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3. Epigenetic-focused CRISPR/Cas9 screen identifies (absent, small, or homeotic)2-like protein (ASH2L) as a regulator of glioblastoma cell survival

Author

Ozyerli-Goknar, Ezgi, Kala, Ezgi Yagmur, Aksu, Ali Cenk, Bulut, Ipek, Cingöz, Ahmet, Nizamuddin, Sheikh, Biniossek, Martin, Seker-Polat, Fidan, Morova, Tunc, Aztekin, Can, Kung, Sonia H. Y., Syed, Hamzah, Tuncbag, Nurcan, Gönen, Mehmet, Philpott, Martin, Cribbs, Adam P., Acilan, Ceyda, Lack, Nathan A., Onder, Tamer T., Timmers, H. T. Marc, and Bagci-Onder, Tugba

Published
2023
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4. Correction: Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma

Author

Kurata, Keiji, James-Bott, Anna, Tye, Mark A., Yamamoto, Leona, Samur, Mehmet K., Tai, Yu-Tzu, Dunford, James, Johansson, Catrine, Senbabaoglu, Filiz, Philpott, Martin, Palmer, Charlotte, Ramasamy, Karthik, Gooding, Sarah, Smilova, Mihaela, Gaeta, Giorgia, Guo, Manman, Christianson, John C., Payne, N. Connor, Singh, Kritika, Karagoz, Kubra, Stokes, Matthew E., Ortiz, Maria, Hagner, Patrick, Thakurta, Anjan, Cribbs, Adam, Mazitschek, Ralph, Hideshima, Teru, Anderson, Kenneth C., and Oppermann, Udo

Published
2023
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5. Prolyl-tRNA synthetase as a novel therapeutic target in multiple myeloma

Author

Kurata, Keiji, Bott, Anna-James, Tye, Mark A., Yamamoto, Leona, Samur, Mehmet K., Tai, Yu-Tzu, Dunford, James, Johansson, Catrine, Senbabaoglu, Filiz, Philpott, Martin, Palmer, Charlotte, Ramasamy, Karthik, Gooding, Sarah, Smilova, Mihaela, Gaeta, Giorgia, Guo, Manman, Christianson, John C., Payne, N. Connor, Singh, Kritika, Karagoz, Kubra, Stokes, Matthew E., Ortiz, Maria, Hagner, Patrick, Thakurta, Anjan, Cribbs, Adam, Mazitschek, Ralph, Hideshima, Teru, Anderson, Kenneth C., and Oppermann, Udo

Published
2023
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6. BRD9-SMAD2/3 Orchestrates Stemness and Tumorigenesis in Pancreatic Ductal Adenocarcinoma

Author

Feng, Yuliang, Cai, Liuyang, Pook, Martin, Liu, Feng, Chang, Chao-Hui, Mouti, Mai Abdel, Nibhani, Reshma, Militi, Stefania, Dunford, James, Philpott, Martin, Fan, Yanbo, Fan, Guo-Chang, Liu, Qi, Qi, Jun, Wang, Cheng, Hong, Wanzi, Morgan, Hannah, Wang, Mingyang, Sadayappan, Sakthivel, Jegga, Anil G., Oppermann, Udo, Wang, Yigang, Huang, Wei, Jiang, Lei, and Pauklin, Siim

Published
2024
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11. EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

Author

Yedier-Bayram, Ozlem, Gokbayrak, Bengul, Kayabolen, Alisan, Aksu, Ali Cenk, Cavga, Ayse Derya, Cingöz, Ahmet, Kala, Ezgi Yagmur, Karabiyik, Goktug, Günsay, Rauf, Esin, Beril, Morova, Tunc, Uyulur, Fırat, Syed, Hamzah, Philpott, Martin, Cribbs, Adam P., Kung, Sonia H. Y., Lack, Nathan A., Onder, Tamer T., and Bagci-Onder, Tugba

Published
2022
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13. Somatostatin receptor 2 expression in nasopharyngeal cancer is induced by Epstein Barr virus infection: impact on prognosis, imaging and therapy

Author

Lechner, Matt, Schartinger, Volker H., Steele, Christopher D., Nei, Wen Long, Ooft, Marc Lucas, Schreiber, Liesa-Marie, Pipinikas, Christodoulos P., Chung, Grace Tin-Yun, Chan, Yuk Yu, Wu, Feng, To, Ka-Fai, Tsang, Chi Man, Pearce, Wayne, Morelli, Daniele, Philpott, Martin, Masterson, Liam, Nibhani, Reshma, Wells, Graham, Bell, Christopher G., Koller, Julia, Delecluse, Susanne, Yip, Yim Ling, Liu, Jacklyn, Forde, Cillian T., Forster, Martin D., Jay, Amrita, Dudás, József, Krapp, Annika, Wan, Simon, Uprimny, Christian, Sprung, Susanne, Haybaeck, Johannes, Fenton, Tim R., Chester, Kerry, Thirlwell, Christina, Royle, Gary, Marafioti, Teresa, Gupta, Rajeev, Indrasari, Sagung Rai, Herdini, Camelia, Slim, Mohd Afiq Mohd, Indrawati, I., Sutton, Liam, Fles, Renske, Tan, Bing, Yeong, Joe, Jain, Amit, Han, Shuting, Wang, Haitao, Loke, Kelvin S. H., He, Wan, Xu, Ruilian, Jin, Hongtao, Cheng, Zhiqiang, Howard, David, Hwang, Peter H., Le, Quynh-Thu, Tay, Joshua K., West, Robert B., Tsao, Sai Wah, Meyer, Tim, Riechelmann, Herbert, Oppermann, Udo, Delecluse, Henri-Jacques, Willems, Stefan M., Chua, Melvin L. K., Busson, Pierre, Lo, Kwok Wai, Wollmann, Guido, Pillay, Nischalan, Vanhaesebroeck, Bart, and Lund, Valerie J.

Published
2021
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15. BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

Author

Feng, Yuliang, primary, Cai, Liuyang, additional, Pook, Martin, additional, Liu, Feng, additional, Chang, Chao-Hui, additional, Mouti, Mai Abdel, additional, Nibhani, Reshma, additional, Militi, Stefania, additional, Dunford, James, additional, Philpott, Martin, additional, Fan, Yanbo, additional, Fan, Guo-Chang, additional, Liu, Qi, additional, Qi, Jun, additional, Wang, Cheng, additional, Hong, Wanzi, additional, Morgan, Hannah, additional, Wang, Mingyang, additional, Sadayappan, Sakthivel, additional, Jegga, Anil G., additional, Oppermann, Udo, additional, Wang, Yigang, additional, Huang, Wei, additional, Jiang, Lei, additional, and Pauklin, Siim, additional

Published
2023
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17. Correcting PCR amplification errors in unique molecular identifiers to generate absolute numbers of sequencing molecules

Author

Sun, Jianfeng, primary, Philpott, Martin, additional, Loi, Danson, additional, Li, Shuang, additional, Monteagudo-Mesas, Pablo, additional, Hoffman, Gabriela, additional, Robson, Jonathan, additional, Mehta, Neelam, additional, Gamble, Vicki, additional, Brown, Tom, additional, Sr, Tom Brown, additional, Canzar, Stefan, additional, Oppermann, Udo, additional, and Cribbs, Adam P, additional

Published
2023
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18. Dataset S2 from Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death

Author

Cottone, Lucia, primary, Cribbs, Adam P., primary, Khandelwal, Garima, primary, Wells, Graham, primary, Ligammari, Lorena, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Lombard, Patrick, primary, Hookway, Edward S., primary, Szommer, Tamas, primary, Johansson, Catrine, primary, Brennan, Paul E., primary, Pillay, Nischalan, primary, Jenner, Richard G., primary, Oppermann, Udo, primary, and Flanagan, Adrienne M., primary

Published
2023
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19. Supplementary Information from Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death

Author

Cottone, Lucia, primary, Cribbs, Adam P., primary, Khandelwal, Garima, primary, Wells, Graham, primary, Ligammari, Lorena, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Lombard, Patrick, primary, Hookway, Edward S., primary, Szommer, Tamas, primary, Johansson, Catrine, primary, Brennan, Paul E., primary, Pillay, Nischalan, primary, Jenner, Richard G., primary, Oppermann, Udo, primary, and Flanagan, Adrienne M., primary

Published
2023
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20. Supplemental Methods and References from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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21. Supplementary Tables S1-S8 from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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22. Data from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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23. Supplemental Figures S1-S6 from Generation of a Selective Small Molecule Inhibitor of the CBP/p300 Bromodomain for Leukemia Therapy

Author

Picaud, Sarah, primary, Fedorov, Oleg, primary, Thanasopoulou, Angeliki, primary, Leonards, Katharina, primary, Jones, Katherine, primary, Meier, Julia, primary, Olzscha, Heidi, primary, Monteiro, Octovia, primary, Martin, Sarah, primary, Philpott, Martin, primary, Tumber, Anthony, primary, Filippakopoulos, Panagis, primary, Yapp, Clarence, primary, Wells, Christopher, primary, Che, Ka Hing, primary, Bannister, Andrew, primary, Robson, Samuel, primary, Kumar, Umesh, primary, Parr, Nigel, primary, Lee, Kevin, primary, Lugo, Dave, primary, Jeffrey, Philip, primary, Taylor, Simon, primary, Vecellio, Matteo L., primary, Bountra, Chas, primary, Brennan, Paul E., primary, O'Mahony, Alison, primary, Velichko, Sharlene, primary, Müller, Susanne, primary, Hay, Duncan, primary, Daniels, Danette L., primary, Urh, Marjeta, primary, La Thangue, Nicholas B., primary, Kouzarides, Tony, primary, Prinjha, Rab, primary, Schwaller, Jürg, primary, and Knapp, Stefan, primary

Published
2023
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24. BRD9-SMAD2/3 orchestrates stemness and tumorigenesis in pancreatic ductal adenocarcinoma

Author

Feng, Yuliang, Cai, Liuyang, Pook, Martin, Liu, Feng, Chang, Chao-Hui, Mouti, Mai Abdel, Nibhani, Reshma, Wu, Shihong, Deng, Siwei, Militi, Stefania, Dunford, James, Philpott, Martin, Fan, Yanbo, Fan, Guo-Chang, Liu, Qi, Qi, Jun, Sadayappan, Sakthivel, Jegga, Anil G., Oppermann, Udo, Wang, Yigang, Huang, Wei, Jiang, Lei, and Pauklin, Siim

Subjects
Article
Abstract

The dismal prognosis of pancreatic ductal adenocarcinoma (PDAC) is linked to the presence of pancreatic cancer stem-like cells (CSCs) that respond poorly to current chemotherapy regimens. By small molecule compound screening targeting 142 epigenetic enzymes, we identified that bromodomain-containing protein BRD9, a component of the BAF histone remodelling complex, is a key chromatin regulator to orchestrate the stemness of pancreatic CSCs via cooperating with the TGFβ/Activin-SMAD2/3 signalling pathway. Inhibition and genetic ablation of BDR9 block the self-renewal, cell cycle entry into G0 phase and invasiveness of CSCs, and improve the sensitivity of CSCs to gemcitabine treatment. In addition, pharmacological inhibition of BRD9 significantly reduced the tumorigenesis in patient-derived xenografts mouse models and eliminated CSCs in tumours from pancreatic cancer patients. Mechanistically, inhibition of BRD9 disrupts enhancer-promoter looping and transcription of stemness genes in CSCs. Collectively, the data suggest BRD9 as a novel therapeutic target for PDAC treatment via modulation of CSC stemness.

Published
2023

25. BRD9-containing non-canonical BAF complex maintains somatic cell transcriptome and acts as a barrier to human reprogramming

Author

Sevinç, Kenan, primary, Sevinç, Gülben Gürhan, additional, Cavga, Ayşe Derya, additional, Philpott, Martin, additional, Kelekçi, Simge, additional, Can, Hazal, additional, Cribbs, Adam P., additional, Yıldız, Abdullah Burak, additional, Yılmaz, Alperen, additional, Ayar, Enes Sefa, additional, Arabacı, Dilşad H., additional, Dunford, James E., additional, Ata, Deniz, additional, Sigua, Logan H., additional, Qi, Jun, additional, Oppermann, Udo, additional, and Onder, Tamer T., additional

Published
2022
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27. Epigenetic-focused CRISPR/Cas9 screen identifies ASH2L as a regulator of glioblastoma cell survival

Author

Ozyerli-Goknar, Ezgi, primary, Kala, Ezgi Yagmur, additional, Aksu, Ali Cenk, additional, Bulut, Ipek, additional, Cingöz, Ahmet, additional, Nizamuddin, Sheikh, additional, Biniossek, Martin, additional, Seker-Polat, Fidan, additional, Morova, Tunc, additional, Aztekin, Can, additional, Kung, Sonia H.A., additional, Syed, Hamzah, additional, Tuncbag, Nurcan, additional, Gonen, Mehmet, additional, Philpott, Martin, additional, Cribbs, Adam P., additional, Acilan, Ceyda, additional, Lack, Nathan A., additional, Onder, Tamer T., additional, Timmers, H.T. Marc, additional, and Bagci-Onder, Tugba, additional

Published
2022
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28. P-065: Development of a mass cytometry-based toolkit to investigate myeloma therapeutic responses ex vivo

Author

Gooding, Sarah, primary, Guo, Manman, additional, Van Oekelen, Oliver, additional, Al-Hourani, Kinda, additional, Watson, Edmund, additional, Palmer, Charlotte, additional, Philpott, Martin, additional, Baker, Warren, additional, Ahern, David, additional, Updahyaya, Bhaskar, additional, Kim-Schulze, Seunghee, additional, Flynt, Erin, additional, Pierceall, William, additional, Ramasamy, Karthik, additional, Cribbs, Adam, additional, Parekh, Samir, additional, Thakurta, Anjan, additional, and Oppermann, Udo, additional

Published
2022
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29. EPIKOL, a chromatin-focused CRISPR/Cas9-based screening platform, to identify cancer-specific epigenetic vulnerabilities

Author

Yedier Bayram, Özlem; Gökbayrak, Bengül; Kayabölen, Alişan; Aksu, Ali Cenk; Cavga, Ayse Derya; Cingöz, Ahmet; Kala, Ezgi Yağmur; Karabıyık, Göktuğ; Günsay, Rauf; Esin, Beril; Morova, Tunç; Uyulur, Fırat; Önder, Tuğba Bağcı (ORCID 0000-0003-3646-2613 & YÖK ID 184359); Syed, Hamzah (ORCID 0000-0001-6981-6962 & YÖK ID 318138); Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842); Önder, Tamer Tevfik (ORCID 0000-0002-2372-9158 & YÖK ID 42946), Philpott, Martin; Cribbs, Adam P.; Kung, Sonia H.Y, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine; Graduate School of Health Sciences, Yedier Bayram, Özlem; Gökbayrak, Bengül; Kayabölen, Alişan; Aksu, Ali Cenk; Cavga, Ayse Derya; Cingöz, Ahmet; Kala, Ezgi Yağmur; Karabıyık, Göktuğ; Günsay, Rauf; Esin, Beril; Morova, Tunç; Uyulur, Fırat; Önder, Tuğba Bağcı (ORCID 0000-0003-3646-2613 & YÖK ID 184359); Syed, Hamzah (ORCID 0000-0001-6981-6962 & YÖK ID 318138); Lack, Nathan Alan (ORCID 0000-0001-7399-5844 & YÖK ID 120842); Önder, Tamer Tevfik (ORCID 0000-0002-2372-9158 & YÖK ID 42946), Philpott, Martin; Cribbs, Adam P.; Kung, Sonia H.Y, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), and School of Medicine; Graduate School of Health Sciences

Abstract

Dysregulation of the epigenome due to alterations in chromatin modifier proteins commonly contribute to malignant transformation. To interrogate the roles of epigenetic modifiers in cancer cells, we generated an epigenome-wide CRISPR-Cas9 knockout library (EPIKOL) that targets a wide-range of epigenetic modifiers and their cofactors. We conducted eight screens in two different cancer types and showed that EPIKOL performs with high efficiency in terms of sgRNA distribution and depletion of essential genes. We discovered novel epigenetic modifiers that regulate triple-negative breast cancer (TNBC) and prostate cancer cell fitness. We confirmed the growth-regulatory functions of individual candidates, including SS18L2 and members of the NSL complex (KANSL2, KANSL3, KAT8) in TNBC cells. Overall, we show that EPIKOL, a focused sgRNA library targeting similar to 800 genes, can reveal epigenetic modifiers that are essential for cancer cell fitness under in vitro and in vivo conditions and enable the identification of novel anti-cancer targets. Due to its comprehensive epigenome-wide targets and relatively high number of sgRNAs per gene, EPIKOL will facilitate studies examining functional roles of epigenetic modifiers in a wide range of contexts, such as screens in primary cells, patient-derived xenografts as well as in vivo models., Scientific and Technological Research Council of Turkey (TÜBİTAK); pLenti-CMVBlast-PIP-FUCCI

Published
2022

32. Discovery of Prolyl-tRNA Synthetase As a Novel Target in Multiple Myeloma

Author

Kurata, Keiji, primary, Bott, Anna-James, additional, Hideshima, Teru, additional, Dunford, James, additional, Senbabaoglu, Filiz, additional, Johansson, Catrine, additional, Cribbs, Adam, additional, Philpott, Martin, additional, Gooding, Sarah, additional, Yamamoto, Leona, additional, Samur, Mehmet K., additional, Tai, Yu-Tzu, additional, Tye, Mark A, additional, Payne, N Connor, additional, Hagner, Patrick, additional, Ramasamy, Karthik, additional, Thakurta, Anjan, additional, Mazitschek, Ralph, additional, Oppermann, Udo, additional, and Anderson, Kenneth C., additional

Published
2021
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33. AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Author

Uğurlu-Çimen, Deniz, primary, Odluyurt, Deniz, additional, Sevinç, Kenan, additional, Özkan-Küçük, Nazlı Ezgi, additional, Özçimen, Burcu, additional, Demirtaş, Deniz, additional, Enüstün, Eray, additional, Aztekin, Can, additional, Philpott, Martin, additional, Oppermann, Udo, additional, Özlü, Nurhan, additional, and Önder, Tamer T., additional

Published
2021
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35. Additional file 1 of AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Author

Uğurlu-Çimen, Deniz, Odluyurt, Deniz, Sevinç, Kenan, Özkan-Küçük, Nazlı Ezgi, Özçimen, Burcu, Demirtaş, Deniz, Enüstün, Eray, Aztekin, Can, Philpott, Martin, Oppermann, Udo, Özlü, Nurhan, and Önder, Tamer T.

Abstract

Additional file 1: Figure S1. Identification of proximal interactors of DOT1L via BioID and their effect on reprogramming. (a) Replicate immunoblot of Fig. 1b. (b) CRAPome analysis of WT-DOT1L proximal proteins identified via BioID assay. Y-axis shows the PSM values from MS data. (c) mRNA levels of shRNA targeted genes were assessed via qRT-PCR. β-actin was used as an internal control and gene expression levels are normalized to control shFF (firefly luciferase targeting shRNA) expressing cells. (d) mRNA levels of shAF9 targeted genes were assessed via qRT-PCR. β-actin was used as an internal control and gene expression levels are normalized to control shFF (firefly luciferase targeting shRNA) expressing cells. (e) Fold change in the number of Tra-1-60 positive colonies upon shAF9 expression. P values were determined by one sample t-test; * P

Published
2021
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36. AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Author

Department of Molecular Biology and Genetics, Önder, Tamer Tevfik (ORCID 0000-0002-2372-9158 & YÖK ID 42946); Özlü, Nurhan (ORCID 0000-0002-5157-8780 & YÖK ID 105301); Uğurlu Çimen, Deniz; Odluyurt, Deniz; Sevinç, Kenan; Özkan Küçük, Nazlı Ezgi; Özçimen, Burcu; Demirtaş, Deniz; Enüstün, Eray; Aztekin, Can, Philpott, Martin; Oppermann, Udo, Department of Molecular Biology and Genetics, Önder, Tamer Tevfik (ORCID 0000-0002-2372-9158 & YÖK ID 42946); Özlü, Nurhan (ORCID 0000-0002-5157-8780 & YÖK ID 105301); Uğurlu Çimen, Deniz; Odluyurt, Deniz; Sevinç, Kenan; Özkan Küçük, Nazlı Ezgi; Özçimen, Burcu; Demirtaş, Deniz; Enüstün, Eray; Aztekin, Can, and Philpott, Martin; Oppermann, Udo

Abstract

Background: the histone H3 lysine 79 (H3K79) methyltransferase DOT1L is a key chromatin-based barrier to somatic cell reprogramming. However, the mechanisms by which DOT1L safeguards cell identity and somatic-specific transcriptional programs remain unknown. Results: we employed a proteomic approach using proximity-based labeling to identify DOT1L-interacting proteins and investigated their effects on reprogramming. Among DOT1L interactors, suppression of AF10 (MLLT10) via RNA interference or CRISPR/Cas9, significantly increases reprogramming efficiency. In somatic cells and induced pluripotent stem cells (iPSCs) higher order H3K79 methylation is dependent on AF10 expression. In AF10 knock-out cells, re-expression wild-type AF10, but not a DOT1L binding-impaired mutant, rescues overall H3K79 methylation and reduces reprogramming efficiency. Transcriptomic analyses during reprogramming show that AF10 suppression results in downregulation of fibroblast-specific genes and accelerates the activation of pluripotency-associated genes. Conclusions: our findings establish AF10 as a novel barrier to reprogramming by regulating H3K79 methylation and thereby sheds light on the mechanism by which cell identity is maintained in somatic cells.

Published
2021

37. AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Author

Önder, Tamer Tevfik (ORCID 0000-0002-2372-9158 & YÖK ID 42946); Özlü, Nurhan (ORCID 0000-0002-5157-8780 & YÖK ID 105301); Uğurlu Çimen, Deniz; Odluyurt, Deniz; Sevinç, Kenan; Özkan Küçük, Nazlı Ezgi; Özçimen, Burcu; Demirtaş, Deniz; Enüstün, Eray; Aztekin, Can, Philpott, Martin; Oppermann, Udo, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Health Sciences, Department of Molecular Biology and Genetics, Önder, Tamer Tevfik (ORCID 0000-0002-2372-9158 & YÖK ID 42946); Özlü, Nurhan (ORCID 0000-0002-5157-8780 & YÖK ID 105301); Uğurlu Çimen, Deniz; Odluyurt, Deniz; Sevinç, Kenan; Özkan Küçük, Nazlı Ezgi; Özçimen, Burcu; Demirtaş, Deniz; Enüstün, Eray; Aztekin, Can, Philpott, Martin; Oppermann, Udo, Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), School of Medicine; College of Sciences; Graduate School of Sciences and Engineering; Graduate School of Health Sciences, and Department of Molecular Biology and Genetics

Abstract

Background: the histone H3 lysine 79 (H3K79) methyltransferase DOT1L is a key chromatin-based barrier to somatic cell reprogramming. However, the mechanisms by which DOT1L safeguards cell identity and somatic-specific transcriptional programs remain unknown. Results: we employed a proteomic approach using proximity-based labeling to identify DOT1L-interacting proteins and investigated their effects on reprogramming. Among DOT1L interactors, suppression of AF10 (MLLT10) via RNA interference or CRISPR/Cas9, significantly increases reprogramming efficiency. In somatic cells and induced pluripotent stem cells (iPSCs) higher order H3K79 methylation is dependent on AF10 expression. In AF10 knock-out cells, re-expression wild-type AF10, but not a DOT1L binding-impaired mutant, rescues overall H3K79 methylation and reduces reprogramming efficiency. Transcriptomic analyses during reprogramming show that AF10 suppression results in downregulation of fibroblast-specific genes and accelerates the activation of pluripotency-associated genes. Conclusions: our findings establish AF10 as a novel barrier to reprogramming by regulating H3K79 methylation and thereby sheds light on the mechanism by which cell identity is maintained in somatic cells., Scientific and Technological Research Council of Turkey (TÜBİTAK) Project; European Union (EU); Horizon 2020; Seventh Framework Programme (FP7/2007-2013) under REA Grant Agreement; People Programme (Marie Curie Actions); Arthritis Research UK; EMBO Installation Grant; Newton Advanced Fellowship; Cancer Research UK; Leducq Foundation LEAN Project

Published
2021

38. BRD9-containing non-canonical BAF complexes safeguard cell identity and prevent reprogramming

Author

Sevinç, Kenan, primary, Sevinç, Gülben Gürhan, additional, Cavga, Ayşe Derya, additional, Philpott, Martin, additional, Kelekçi, Simge, additional, Can, Hazal, additional, Cribbs, Adam P., additional, Ayar, Enes Sefa, additional, Arabacı, Dilşad H., additional, Dunford, James E., additional, Demir, Ata B., additional, Sigua, Logan H., additional, Qi, Jun, additional, Oppermann, Udo, additional, and Onder, Tamer T., additional

Published
2021
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40. KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

Author

Heward, James, primary, Koniali, Lola, additional, D’Avola, Annalisa, additional, Close, Karina, additional, Yeomans, Alison, additional, Philpott, Martin, additional, Dunford, James, additional, Rahim, Tahrima, additional, Al Seraihi, Ahad F., additional, Wang, Jun, additional, Korfi, Koorosh, additional, Araf, Shamzah, additional, Iqbal, Sameena, additional, Bewicke-Copley, Findlay, additional, Kumar, Emil, additional, Barisic, Darko, additional, Calaminici, Maria, additional, Clear, Andrew, additional, Gribben, John, additional, Johnson, Peter, additional, Neve, Richard, additional, Cutillas, Pedro, additional, Okosun, Jessica, additional, Oppermann, Udo, additional, Melnick, Ari, additional, Packham, Graham, additional, and Fitzgibbon, Jude, additional

Published
2021
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41. The Prolyl-tRNA Synthetase Inhibitor Halofuginone Inhibits SARS-CoV-2 Infection

Author

Sandoval, Daniel R., primary, Clausen, Thomas Mandel, additional, Nora, Chelsea, additional, Cribbs, Adam P., additional, Denardo, Andrea, additional, Clark, Alex E., additional, Garretson, Aaron F., additional, Coker, Joanna K.C., additional, Narayanan, Anoop, additional, Majowicz, Sydney A., additional, Philpott, Martin, additional, Johansson, Catrine, additional, Dunford, James E., additional, Spliid, Charlotte B., additional, Golden, Gregory J., additional, Payne, N. Connor, additional, Tye, Mark A., additional, Nowell, Cameron J., additional, Griffis, Eric R., additional, Piermatteo, Ann, additional, Grunddal, Kaare V., additional, Alle, Thibault, additional, Magida, Jason A., additional, Hauser, Blake M., additional, Feldman, Jared, additional, Caradonna, Timothy M., additional, Pu, Yuan, additional, Yin, Xin, additional, McVicar, Rachael N., additional, Kwong, Elizabeth M., additional, Weiss, Ryan J., additional, Downes, Michael, additional, Tsimikas, Sotirios, additional, Smidt, Aaron G., additional, Ballatore, Carlo, additional, Zengler, Karsten, additional, Evans, Ron M., additional, Chanda, Sumit K., additional, Croker, Ben A., additional, Leibel, Sandra L., additional, Jose, Joyce, additional, Mazitschek, Ralph, additional, Oppermann, Udo, additional, Esko, Jeffrey D., additional, Carlin, Aaron F., additional, and Gordts, Philip L.S.M., additional

Published
2021
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44. AF10 (MLLT10) prevents somatic cell reprogramming through regulation of DOT1L-mediated H3K79 methylation

Author

Uğurlu-Çimen, Deniz, primary, Odluyurt, Deniz, additional, Sevinç, Kenan, additional, Özkan-Küçük, Nazlı Ezgi, additional, Özçimen, Burcu, additional, Demirtaş, Deniz, additional, Enüstün, Eray, additional, Aztekin, Can, additional, Philpott, Martin, additional, Oppermann, Udo, additional, Özlü, Nurhan, additional, and Önder, Tamer T., additional

Published
2020
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46. Nutrigenomics

Author

Ferguson, Lynette R., primary, Philpott, Martin, additional, and Barnett, Matthew P.G., additional

Published
2010
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47. Contributors

Author

Ahmed, Farid E., primary, Andersen, Claus L., additional, Ansorge, Wilhelm J., additional, Athanassiadou, Aglaia, additional, Baralle, Francisco E., additional, Barnett, Matthew P.G., additional, Bavari, Sina, additional, Belkum, Alex van, additional, Bell, Walter, additional, Benavides, Fernando, additional, Birkenkamp-Demtroder, Karin, additional, Blakesley, Lauryn, additional, Bosserhoff, Anja Katrin, additional, Budowle, Bruce, additional, Bui, Chinh Thien, additional, Burnett, David, additional, Campbell, Rowan S., additional, Caulfield, Timothy, additional, Chiotis, Maria, additional, Conze, Tim, additional, Corach, Daniel, additional, Cotton, Richard G.H., additional, Dalsgaard-Sørensen, Karina, additional, Delaney, Carol A., additional, Rycke, Martine de, additional, den Dunnen, Johan T., additional, Dyrskjøt, Lars, additional, Eisenberg, Arthur J., additional, Faca, Vitor, additional, Farrar, Jared S., additional, Ferguson, Lynnette R., additional, Fortina, Paolo, additional, Fredenburgh, Jerry, additional, Fruehauf, Stefan, additional, Giulietti, Anna-Paula, additional, Godwin, Andrew K., additional, Gold, Bert, additional, Göransson, Jenny, additional, Grizzle, William E., additional, Grodzinski, Piotr, additional, Grundberg, Ida, additional, Guénet, Jean-Louis, additional, Gut, Ivo G., additional, Hanash, Samir, additional, Hellerbrand, Claus, additional, Henriksson, Sara, additional, Innocenti, Federico, additional, Isaksson, Magnus, additional, Jarvius, Malin, additional, Jensen, Jens L., additional, Joly, Yann, additional, Kamali-Moghaddam, Masood, additional, Kehn-Hall, Kylene, additional, Köcher, Thomas, additional, Krjutskov, Kaarel, additional, Kruhøffer, Mogens, additional, Kurg, Ants, additional, Lambrinakos, Andreana, additional, Landegren, Ulf, additional, Larsson, Chatarina, additional, Laufs, Stephanie, additional, Leego, Merike, additional, Leuchowius, Karl-Johan, additional, Lind, Ilona, additional, Liu, Robin, additional, Maier, Patrick W., additional, Marsh, Sharon, additional, Mathieu, Chantal, additional, Menounos, Panayiotis G., additional, Metspalu, Andres, additional, Nicolas, Emmanuelle, additional, Nilsson, Mats, additional, Oitmaa, Eneli, additional, Ørntoft, Torben F., additional, Overbergh, Lut, additional, Pagani, Franco, additional, Papachatzopoulou, Adamandia, additional, Pardali, Katerina, additional, Patenaude, Andrea Farkas, additional, Patrinos, George P., additional, Perera, Minoli, additional, Peters, Hartmut, additional, Petrou, Mary, additional, Philpott, Martin, additional, Planz, John V., additional, Pullat, Janne, additional, Qiu, Ji, additional, Reed, Gudrun H., additional, Rees, Kylee, additional, Robinson, Peter N., additional, Sallmann, Georgina, additional, Schouten, Jan P., additional, Schubert, Luisa, additional, Scott, Kathryn E., additional, Sepers, Eline M., additional, Sermon, Karen, additional, Söderberg, Ola, additional, Stampe-Ostenfeld, Marie, additional, Stavrou, Eleana, additional, Stenberg, Johan, additional, Superti-Furga, Giulio, additional, Surrey, Saul, additional, Taylor, Graham. R., additional, Thorsen, Kasper, additional, Tonisson, Neeme, additional, Tönnies, Holger, additional, Tost, Jörg, additional, Trounce, Ian, additional, Valckx, Dirk, additional, Ward, Michael, additional, Weibrecht, Irene, additional, Wittwer, Carl T., additional, Yeung, Anthony T., additional, and Jens Zeller, W., additional

Published
2010
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49. Inhibition of Histone H3K27 Demethylases Inactivates Brachyury (TBXT) and Promotes Chordoma Cell Death

Author

Cottone, Lucia, primary, Cribbs, Adam P., additional, Khandelwal, Garima, additional, Wells, Graham, additional, Ligammari, Lorena, additional, Philpott, Martin, additional, Tumber, Anthony, additional, Lombard, Patrick, additional, Hookway, Edward S., additional, Szommer, Tamas, additional, Johansson, Catrine, additional, Brennan, Paul E., additional, Pillay, Nischalan, additional, Jenner, Richard G., additional, Oppermann, Udo, additional, and Flanagan, Adrienne M., additional

Published
2020
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50. KDM5 inhibition offers a novel therapeutic strategy for the treatment of KMT2D mutant lymphomas

Author

Heward, James A, primary, Konali, Lola, additional, D’Avola, Annalisa, additional, Close, Karina, additional, Yeomans, Alison, additional, Philpott, Martin, additional, Dunford, James, additional, Rahim, Tahrima, additional, Al Seraihi, Ahad F, additional, Wang, Jun, additional, Korfi, Koorosh, additional, Araf, Shamzah, additional, Iqbal, Sameena, additional, Bewicke-Copley, Findlay, additional, Kumar, Emil, additional, Barisic, Darko, additional, Calaminici, Maria, additional, Clear, Andrew, additional, Gribben, John, additional, Johnson, Peter, additional, Neve, Richard, additional, Okosun, Jessica, additional, Oppermann, Udo, additional, Melnick, Ari, additional, Packham, Graham, additional, and Fitzgibbon, Jude, additional

Published
2020
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