kristy, Poupardin Rodophe, Mittermeir Michaela, Textor Martin, Salaheddine Ali, Wolf Martin, Ellinghaus Agnes, Jacobi Dorit, Elmiger Juri A.J., Donsante Samantha, Riminucci Mara, Schäfer Richard, Kornak Uwe, Klein Oliver, Schallmoser Katharina, Schmidt-Bleek Katharina, Duda Georg N., Polansky Julia K., Geissler Sven, and Strunk Dirk

Abstract

Multipotent stromal cells are considered attractive sources for cell therapy and tissue engineering. Despite numerous experimental and clinical studies, broad application of stromal cell therapeutics is not yet emerging. A major challenge is the functional diversity of available cell sources. Here, we investigated the regenerative potential of clinically relevant human stromal cells from bone marrow (BMSCs), white adipose tissue, and umbilical cord compared to mature chondrocytes and skin fibroblasts in-vitro and in vivo. Although all stromal cell types can express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs in vitro that fully regenerated critical-sized femoral defects after transplantation into mice. We identified cell type-specific epigenetic landscapes as the underlying molecular mechanism controlling transcriptional stromal differentiation networks. Binding sites of commonly expressed transcription factors in the enhancer and promoter regions of ossification-related genes, including Runt and bZIP families, were accessible only in BMSCs but not in extra-skeletal stromal cells. This suggests an epigenetically predetermined differentiation potential depending on cell origin that allows common transcription factors to trigger distinct organ-specific transcriptional programs, facilitating forward selection of regeneration-competent cell sources. Last, we demonstrate that viable human BMSCs initiated defect healing through the secretion of osteopontin and contributed to transient mineralized bone hard callus formation after transplantation into immunodeficient mice, which was eventually replaced by murine recipient bone during final tissue remodeling., Here we provided data and R script for the gene expression profiling meta-analysis of different stromal cells. Scripts for processing ATAC and CHIP-seq data are also provided. The epigenetic raw data is available at Gene Expression Omnibus (GEO), NCBI, https://www.ncbi.nlm.nih.gov/geo/, Accession-ID: GSE182497.

Published
2023
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7. Variant-to-gene-mapping analyses reveal a role for pancreatic islet cells in conferring genetic susceptibility to sleep-related traits

Author

Lasconi, Chiara, primary, Pahl, Matthew C, additional, Pippin, James A, additional, Su, Chun, additional, Johnson, Matthew E, additional, Chesi, Alessandra, additional, Boehm, Keith, additional, Manduchi, Elisabetta, additional, Ou, Kristy, additional, Golson, Maria L, additional, Wells, Andrew D, additional, Kaestner, Klaus H, additional, and Grant, Struan F A, additional

Published
2022
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8. Strong Expansion of Human Regulatory T Cells for Adoptive Cell Therapy Results in Epigenetic Changes Which May Impact Their Survival and Function

Author

Ou, Kristy, primary, Hamo, Dania, additional, Schulze, Anne, additional, Roemhild, Andy, additional, Kaiser, Daniel, additional, Gasparoni, Gilles, additional, Salhab, Abdulrahman, additional, Zarrinrad, Ghazaleh, additional, Amini, Leila, additional, Schlickeiser, Stephan, additional, Streitz, Mathias, additional, Walter, Jörn, additional, Volk, Hans-Dieter, additional, Schmueck-Henneresse, Michael, additional, Reinke, Petra, additional, and Polansky, Julia K., additional

Published
2021
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9. Ins1-Cre and Ins1-CreER Gene Replacement Alleles Are Susceptible To Silencing By DNA Hypermethylation

Author

Mosleh, Elham, primary, Ou, Kristy, additional, Haemmerle, Matthew W, additional, Tembo, Teguru, additional, Yuhas, Andrew, additional, Carboneau, Bethany A, additional, Townsend, Shannon E, additional, Bosma, Karin J, additional, Gannon, Maureen, additional, O’Brien, Richard M, additional, Stoffers, Doris A, additional, and Golson, Maria L, additional

Published
2020
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11. Expression-Based Cell Lineage Analysis inDrosophilaThrough a Course-Based Research Experience for Early Undergraduates

Author

Olson, John M, primary, Evans, Cory J, additional, Ngo, Kathy T, additional, Kim, Hee Jong, additional, Nguyen, Joseph Duy, additional, Gurley, Kayla G H, additional, Ta, Truc, additional, Patel, Vijay, additional, Han, Lisa, additional, Truong-N, Khoa T, additional, Liang, Letty, additional, Chu, Maggie K, additional, Lam, Hiu, additional, Ahn, Hannah G, additional, Banerjee, Abhik Kumar, additional, Choi, In Young, additional, Kelley, Ross G, additional, Moridzadeh, Naseem, additional, Khan, Awais M, additional, Khan, Omair, additional, Lee, Szuyao, additional, Johnson, Elizabeth B, additional, Tigranyan, Annie, additional, Wang, Jay, additional, Gandhi, Anand D, additional, Padhiar, Manish M, additional, Calvopina, Joseph Hargan, additional, Sumra, Kirandeep, additional, Ou, Kristy, additional, Wu, Jessie C, additional, Dickan, Joseph N, additional, Ahmadi, Sabrena M, additional, Allen, Donald N, additional, Mai, Van Thanh, additional, Ansari, Saif, additional, Yeh, George, additional, Yoon, Earl, additional, Gon, Kimberly, additional, Yu, John Y, additional, He, Johnny, additional, Zaretsky, Jesse M, additional, Lee, Noemi E, additional, Kuoy, Edward, additional, Patananan, Alexander N, additional, Sitz, Daniel, additional, Tran, PhuongThao, additional, Do, Minh-Tu, additional, Akhave, Samira J, additional, Alvarez, Silverio D, additional, Asem, Bobby, additional, Asem, Neda, additional, Azarian, Nicole A, additional, Babaesfahani, Arezou, additional, Bahrami, Ahmad, additional, Bhamra, Manjeet, additional, Bhargava, Ragini, additional, Bhatia, Rakesh, additional, Bhatia, Subir, additional, Bumacod, Nicholas, additional, Caine, Jonathan J, additional, Caldwell, Thomas A, additional, Calica, Nicole A, additional, Calonico, Elise M, additional, Chan, Carman, additional, Chan, Helen H-L, additional, Chang, Albert, additional, Chang, Chiaen, additional, Chang, Daniel, additional, Chang, Jennifer S, additional, Charania, Nauman, additional, Chen, Jasmine Y, additional, Chen, Kevin, additional, Chen, Lu, additional, Chen, Yuyu, additional, Cheung, Derek J, additional, Cheung, Jesse J, additional, Chew, Jessica J, additional, Chew, Nicole B, additional, Chien, Cheng-An Tony, additional, Chin, Alana M, additional, Chin, Chee Jia, additional, Cho, Youngho, additional, Chou, Man Ting, additional, Chow, Ke-Huan K, additional, Chu, Carolyn, additional, Chu, Derrick M, additional, Chu, Virginia, additional, Chuang, Katherine, additional, Chugh, Arunit Singh, additional, Cubberly, Mark R, additional, Daniel, Michael Guillermo, additional, Datta, Sangita, additional, Dhaliwal, Raj, additional, Dinh, Jenny, additional, Dixit, Dhaval, additional, Dowling, Emmylou, additional, Feng, Melinda, additional, From, Christopher M, additional, Furukawa, Daisuke, additional, Gaddipati, Himaja, additional, Gevorgyan, Lilit, additional, Ghaznavi, Zunera, additional, Ghosh, Tulika, additional, Gill, Jaskaran, additional, Groves, David J, additional, Gurara, Kalkidan K, additional, Haghighi, Ali R, additional, Havard, Alexandra L, additional, Heyrani, Nasser, additional, Hioe, Tanya, additional, Hong, Kirim, additional, Houman, Justin J, additional, Howland, Molly, additional, Hsia, Elaine L, additional, Hsueh, Justin, additional, Hu, Stacy, additional, Huang, Andrew J, additional, Huynh, Jasmine C, additional, Huynh, Jenny, additional, Iwuchukwu, Chris, additional, Jang, Michael J, additional, Jiang, An An, additional, Kahlon, Simran, additional, Kao, Pei-Yun, additional, Kaur, Manpreet, additional, Keehn, Matthew G, additional, Kim, Elizabeth J, additional, Kim, Hannah, additional, Kim, Michelle J, additional, Kim, Shawn J, additional, Kitich, Aleksandar, additional, Kornberg, Ross A, additional, Kouzelos, Nicholas G, additional, Kuon, Jane, additional, Lau, Bryan, additional, Lau, Roger K, additional, Law, Rona, additional, Le, Huy D, additional, Le, Rachael, additional, Lee, Carrou, additional, Lee, Christina, additional, Lee, Grace E, additional, Lee, Kenny, additional, Lee, Michelle J, additional, Lee, Regina V, additional, Lee, Sean H K, additional, Lee, Sung Kyu, additional, Lee, Sung-Ling D, additional, Lee, Yong Jun, additional, Leong, Megan J, additional, Li, David M, additional, Li, Hao, additional, Liang, Xingfu, additional, Lin, Eric, additional, Lin, Michelle M, additional, Lin, Peter, additional, Lin, Tiffany, additional, Lu, Stacey, additional, Luong, Serena S, additional, Ma, Jessica S, additional, Ma, Li, additional, Maghen, Justin N, additional, Mallam, Sravya, additional, Mann, Shivtaj, additional, Melehani, Jason H, additional, Miller, Ryan C, additional, Mittal, Nitish, additional, Moazez, Carmel M, additional, Moon, Susie, additional, Moridzadeh, Rameen, additional, Ngo, Kaley, additional, Nguyen, Hanh H, additional, Nguyen, Kambria, additional, Nguyen, Thien H, additional, Nieh, Angela W, additional, Niu, Isabella, additional, Oh, Seo-Kyung, additional, Ong, Jessica R, additional, Oyama, Randi K, additional, Park, Joseph, additional, Park, Yaelim A, additional, Passmore, Kimberly A, additional, Patel, Ami, additional, Patel, Amy A, additional, Patel, Dhruv, additional, Patel, Tirth, additional, Peterson, Katherine E, additional, Pham, An Huynh, additional, Pham, Steven V, additional, Phuphanich, Melissa E, additional, Poria, Neil D, additional, Pourzia, Alexandra, additional, Ragland, Victoria, additional, Ranat, Riki D, additional, Rice, Cameron M, additional, Roh, David, additional, Rojhani, Solomon, additional, Sadri, Lili, additional, Saguros, Agafe, additional, Saifee, Zainab, additional, Sandhu, Manjot, additional, Scruggs, Brooke, additional, Scully, Lisa M, additional, Shih, Vanessa, additional, Shin, Brian A, additional, Sholklapper, Tamir, additional, Singh, Harnek, additional, Singh, Sumedha, additional, Snyder, Sondra L, additional, Sobotka, Katelyn F, additional, Song, Sae Ho, additional, Sukumar, Siddharth, additional, Sullivan, Halley C, additional, Sy, Mark, additional, Tan, Hande, additional, Taylor, Sara K, additional, Thaker, Shivani K, additional, Thakore, Tulsi, additional, Tong, Gregory E, additional, Tran, Jacinda N, additional, Tran, Jonathan, additional, Tran, Tuan D, additional, Tran, Vivi, additional, Trang, Cindy L, additional, Trinh, Hung G, additional, Trinh, Peter, additional, Tseng, Han-Ching H, additional, Uotani, Ted T, additional, Uraizee, Akram V, additional, Vu, Kent K T, additional, Vu, Kevin K T, additional, Wadhwani, Komal, additional, Walia, Paluk K, additional, Wang, Rebecca S, additional, Wang, Shuo, additional, Wang, Stephanie J, additional, Wiredja, Danica D, additional, Wong, Andrew L, additional, Wu, Daniel, additional, Xue, Xi, additional, Yanez, Griselda, additional, Yang, Yung-Hsuan, additional, Ye, Zhong, additional, Yee, Victor W, additional, Yeh, Cynthia, additional, Zhao, Yue, additional, Zheng, Xin, additional, Ziegenbalg, Anke, additional, Alkali, Jon, additional, Azizkhanian, Ida, additional, Bhakta, Akash, additional, Berry, Luke, additional, Castillo, Ryen, additional, Darwish, Sonja, additional, Dickinson, Holly, additional, Dutta, Ritika, additional, Ghosh, Rahul Kumar, additional, Guerin, Riley, additional, Hofman, Jonathan, additional, Iwamoto, Garrick, additional, Kang, Sarah, additional, Kim, Andrew, additional, Kim, Brian, additional, Kim, Hanwool, additional, Kim, Kristine, additional, Kim, Suji, additional, Ko, Julie, additional, Koenig, Michael, additional, LaRiviere, Alejandro, additional, Lee, Clifton, additional, Lee, Jiwon, additional, Lung, Brandon, additional, Mittelman, Max, additional, Murata, Mark, additional, Park, Yujin, additional, Rothberg, Daniel, additional, Sprung-Keyser, Ben, additional, Thaker, Kunal, additional, Yip, Vivian, additional, Picard, Paul, additional, Diep, Francie, additional, Villarasa, Nikki, additional, Hartenstein, Volker, additional, Shapiro, Casey, additional, Levis-Fitzgerald, Marc, additional, Jaworski, Leslie, additional, Loppato, David, additional, Clark, Ira E, additional, and Banerjee, Utpal, additional

Published
2019
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12. Loss of cardio-protective effects at the ADAMTS7 locus due to gene-smoking interactions

Author

Saleheen, Danish, Zhao, Wei, Young, Robin, Nelson, Christopher P., Ho, Weang Kee, Ferguson, Jane F., Rasheed, Asif, Ou, Kristy, Nurnberg, Sylvia T., Bauer, Robert C., Goel, Anuj, Do, Ron, Stewart, Alexandre F.R., Hartiala, Jaana, Zhang, Weihua, Thorleifsson, Gudmar, Strawbridge, Rona J., Sinisalo, Juha, Kanoni, Stavroula, Sedaghat, Sanaz, Marouli, Eirini, Kristiansson, Kati, Zhao, Jing Hua, Scott, Robert, Gauguier, Dominique, Shah, Svati H., Smith, Albert Vernon, Van Zuydam, Natalie, Cox, Amanda J., Willenborg, Christina, Kessler, Thorsten, Zeng, Lingyao, Province, Michael A., Ganna, Andrea, Lind, Lars, Pedersen, Nancy L., White, Charles C., Joensuu, Anni, Kleber, Marcus Edi, Hall, Alistair S., März, Winfried, Salomaa, Veikko, O'Donnell, Christopher, Ingelsson, Erik, Feitosa, Mary F., Erdmann, Jeanette, Bowden, Donald W., Palmer, Colin N.A., Gudnason, Vilmundur, de Faire, Ulf, Zalloua, Pierre, Wareham, Nicholas, Thompson, John R., Kuulasmaa, Kari, Dedoussis, George, Perola, Markus, Dehghan, Abbas, Chambers, John C., Kooner, Jaspal, Allayee, Hooman, Deloukas, Panos, McPherson, Ruth, Stefansson, Kari, Schunkert, Heribert, Kathiresan, Sekar, Farrall, Martin, Frossard, Philippe M., Rader, Daniel J., Samani, Nilesh, and Reilly, Muredach P.

Abstract

Background—Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-environment interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk.\ud \ud Methods—We analyzed data on 60,919 CHD cases and 80,243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to associate with CHD risk. We also studied 5 loci associated with smoking behavior. Study specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P-value< 1.0x10-3 (Bonferroni correction for 50 tests).\ud \ud Results—We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P-value: 1.3x10-16) compared to 5% in ever-smokers (P-value: 2.5x10-4) translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (Interaction P-value: 8.7x10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7.\ud \ud Conclusions—Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in "never-smokers" compared to "ever-smokers". Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

Published
2017

14. Targeted demethylation at the CDKN1C/p57 locus induces human β cell replication

Author

Ou, Kristy, primary, Yu, Ming, additional, Moss, Nicholas G., additional, Wang, Yue J., additional, Wang, Amber W., additional, Nguyen, Son C., additional, Jiang, Connie, additional, Feleke, Eseye, additional, Kameswaran, Vasumathi, additional, Joyce, Eric F., additional, Naji, Ali, additional, Glaser, Benjamin, additional, Avrahami, Dana, additional, and Kaestner, Klaus H., additional

Published
2018
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16. Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

Author

Saleheen, Danish, Zhao, Wei, Young, Robin, Nelson, Christopher P., Ho, WeangKee, Ferguson, Jane F., Rasheed, Asif, Ou, Kristy, Nurnberg, Sylvia T., Bauer, Robert C., Goel, Anuj, Do, Ron, Stewart, Alexandre F. R., Hartiala, Jaana, Zhang, Weihua, Thorleifsson, Gudmar, Strawbridge, Rona J., Sinisalo, Juha, Kanoni, Stavroula, Sedaghat, Sanaz, Marouli, Eirini, Kristiansson, Kati, Zhao, Jing Hua, Scott, Robert, Gauguier, Dominique, Shah, Svati H., Smith, Albert Vernon, van Zuydam, Natalie, Cox, Amanda J., Willenborg, Christina, Kessler, Thorsten, Zeng, Lingyao, Province, Michael A., Ganna, Andrea, Lind, Lars, Pedersen, Nancy L., White, Charles C., Joensuu, Anni, Kleber, Marcus Edi, Hall, Alistair S., Maerz, Winfried, Salomaa, Veikko, O'Donnell, Christopher, Ingelsson, Erik, Feitosa, Mary F., Erdmann, Jeanette, Bowden, Donald W., Palmer, Colin N. A., Gudnason, Vilmundur, De Faire, Ulf, Zalloua, Pierre, Wareham, Nicholas, Thompson, John R., Kuulasmaa, Kari, Dedoussis, George, Perola, Markus, Dehghan, Abbas, Chambers, John C., Kooner, Jaspal, Allayee, Hooman, Deloukas, Panos, McPherson, Ruth, Stefansson, Kari, Schunkert, Heribert, Kathiresan, Sekar, Farrall, Martin, Frossard, Philippe Marcel, Rader, Daniel J., Samani, Nilesh J., Reilly, Muredach P., Saleheen, Danish, Zhao, Wei, Young, Robin, Nelson, Christopher P., Ho, WeangKee, Ferguson, Jane F., Rasheed, Asif, Ou, Kristy, Nurnberg, Sylvia T., Bauer, Robert C., Goel, Anuj, Do, Ron, Stewart, Alexandre F. R., Hartiala, Jaana, Zhang, Weihua, Thorleifsson, Gudmar, Strawbridge, Rona J., Sinisalo, Juha, Kanoni, Stavroula, Sedaghat, Sanaz, Marouli, Eirini, Kristiansson, Kati, Zhao, Jing Hua, Scott, Robert, Gauguier, Dominique, Shah, Svati H., Smith, Albert Vernon, van Zuydam, Natalie, Cox, Amanda J., Willenborg, Christina, Kessler, Thorsten, Zeng, Lingyao, Province, Michael A., Ganna, Andrea, Lind, Lars, Pedersen, Nancy L., White, Charles C., Joensuu, Anni, Kleber, Marcus Edi, Hall, Alistair S., Maerz, Winfried, Salomaa, Veikko, O'Donnell, Christopher, Ingelsson, Erik, Feitosa, Mary F., Erdmann, Jeanette, Bowden, Donald W., Palmer, Colin N. A., Gudnason, Vilmundur, De Faire, Ulf, Zalloua, Pierre, Wareham, Nicholas, Thompson, John R., Kuulasmaa, Kari, Dedoussis, George, Perola, Markus, Dehghan, Abbas, Chambers, John C., Kooner, Jaspal, Allayee, Hooman, Deloukas, Panos, McPherson, Ruth, Stefansson, Kari, Schunkert, Heribert, Kathiresan, Sekar, Farrall, Martin, Frossard, Philippe Marcel, Rader, Daniel J., Samani, Nilesh J., and Reilly, Muredach P.

Abstract

BACKGROUND: Common diseases such as coronary heart disease (CHD) are complex in etiology. The interaction of genetic susceptibility with lifestyle factors may play a prominent role. However, gene-lifestyle interactions for CHD have been difficult to identify. Here, we investigate interaction of smoking behavior, a potent lifestyle factor, with genotypes that have been shown to associate with CHD risk. METHODS: We analyzed data on 60 919 CHD cases and 80 243 controls from 29 studies for gene-smoking interactions for genetic variants at 45 loci previously reported to be associated with CHD risk. We also studied 5 loci associated with smoking behavior. Study-specific gene-smoking interaction effects were calculated and pooled using fixed-effects meta-analyses. Interaction analyses were declared to be significant at a P value of < 1.0x10-3 (Bonferroni correction for 50 tests). RESULTS: We identified novel gene-smoking interaction for a variant upstream of the ADAMTS7 gene. Every T allele of rs7178051 was associated with lower CHD risk by 12% in never-smokers (P= 1.3x10(-16)) in comparison with 5% in ever-smokers (P= 2.5x10-4), translating to a 60% loss of CHD protection conferred by this allelic variation in people who smoked tobacco (interaction P value= 8.7x10-5). The protective T allele at rs7178051 was also associated with reduced ADAMTS7 expression in human aortic endothelial cells and lymphoblastoid cell lines. Exposure of human coronary artery smooth muscle cells to cigarette smoke extract led to induction of ADAMTS7. CONCLUSIONS: Allelic variation at rs7178051 that associates with reduced ADAMTS7 expression confers stronger CHD protection in never-smokers than in ever-smokers. Increased vascular ADAMTS7 expression may contribute to the loss of CHD protection in smokers.

Published
2017
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17. Loss of Cardioprotective Effects at the ADAMTS7 Locus as a Result of Gene-Smoking Interactions

Author

Saleheen, Danish, primary, Zhao, Wei, additional, Young, Robin, additional, Nelson, Christopher P., additional, Ho, WeangKee, additional, Ferguson, Jane F., additional, Rasheed, Asif, additional, Ou, Kristy, additional, Nurnberg, Sylvia T., additional, Bauer, Robert C., additional, Goel, Anuj, additional, Do, Ron, additional, Stewart, Alexandre F.R., additional, Hartiala, Jaana, additional, Zhang, Weihua, additional, Thorleifsson, Gudmar, additional, Strawbridge, Rona J., additional, Sinisalo, Juha, additional, Kanoni, Stavroula, additional, Sedaghat, Sanaz, additional, Marouli, Eirini, additional, Kristiansson, Kati, additional, Hua Zhao, Jing, additional, Scott, Robert, additional, Gauguier, Dominique, additional, Shah, Svati H., additional, Smith, Albert Vernon, additional, van Zuydam, Natalie, additional, Cox, Amanda J., additional, Willenborg, Christina, additional, Kessler, Thorsten, additional, Zeng, Lingyao, additional, Province, Michael A., additional, Ganna, Andrea, additional, Lind, Lars, additional, Pedersen, Nancy L., additional, White, Charles C., additional, Joensuu, Anni, additional, Edi Kleber, Marcus, additional, Hall, Alistair S., additional, März, Winfried, additional, Salomaa, Veikko, additional, O’Donnell, Christopher, additional, Ingelsson, Erik, additional, Feitosa, Mary F., additional, Erdmann, Jeanette, additional, Bowden, Donald W., additional, Palmer, Colin N.A., additional, Gudnason, Vilmundur, additional, Faire, Ulf De, additional, Zalloua, Pierre, additional, Wareham, Nicholas, additional, Thompson, John R., additional, Kuulasmaa, Kari, additional, Dedoussis, George, additional, Perola, Markus, additional, Dehghan, Abbas, additional, Chambers, John C., additional, Kooner, Jaspal, additional, Allayee, Hooman, additional, Deloukas, Panos, additional, McPherson, Ruth, additional, Stefansson, Kari, additional, Schunkert, Heribert, additional, Kathiresan, Sekar, additional, Farrall, Martin, additional, Marcel Frossard, Philippe, additional, Rader, Daniel J., additional, Samani, Nilesh J., additional, and Reilly, Muredach P., additional

Published
2017
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19. The Dysregulation of the - Locus in Islets From Patients With Type 2 Diabetes Is Mimicked by Targeted Epimutation of Its Promoter With TALE-DNMT Constructs.

Author

Kameswaran, Vasumathi, Golson, Maria L., Ramos-Rodríguez, Mireia, Kristy Ou, Wang, Yue J., Jia Zhang, Pasquali, Lorenzo, Kaestner, Klaus H., Golson, Maria, Ou, Kristy, and Zhang, Jia

Subjects
TYPE 2 diabetes, INSULIN resistance, DRUG resistance, INSULIN antibodies, GLUCOSE intolerance, METABOLIC disorders, HYPERINSULINISM
Abstract

Type 2 diabetes mellitus (T2DM) is characterized by the inability of the insulin-producing β-cells to overcome insulin resistance. We previously identified an imprinted region on chromosome 14, the DLK1-MEG3 locus, as being downregulated in islets from humans with T2DM. In this study, using targeted epigenetic modifiers, we prove that increased methylation at the promoter of Meg3 in mouse βTC6 β-cells results in decreased transcription of the maternal transcripts associated with this locus. As a result, the sensitivity of β-cells to cytokine-mediated oxidative stress was increased. Additionally, we demonstrate that an evolutionarily conserved intronic region at the MEG3 locus can function as an enhancer in βTC6 β-cells. Using circular chromosome conformation capture followed by high-throughput sequencing, we demonstrate that the promoter of MEG3 physically interacts with this novel enhancer and other putative regulatory elements in this imprinted region in human islets. Remarkably, this enhancer is bound in an allele-specific manner by the transcription factors FOXA2, PDX1, and NKX2.2. Overall, these data suggest that the intronic MEG3 enhancer plays an important role in the regulation of allele-specific expression at the imprinted DLK1-MEG3 locus in human β-cells, which in turn impacts the sensitivity of β-cells to cytokine-mediated oxidative stress. [ABSTRACT FROM AUTHOR]

Published
2018
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27. Loss of Cardioprotective Effects at the ADAMTS7Locus as a Result of Gene-Smoking Interactions

Author

Saleheen, Danish, Zhao, Wei, Young, Robin, Nelson, Christopher P., Ho, WeangKee, Ferguson, Jane F., Rasheed, Asif, Ou, Kristy, Nurnberg, Sylvia T., Bauer, Robert C., Goel, Anuj, Do, Ron, Stewart, Alexandre F.R., Hartiala, Jaana, Zhang, Weihua, Thorleifsson, Gudmar, Strawbridge, Rona J., Sinisalo, Juha, Kanoni, Stavroula, Sedaghat, Sanaz, Marouli, Eirini, Kristiansson, Kati, Hua Zhao, Jing, Scott, Robert, Gauguier, Dominique, Shah, Svati H., Smith, Albert Vernon, van Zuydam, Natalie, Cox, Amanda J., Willenborg, Christina, Kessler, Thorsten, Zeng, Lingyao, Province, Michael A., Ganna, Andrea, Lind, Lars, Pedersen, Nancy L., White, Charles C., Joensuu, Anni, Edi Kleber, Marcus, Hall, Alistair S., März, Winfried, Salomaa, Veikko, O’Donnell, Christopher, Ingelsson, Erik, Feitosa, Mary F., Erdmann, Jeanette, Bowden, Donald W., Palmer, Colin N.A., Gudnason, Vilmundur, Faire, Ulf De, Zalloua, Pierre, Wareham, Nicholas, Thompson, John R., Kuulasmaa, Kari, Dedoussis, George, Perola, Markus, Dehghan, Abbas, Chambers, John C., Kooner, Jaspal, Allayee, Hooman, Deloukas, Panos, McPherson, Ruth, Stefansson, Kari, Schunkert, Heribert, Kathiresan, Sekar, Farrall, Martin, Marcel Frossard, Philippe, Rader, Daniel J., Samani, Nilesh J., and Reilly, Muredach P.

Abstract

Supplemental Digital Content is available in the text.

Published
2017
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