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2. DMRT1 regulates human germline commitment

Author

Irie, Naoko, Lee, Sun-Min, Lorenzi, Valentina, Xu, Haiqi, Chen, Jinfeng, Inoue, Masato, Kobayashi, Toshihiro, Sancho-Serra, Carmen, Drousioti, Elena, Dietmann, Sabine, Vento-Tormo, Roser, Song, Chun-Xiao, and Surani, M. Azim

Published
2023
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3. METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Author

García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D’Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizabal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023
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5. The ancient mammalian KRAB zinc finger gene cluster on human chromosome 8q24.3 illustrates principles of C2H2 zinc finger evolution associated with unique expression profiles in human tissues

Author

Ding Guohui, Wen Gaiping, Gad Sophie, Autran Sandra, Koczan Dirk, Wilhelm Thomas, Dietmann Sabine, Lorenz Peter, Li Yixue, Rousseau-Merck Marie-Françoise, and Thiesen Hans-Juergen

Subjects
Biotechnology, TP248.13-248.65, Genetics, QH426-470
Abstract

Abstract Background Expansion of multi-C2H2 domain zinc finger (ZNF) genes, including the Krüppel-associated box (KRAB) subfamily, paralleled the evolution of tetrapodes, particularly in mammalian lineages. Advances in their cataloging and characterization suggest that the functions of the KRAB-ZNF gene family contributed to mammalian speciation. Results Here, we characterized the human 8q24.3 ZNF cluster on the genomic, the phylogenetic, the structural and the transcriptome level. Six (ZNF7, ZNF34, ZNF250, ZNF251, ZNF252, ZNF517) of the seven locus members contain exons encoding KRAB domains, one (ZNF16) does not. They form a paralog group in which the encoded KRAB and ZNF protein domains generally share more similarities with each other than with other members of the human ZNF superfamily. The closest relatives with respect to their DNA-binding domain were ZNF7 and ZNF251. The analysis of orthologs in therian mammalian species revealed strong conservation and purifying selection of the KRAB-A and zinc finger domains. These findings underscore structural/functional constraints during evolution. Gene losses in the murine lineage (ZNF16, ZNF34, ZNF252, ZNF517) and potential protein truncations in primates (ZNF252) illustrate ongoing speciation processes. Tissue expression profiling by quantitative real-time PCR showed similar but distinct patterns for all tested ZNF genes with the most prominent expression in fetal brain. Based on accompanying expression signatures in twenty-six other human tissues ZNF34 and ZNF250 revealed the closest expression profiles. Together, the 8q24.3 ZNF genes can be assigned to a cerebellum, a testis or a prostate/thyroid subgroup. These results are consistent with potential functions of the ZNF genes in morphogenesis and differentiation. Promoter regions of the seven 8q24.3 ZNF genes display common characteristics like missing TATA-box, CpG island-association and transcription factor binding site (TFBS) modules. Common TFBS modules partly explain the observed expression pattern similarities. Conclusions The ZNF genes at human 8q24.3 form a relatively old mammalian paralog group conserved in eutherian mammals for at least 130 million years. The members persisted after initial duplications by undergoing subfunctionalizations in their expression patterns and target site recognition. KRAB-ZNF mediated repression of transcription might have shaped organogenesis in mammalian ontogeny.

Published
2010
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10. Global and single-nucleotide resolution detection of 7-methylguanosine in RNA

Author

D’Ambrosi, Silvia, primary, García-Vílchez, Raquel, additional, Kedra, Darek, additional, Vitali, Patrice, additional, Macias-Cámara, Nuria, additional, Bárcena, Laura, additional, Gonzalez-Lopez, Monika, additional, Aransay, Ana M., additional, Dietmann, Sabine, additional, Hurtado, Antonio, additional, and Blanco, Sandra, additional

Published
2024
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11. Technologies and perspectives for achieving carbon neutrality

Author

Wang, Fang, Harindintwali, Jean Damascene, Yuan, Zhizhang, Wang, Min, Wang, Faming, Li, Sheng, Yin, Zhigang, Huang, Lei, Fu, Yuhao, Li, Lei, Chang, Scott X., Zhang, Linjuan, Rinklebe, Jörg, Yuan, Zuoqiang, Zhu, Qinggong, Xiang, Leilei, Tsang, Daniel C.W., Xu, Liang, Jiang, Xin, Liu, Jihua, Wei, Ning, Kästner, Matthias, Zou, Yang, Ok, Yong Sik, Shen, Jianlin, Peng, Dailiang, Zhang, Wei, Barceló, Damià, Zhou, Yongjin, Bai, Zhaohai, Li, Boqiang, Zhang, Bin, Wei, Ke, Cao, Hujun, Tan, Zhiliang, Zhao, Liu-bin, He, Xiao, Zheng, Jinxing, Bolan, Nanthi, Liu, Xiaohong, Huang, Changping, Dietmann, Sabine, Luo, Ming, Sun, Nannan, Gong, Jirui, Gong, Yulie, Brahushi, Ferdi, Zhang, Tangtang, Xiao, Cunde, Li, Xianfeng, Chen, Wenfu, Jiao, Nianzhi, Lehmann, Johannes, Zhu, Yong-Guan, Jin, Hongguang, Schäffer, Andreas, Tiedje, James M., and Chen, Jing M.

Published
2021
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12. Artificial intelligence: A powerful paradigm for scientific research

Author

Xu, Yongjun, Liu, Xin, Cao, Xin, Huang, Changping, Liu, Enke, Qian, Sen, Liu, Xingchen, Wu, Yanjun, Dong, Fengliang, Qiu, Cheng-Wei, Qiu, Junjun, Hua, Keqin, Su, Wentao, Wu, Jian, Xu, Huiyu, Han, Yong, Fu, Chenguang, Yin, Zhigang, Liu, Miao, Roepman, Ronald, Dietmann, Sabine, Virta, Marko, Kengara, Fredrick, Zhang, Ze, Zhang, Lifu, Zhao, Taolan, Dai, Ji, Yang, Jialiang, Lan, Liang, Luo, Ming, Liu, Zhaofeng, An, Tao, Zhang, Bin, He, Xiao, Cong, Shan, Liu, Xiaohong, Zhang, Wei, Lewis, James P., Tiedje, James M., Wang, Qi, An, Zhulin, Wang, Fei, Zhang, Libo, Huang, Tao, Lu, Chuan, Cai, Zhipeng, Wang, Fang, and Zhang, Jiabao

Published
2021
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13. Global and single-nucleotide resolution detection of 7-methylguanosine in RNA

Author

Ministerio de Ciencia e Innovación (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Asociación Española Contra el Cáncer, Universidad de Salamanca, Fundación Memoria de D. Samuel Solorzano Barruso, Junta de Castilla y León, Consejo Superior de Investigaciones Científicas (España), D’Ambrosia, Silvia, García-Vílchez, Raquel, Kedrac, Darek, Vitalie, Patrice, Macias-Cámara, Nuria, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Dietmann, Sabine, Hurtado, Antonio, Blanco, Sandra, Ministerio de Ciencia e Innovación (España), Ministerio de Economía y Competitividad (España), Agencia Estatal de Investigación (España), Asociación Española Contra el Cáncer, Universidad de Salamanca, Fundación Memoria de D. Samuel Solorzano Barruso, Junta de Castilla y León, Consejo Superior de Investigaciones Científicas (España), D’Ambrosia, Silvia, García-Vílchez, Raquel, Kedrac, Darek, Vitalie, Patrice, Macias-Cámara, Nuria, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Dietmann, Sabine, Hurtado, Antonio, and Blanco, Sandra

Abstract

RNA modifications, including N-7-methylguanosine (m7G), are pivotal in governing RNA stability and gene expression regulation. The accurate detection of internal m7G modifications is of paramount significance, given recent associations between altered m7G deposition and elevated expression of the methyltransferase METTL1 in various human cancers. The development of robust m7G detection techniques has posed a significant challenge in the field of epitranscriptomics. In this study, we introduce two methodologies for the global and accurate identification of m7G modifications in human RNA. We introduce borohydride reduction sequencing (Bo-Seq), which provides base resolution mapping of m7G modifications. Bo-Seq achieves exceptional performance through the optimization of RNA depurination and scission, involving the strategic use of high concentrations of NaBH4, neutral pH and the addition of 7-methylguanosine monophosphate (m7GMP) during the reducing reaction. Notably, compared to NaBH4-based methods, Bo-Seq enhances the m7G detection performance, and simplifies the detection process, eliminating the necessity for intricate chemical steps and reducing the protocol duration. In addition, we present an antibody-based approach, which enables the assessment of m7G relative levels across RNA molecules and biological samples, however it should be used with caution due to limitations associated with variations in antibody quality between batches. In summary, our novel approaches address the pressing need for reliable and accessible methods to detect RNA m7G methylation in human cells. These advancements hold the potential to catalyse future investigations in the critical field of epitranscriptomics, shedding light on the complex regulatory roles of m7G in gene expression and its implications in cancer biology.

Published
2024

15. Bone Marrow Mesenchymal Stem Cells Support Acute Myeloid Leukemia Bioenergetics and Enhance Antioxidant Defense and Escape from Chemotherapy

Author

Forte, Dorian, García-Fernández, María, Sánchez-Aguilera, Abel, Stavropoulou, Vaia, Fielding, Claire, Martín-Pérez, Daniel, López, Juan Antonio, Costa, Ana S.H., Tronci, Laura, Nikitopoulou, Efterpi, Barber, Michael, Gallipoli, Paolo, Marando, Ludovica, Fernández de Castillejo, Carlos López, Tzankov, Alexandar, Dietmann, Sabine, Cavo, Michele, Catani, Lucia, Curti, Antonio, Vázquez, Jesús, Frezza, Christian, Huntly, Brian J., Schwaller, Juerg, and Méndez-Ferrer, Simón

Published
2020
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18. OCT4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human

Author

Huang, Xin, Park, Kyoung-mi, Gontarz, Paul, Zhang, Bo, Pan, Joshua, McKenzie, Zachary, Fischer, Laura A., Dong, Chen, Dietmann, Sabine, Xing, Xiaoyun, Shliaha, Pavel V., Yang, Jihong, Li, Dan, Ding, Junjun, Lungjangwa, Tenzin, Mitalipova, Maya, Khan, Shafqat A., Imsoonthornruksa, Sumeth, Jensen, Nick, Wang, Ting, Kadoch, Cigall, Jaenisch, Rudolf, Wang, Jianlong, and Theunissen, Thorold W.

Published
2021
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19. TP53 mutations, tetraploidy and homologous recombination repair defects in early stage high-grade serous ovarian cancer

Author

Chien, Jeremy, Sicotte, Hugues, Fan, Jian-Bing, Humphray, Sean, Cunningham, Julie M, Kalli, Kimberly R, Oberg, Ann L, Hart, Steven N, Li, Ying, Davila, Jaime I, Baheti, Saurabh, Wang, Chen, Dietmann, Sabine, Atkinson, Elizabeth J, Asmann, Yan W, Bell, Debra A, Ota, Takayo, Tarabishy, Yaman, Kuang, Rui, Bibikova, Marina, Cheetham, R Keira, Grocock, Russell J, Swisher, Elizabeth M, Peden, John, Bentley, David, Kocher, Jean-Pierre A, Kaufmann, Scott H, Hartmann, Lynn C, Shridhar, Viji, and Goode, Ellen L

Subjects
Ovarian Cancer, Genetics, Human Genome, Rare Diseases, Prevention, Biotechnology, Cancer, 2.1 Biological and endogenous factors, Aetiology, Carcinoma, DNA Primase, Female, Genes, p53, Humans, Loss of Heterozygosity, Mutation, Mutation Rate, Ovarian Neoplasms, Recombinational DNA Repair, Tetraploidy, Environmental Sciences, Biological Sciences, Information and Computing Sciences, Developmental Biology
Abstract

To determine early somatic changes in high-grade serous ovarian cancer (HGSOC), we performed whole genome sequencing on a rare collection of 16 low stage HGSOCs. The majority showed extensive structural alterations (one had an ultramutated profile), exhibited high levels of p53 immunoreactivity, and harboured a TP53 mutation, deletion or inactivation. BRCA1 and BRCA2 mutations were observed in two tumors, with nine showing evidence of a homologous recombination (HR) defect. Combined Analysis with The Cancer Genome Atlas (TCGA) indicated that low and late stage HGSOCs have similar mutation and copy number profiles. We also found evidence that deleterious TP53 mutations are the earliest events, followed by deletions or loss of heterozygosity (LOH) of chromosomes carrying TP53, BRCA1 or BRCA2. Inactivation of HR appears to be an early event, as 62.5% of tumours showed a LOH pattern suggestive of HR defects. Three tumours with the highest ploidy had little genome-wide LOH, yet one of these had a homozygous somatic frame-shift BRCA2 mutation, suggesting that some carcinomas begin as tetraploid then descend into diploidy accompanied by genome-wide LOH. Lastly, we found evidence that structural variants (SV) cluster in HGSOC, but are absent in one ultramutated tumor, providing insights into the pathogenesis of low stage HGSOC.

Published
2015

20. Identification of a myofibroblast differentiation program during neonatal lung development.

Author

Yongjun Yin, Koenitzer, Jeffrey R., Patra, Debabrata, Dietmann, Sabine, Bayguinov, Peter, Hagan, Andrew S., and Ornitz, David M.

Subjects
LUNG development, PRIMARY cell culture, CELL populations, LUNGS, SEPTUM (Brain), RNA sequencing, PROGENITOR cells
Abstract

Alveologenesis is the final stage of lung development in which the internal surface area of the lung is increased to facilitate efficient gas exchange in the mature organism. The first phase of alveologenesis involves the formation of septal ridges (secondary septae) and the second phase involves thinning of the alveolar septa. Within secondary septa, mesenchymal cells include a transient population of alveolar myofibroblasts (MyoFBs) and a stable but poorly described population of lipid-rich cells that have been referred to as lipofibroblasts or matrix fibroblasts (MatFBs). Using a unique Fgf18CreER lineage trace mouse line, cell sorting, single-cell RNA sequencing and primary cell culture, we have identified multiple subtypes of mesenchymal cells in the neonatal lung, including an immature progenitor cell that gives rise to mature MyoFB. We also show that the endogenous and targeted ROSA26 locus serves as a sensitive reporter for MyoFB maturation. These studies identify a MyoFB differentiation program that is distinct from other mesenchymal cell types and increases the known repertoire of mesenchymal cell types in the neonatal lung. [ABSTRACT FROM AUTHOR]

Published
2024
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21. 3D-cultured blastoids model human embryogenesis from pre-implantation to early gastrulation stages

Author

Karvas, Rowan M., primary, Zemke, Joseph E., additional, Ali, Syed Shahzaib, additional, Upton, Eric, additional, Sane, Eshan, additional, Fischer, Laura A., additional, Dong, Chen, additional, Park, Kyoung-mi, additional, Wang, Fei, additional, Park, Kibeom, additional, Hao, Senyue, additional, Chew, Brian, additional, Meyer, Brittany, additional, Zhou, Chao, additional, Dietmann, Sabine, additional, and Theunissen, Thorold W., additional

Published
2023
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23. NOP16 is a histone mimetic that regulates Histone H3K27 methylation and gene repression

Author

Takashima, Ken, Lee, Dian-Jang, Trovero, María Fernanda, Rothi, M. Hafiz, Mistry, Meeta, Zhang, Ying, Li, Zhouyihan, Davis, Christopher P., Li, Zilan, Natale, Julia, Schmid, Ernst, Al Haddad, Joseph, Hoffmann, Gabriela Brunsting, Dietmann, Sabine, Sui, Shannan Ho, Oshiumi, Hiroyuki, Lieberman, Judy, and Greer, Eric Lieberman

Subjects
Article
Abstract

Post-translational modifications of histone tails alter chromatin accessibility to regulate gene expression. Some viruses exploit the importance of histone modifications by expressing histone mimetic proteins that contain histone-like sequences to sequester complexes that recognize modified histones. Here we identify an evolutionarily conserved and ubiquitously expressed, endogenous mammalian protein Nucleolar protein 16 (NOP16) that functions as a H3K27 mimic. NOP16 binds to EED in the H3K27 trimethylation PRC2 complex and to the H3K27 demethylase JMJD3. NOP16 knockout selectively globally increases H3K27me3, a heterochromatin mark, without altering methylation of H3K4, H3K9, or H3K36 or acetylation of H3K27. NOP16 is overexpressed and linked to poor prognosis in breast cancer. Depletion of NOP16 in breast cancer cell lines causes cell cycle arrest, decreases cell proliferation and selectively decreases expression of E2F target genes and of genes involved in cell cycle, growth and apoptosis. Conversely, ectopic NOP16 expression in triple negative breast cancer cell lines increases cell proliferation, cell migration and invasivity in vitro and tumor growth in vivo , while NOP16 knockout or knockdown has the opposite effect. Thus, NOP16 is a histone mimic that competes with Histone H3 for H3K27 methylation and demethylation. When it is overexpressed in cancer, it derepresses genes that promote cell cycle progression to augment breast cancer growth.

Published
2023

24. Epigenetic resetting in the human germ line entails histone modification remodeling

Author

Gruhn, Wolfram H, Tang, Walfred WC, Dietmann, Sabine, Alves-Lopes, João P, Penfold, Christopher A, Wong, Frederick CK, Ramakrishna, Navin B, Surani, M Azim, Gruhn, Wolfram H [0000-0001-6072-1916], Tang, Walfred WC [0000-0002-5803-1681], Dietmann, Sabine [0000-0001-6672-8457], Alves-Lopes, João P [0000-0003-3042-6988], Penfold, Christopher A [0000-0001-5823-4705], Wong, Frederick CK [0000-0002-0503-4360], Ramakrishna, Navin B [0000-0003-2974-9886], Surani, M Azim [0000-0002-8640-4318], and Apollo - University of Cambridge Repository

Subjects
Histone Code, Mammals, Germ Cells, DNA Transposable Elements, Animals, Humans, DNA Methylation, Epigenesis, Genetic
Abstract

Epigenetic resetting in the mammalian germ line entails acute DNA demethylation, which lays the foundation for gametogenesis, totipotency, and embryonic development. We characterize the epigenome of hypomethylated human primordial germ cells (hPGCs) to reveal mechanisms preventing the widespread derepression of genes and transposable elements (TEs). Along with the loss of DNA methylation, we show that hPGCs exhibit a profound reduction of repressive histone modifications resulting in diminished heterochromatic signatures at most genes and TEs and the acquisition of a neutral or paused epigenetic state without transcriptional activation. Efficient maintenance of a heterochromatic state is limited to a subset of genomic loci, such as evolutionarily young TEs and some developmental genes, which require H3K9me3 and H3K27me3, respectively, for efficient transcriptional repression. Accordingly, transcriptional repression in hPGCs presents an exemplary balanced system relying on local maintenance of heterochromatic features and a lack of inductive cues.

Published
2023
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25. Human primary liver cancer-derived organoid cultures for disease modeling and drug screening

Author

Broutier, Laura, Mastrogiovanni, Gianmarco, Verstegen, Monique MA, Francies, Hayley E, Gavarró, Lena Morrill, Bradshaw, Charles R, Allen, George E, Arnes-Benito, Robert, Sidorova, Olga, Gaspersz, Marcia P, Georgakopoulos, Nikitas, Koo, Bon-Kyoung, Dietmann, Sabine, Davies, Susan E, Praseedom, Raaj K, Lieshout, Ruby, IJzermans, Jan N M, Wigmore, Stephen J, Saeb-Parsy, Kourosh, Garnett, Mathew J, van der Laan, Luc JW, and Huch, Meritxell

Subjects
Liver cancer -- Development and progression -- Models -- Research, Cell culture -- Usage -- Research, Biological sciences, Health
Abstract

Human liver cancer research currently lacks in vitro models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved in vivo. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease., Author(s): Laura Broutier [1]; Gianmarco Mastrogiovanni [1, 2]; Monique MA Verstegen [3]; Hayley E Francies [4]; Lena Morrill Gavarró [2]; Charles R Bradshaw [1]; George E Allen [1]; Robert Arnes-Benito [...]

Published
2017
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27. N7-methylguanosine methylation of tRNAs regulates survival to stress in cancer

Author

Universidad de Sevilla. Departamento de Genética, Ministerio de Ciencia e Innovación (MICIN). España, Ministerio de Economía y Competitividad (MINECO). España, Junta de Castilla-León, Consejo Superior de Investigaciones Científicas (CSIC), García Vílchez, Raquel, Añazco Guenkova, Ana M., López, Judith, Dietmann, Sabine, Tomé, Mercedes, Jimeno González, Sonia, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Huertas Sánchez, Pablo, Blanco, Sandra, Universidad de Sevilla. Departamento de Genética, Ministerio de Ciencia e Innovación (MICIN). España, Ministerio de Economía y Competitividad (MINECO). España, Junta de Castilla-León, Consejo Superior de Investigaciones Científicas (CSIC), García Vílchez, Raquel, Añazco Guenkova, Ana M., López, Judith, Dietmann, Sabine, Tomé, Mercedes, Jimeno González, Sonia, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Huertas Sánchez, Pablo, and Blanco, Sandra

Abstract

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N7-guanosine methylation (m7G) of tRNAs, mediated by METTL1, regulates survival to stress conditions in cancer cells. Mechanistically, we find that m7G in tRNAs protects them from stress-induced cleavage and processing into 5’ tRNA fragments. Our analyses reveal that the loss of tRNA m7G methylation activates stress response pathways, sensitising cancer cells to stress. Furthermore, we find that the loss of METTL1 reduces tumour growth and increases cytotoxic stress in vivo. Our study uncovers the role of m7G methylation of tRNAs in stress responses and highlights the potential of targeting METTL1 to sensitise cancer cells to chemotherapy.

Published
2023

28. METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer

Author

Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Universidad de Salamanca, Banco Santander, Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Fundación la Caixa, European Research Council, European Commission, García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Agencia Estatal de Investigación (España), Instituto de Salud Carlos III, Junta de Castilla y León, Universidad de Salamanca, Banco Santander, Asociación Española Contra el Cáncer, Fundación CRIS contra el Cáncer, Fundación la Caixa, European Research Council, European Commission, García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Abstract

Newly growing evidence highlights the essential role that epitranscriptomic marks play in the development of many cancers; however, little is known about the role and implications of altered epitranscriptome deposition in prostate cancer. Here, we show that the transfer RNA N7-methylguanosine (m7G) transferase METTL1 is highly expressed in primary and advanced prostate tumours. Mechanistically, we find that METTL1 depletion causes the loss of m7G tRNA methylation and promotes the biogenesis of a novel class of small non-coding RNAs derived from 5'tRNA fragments. 5'tRNA-derived small RNAs steer translation control to favour the synthesis of key regulators of tumour growth suppression, interferon pathway, and immune effectors. Knockdown of Mettl1 in prostate cancer preclinical models increases intratumoural infiltration of pro-inflammatory immune cells and enhances responses to immunotherapy. Collectively, our findings reveal a therapeutically actionable role of METTL1-directed m7G tRNA methylation in cancer cell translation control and tumour biology.

Published
2023

29. N7-methylguanosine methylation of tRNAs regulates survival to stress in cancer

Author

Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Junta de Castilla y León, Banco Santander, Universidad de Salamanca, Asociación Española Contra el Cáncer, European Commission, Consejo Superior de Investigaciones Científicas (España), Añazco-Guenkova, Ana M. [0000-0001-6483-0415], García-Vílchez, Raquel, Añazco-Guenkova, Ana M., López, Judith, Dietmann, Sabine, Tomé, Mercedes, Jimeno, Sonia, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Sánchez-Martín, Manuel A., Huertas, Pablo, Durán, Raúl V., Blanco, Sandra, Ministerio de Ciencia e Innovación (España), Agencia Estatal de Investigación (España), Ministerio de Economía y Competitividad (España), Ministerio de Ciencia, Innovación y Universidades (España), Junta de Castilla y León, Banco Santander, Universidad de Salamanca, Asociación Española Contra el Cáncer, European Commission, Consejo Superior de Investigaciones Científicas (España), Añazco-Guenkova, Ana M. [0000-0001-6483-0415], García-Vílchez, Raquel, Añazco-Guenkova, Ana M., López, Judith, Dietmann, Sabine, Tomé, Mercedes, Jimeno, Sonia, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Sánchez-Martín, Manuel A., Huertas, Pablo, Durán, Raúl V., and Blanco, Sandra

Abstract

Tumour progression and therapy tolerance are highly regulated and complex processes largely dependent on the plasticity of cancer cells and their capacity to respond to stress. The higher plasticity of cancer cells highlights the need for identifying targetable molecular pathways that challenge cancer cell survival. Here, we show that N7-guanosine methylation (m7G) of tRNAs, mediated by METTL1, regulates survival to stress conditions in cancer cells. Mechanistically, we find that m7G in tRNAs protects them from stress-induced cleavage and processing into 5' tRNA fragments. Our analyses reveal that the loss of tRNA m7G methylation activates stress response pathways, sensitising cancer cells to stress. Furthermore, we find that the loss of METTL1 reduces tumour growth and increases cytotoxic stress in vivo. Our study uncovers the role of m7G methylation of tRNAs in stress responses and highlights the potential of targeting METTL1 to sensitise cancer cells to chemotherapy.

Published
2023

30. Additional file 10 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

31. Additional file 7 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

32. Additional file 8 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

33. Additional file 9 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

34. Additional file 2 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

35. Additional file 3 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

36. Additional file 4 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

37. Additional file 6 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

38. Additional file 5 of METTL1 promotes tumorigenesis through tRNA-derived fragment biogenesis in prostate cancer [Dataset]

Author

Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, Blanco, Sandra, Consejo Superior de Investigaciones Científicas (España), García-Vílchez, Raquel, Añazco-Guenkova, Ana M., Dietmann, Sabine, López, Judith, Morón-Calvente, Virginia, D'Ambrosi, Silvia, Nombela, Paz, Zamacola, Kepa, Mendizábal, Isabel, García-Longarte, Saioa, Zabala-Letona, Amaia, Astobiza, Ianire, Fernández, Sonia, Paniagua, Alejandro, Miguel-López, Borja, Marchand, Virginie, Alonso-López, Diego, Merkel, Angelika, García-Tuñón, Ignacio, Ugalde-Olano, Aitziber, Loizaga-Iriarte, Ana, Lacasa-Viscasillas, Isabel, Unda, Miguel, Azkargorta, Mikel, Elortza, Félix, Bárcena, Laura, Gonzalez-Lopez, Monika, Aransay, Ana M., Di Domenico, Tomás, Sánchez-Martín, Manuel A., De Las Rivas, Javier, Guil, Sònia, Motorin, Yuri, Helm, Mark, Pandolfi, Pier Paolo, Carracedo, Arkaitz, and Blanco, Sandra

Published
2023

44. Author Correction: Segregation of mitochondrial DNA heteroplasmy through a developmental genetic bottleneck in human embryos

Author

Floros, Vasileios I., primary, Pyle, Angela, additional, Dietmann, Sabine, additional, Wei, Wei, additional, Tang, Walfred W. C., additional, Irie, Naoko, additional, Payne, Brendan, additional, Capalbo, Antonio, additional, Noli, Laila, additional, Coxhead, Jonathan, additional, Hudson, Gavin, additional, Crosier, Moira, additional, Strahl, Henrik, additional, Khalaf, Yacoub, additional, Saitou, Mitinori, additional, Ilic, Dusko, additional, Surani, M. Azim, additional, and Chinnery, Patrick F., additional

Published
2022
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45. Specification and epigenomic resetting of the pig germline exhibit conservation with the human lineage

Author

China Scholarship Council, University of Nottingham, European Commission, Croucher Foundation, Biotechnology and Biological Sciences Research Council (UK), Zhu, Qifan [0000-0001-5146-3337], Sang, F. [0000-0002-8746-5868], Withey, S. [0000-0003-0520-0290], Tang, Walfred [0000-0002-5803-1681], Dietmann, Sabine [0000-0001-6672-8457], Klisch, D. [0000-0002-5772-2261], Ramos Ibeas, Priscila [0000-0003-4578-0189], Zhang, Haixin [0000-0002-8840-053X], Requena, Cristina E. [0000-0001-5239-9162], Hajkova, Petra [0000-0003-4145-1468], Loose, M. [0000-0002-5264-0929], Surani, M. A. [0000-0002-8640-4318], Alberio, Ramiro [0000-0001-6560-3919], Zhu, Qifan, Sang, F., Withey, S., Tang, Walfred, Dietmann, Sabine, Klisch, D., Ramos Ibeas, Priscila, Zhang, Haixin, Requena, Cristina E, Hajkova, Petra, Loose, M., Surani, M. A., Alberio, Ramiro, China Scholarship Council, University of Nottingham, European Commission, Croucher Foundation, Biotechnology and Biological Sciences Research Council (UK), Zhu, Qifan [0000-0001-5146-3337], Sang, F. [0000-0002-8746-5868], Withey, S. [0000-0003-0520-0290], Tang, Walfred [0000-0002-5803-1681], Dietmann, Sabine [0000-0001-6672-8457], Klisch, D. [0000-0002-5772-2261], Ramos Ibeas, Priscila [0000-0003-4578-0189], Zhang, Haixin [0000-0002-8840-053X], Requena, Cristina E. [0000-0001-5239-9162], Hajkova, Petra [0000-0003-4145-1468], Loose, M. [0000-0002-5264-0929], Surani, M. A. [0000-0002-8640-4318], Alberio, Ramiro [0000-0001-6560-3919], Zhu, Qifan, Sang, F., Withey, S., Tang, Walfred, Dietmann, Sabine, Klisch, D., Ramos Ibeas, Priscila, Zhang, Haixin, Requena, Cristina E, Hajkova, Petra, Loose, M., Surani, M. A., and Alberio, Ramiro

Abstract

Investigations of the human germline and programming are challenging because of limited access to embryonic material. However, the pig as a model may provide insights into transcriptional network and epigenetic reprogramming applicable to both species. Here we show that, during the pre- and early migratory stages, pig primordial germ cells (PGCs) initiate large-scale epigenomic reprogramming, including DNA demethylation involving TET-mediated hydroxylation and, potentially, base excision repair (BER). There is also macroH2A1 depletion and increased H3K27me3 as well as X chromosome reactivation (XCR) in females. Concomitantly, there is dampening of glycolytic metabolism genes and re-expression of some pluripotency genes like those in preimplantation embryos. We identified evolutionarily young transposable elements and gene coding regions resistant to DNA demethylation in acutely hypomethylated gonadal PGCs, with potential for transgenerational epigenetic inheritance. Detailed insights into the pig germline will likely contribute significantly to advances in human germline biology, including in vitro gametogenesis.

Published
2021

47. Stem cell function and stress response are controlled by protein synthesis

Author

Blanco, Sandra, Bandiera, Roberto, Popis, Martyna, Hussain, Shobbir, Lombard, Patrick, Aleksic, Jelena, Sajini, Abdulrahim, Tanna, Hinal, Cortes-Garrido, Rosana, Gkatza, Nikoletta, Dietmann, Sabine, and Frye, Michaela

Subjects
Stem cells -- Genetic aspects -- Growth, Protein biosynthesis -- Observations, Stress (Physiology) -- Genetic aspects, Company growth, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Whether protein synthesis and cellular stress response pathways interact to control stem cell function is currently unknown. Here we show that mouse skin stem cells synthesize less protein than their immediate progenitors in vivo, even when forced to proliferate. Our analyses reveal that activation of stress response pathways drives both a global reduction of protein synthesis and altered translational programmes that together promote stem cell functions and tumorigenesis. Mechanistically, we show that inhibition of post-transcriptional cytosine-5 methylation locks tumour- initiating cells in this distinct translational inhibition programme. Paradoxically, this inhibition renders stem cells hypersensitive to cytotoxic stress, as tumour regeneration after treatment with 5-fluorouracil is blocked. Thus, stem cells must revoke translation inhibition pathways to regenerate a tissue or tumour., Protein synthesis is a fundamental process for all cells, but its precise regulatory roles in development, stem cells and cancer are not well understood. We recently identified post-transcriptional methylation of [...]

Published
2016
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48. NANOG alone induces germ cells in primed epiblast in vitro by activation of enhancers

Author

Murakami, Kazuhiro, Gunesdogan, Ufuk, Zylicz, Jan J., Tang, Walfred W.C., Sengupta, Roopsha, Kobayashi, Toshihiro, Kim, Shinseog, Butler, Richard, Dietmann, Sabine, and Surani, M. Azim

Subjects
Transcription factors -- Physiological aspects, Germ cells -- Physiological aspects, Environmental issues, Science and technology, Zoology and wildlife conservation
Abstract

Nanog, a core pluripotency factor in the inner cell mass of blastocysts, is also expressed in unipotent primordial germ cells (PGCs) in mice1, where its precise role is yet unclear (2-4). We investigated this in an in vitro model, in which naive pluripotent embryonic stem (ES) cells cultured in basic fibroblast growth factor (bFGF) and activin A develop as epiblast-like cells (EpiLCs) and gain competence for a PGC-like fate (5). Consequently, bone morphogenetic protein 4 (BMP4), or ectopic expression of key germline transcription factors Prdm1, Prdm14 and Tfap2c, directly induce PGC-like cells (PGCLCs) in EpiLCs, but not in ES cells (6-8). Here we report an unexpected discovery that Nanog alone can induce PGCLCs in EpiLCs, independently of BMP4. We propose that after the dissolution of the naive ES-cell pluripotency network during establishment of EpiLCs (9,10), the epigenome is reset for cell fate determination. Indeed, we found genome-wide changes in NANOG-binding patterns between ES cells and EpiLCs, indicating epigenetic resetting of regulatory elements. Accordingly, we show that NANOG can bind and activate enhancers of Prdm1 and Prdm14 in EpiLCs in vitro; BLIMP1 (encoded by Prdm1) then directly induces Tfap2c. Furthermore, while SOX2 and NANOG promote the pluripotent state in ES cells, they show contrasting roles in EpiLCs, as Sox2 specifically represses PGCLC induction by Nanog. This study demonstrates a broadly applicable mechanistic principle for how cells acquire competence for cell fate determination, resulting in the context-dependent roles of key transcription factors during development., Transcription factors and epigenetic changes confer competence for somatic and PGC fates when naive pluripotent inner cell mass (ICM) from embryonic day (E)3.5-4.5 blastocysts develop to primed epiblast at ~E6.0 [...]

Published
2016

49. OCT4 cooperates with distinct ATP-dependent chromatin remodelers in naïve and primed pluripotent states in human

Author

Massachusetts Institute of Technology. Department of Biology, Huang, Xin, Park, Kyoung-mi, Gontarz, Paul, Zhang, Bo, Pan, Joshua, McKenzie, Zachary, Fischer, Laura A, Dong, Chen, Dietmann, Sabine, Xing, Xiaoyun, Shliaha, Pavel V, Yang, Jihong, Li, Dan, Ding, Junjun, Lungjangwa, Tenzin, Mitalipova, Maya, Khan, Shafqat A, Imsoonthornruksa, Sumeth, Jensen, Nick, Wang, Ting, Kadoch, Cigall, Jaenisch, Rudolf, Wang, Jianlong, Theunissen, Thorold W, Massachusetts Institute of Technology. Department of Biology, Huang, Xin, Park, Kyoung-mi, Gontarz, Paul, Zhang, Bo, Pan, Joshua, McKenzie, Zachary, Fischer, Laura A, Dong, Chen, Dietmann, Sabine, Xing, Xiaoyun, Shliaha, Pavel V, Yang, Jihong, Li, Dan, Ding, Junjun, Lungjangwa, Tenzin, Mitalipova, Maya, Khan, Shafqat A, Imsoonthornruksa, Sumeth, Jensen, Nick, Wang, Ting, Kadoch, Cigall, Jaenisch, Rudolf, Wang, Jianlong, and Theunissen, Thorold W

Abstract

AbstractUnderstanding the molecular underpinnings of pluripotency is a prerequisite for optimal maintenance and application of embryonic stem cells (ESCs). While the protein-protein interactions of core pluripotency factors have been identified in mouse ESCs, their interactome in human ESCs (hESCs) has not to date been explored. Here we mapped the OCT4 interactomes in naïve and primed hESCs, revealing extensive connections to mammalian ATP-dependent nucleosome remodeling complexes. In naïve hESCs, OCT4 is associated with both BRG1 and BRM, the two paralog ATPases of the BAF complex. Genome-wide location analyses and genetic studies reveal that these two enzymes cooperate in a functionally redundant manner in the transcriptional regulation of blastocyst-specific genes. In contrast, in primed hESCs, OCT4 cooperates with BRG1 and SOX2 to promote chromatin accessibility at ectodermal genes. This work reveals how a common transcription factor utilizes differential BAF complexes to control distinct transcriptional programs in naïve and primed hESCs.

Published
2022

50. Probing the signaling requirements for naive human pluripotency by high-throughput chemical screening

Author

Khan, Shafqat A., Park, Kyoung-mi, Fischer, Laura A., Dong, Chen, Lungjangwa, Tenzin, Jimenez, Marta, Casalena, Dominick, Chew, Brian, Dietmann, Sabine, Auld, Douglas S., Jaenisch, Rudolf, Theunissen, Thorold W., Khan, Shafqat A., Park, Kyoung-mi, Fischer, Laura A., Dong, Chen, Lungjangwa, Tenzin, Jimenez, Marta, Casalena, Dominick, Chew, Brian, Dietmann, Sabine, Auld, Douglas S., Jaenisch, Rudolf, and Theunissen, Thorold W.

Abstract

Naive human embryonic stem cells (hESCs) have been isolated that more closely resemble the pre-implantation epiblast compared to conventional "primed" hESCs, but the signaling principles underlying these discrete stem cell states remain incompletely understood. Here, we describe the results from a high-throughput screen using ∼3,000 well-annotated compounds to identify essential signaling requirements for naive human pluripotency. We report that MEK1/2 inhibitors can be replaced during maintenance of naive human pluripotency by inhibitors targeting either upstream (FGFR, RAF) or downstream (ERK1/2) kinases. Naive hESCs maintained under these alternative conditions display elevated levels of ERK phosphorylation but retain genome-wide DNA hypomethylation and a transcriptional identity of the pre-implantation epiblast. In contrast, dual inhibition of MEK and ERK promotes efficient primed-to-naive resetting in combination with PKC, ROCK, and TNKS inhibitors and activin A. This work demonstrates that induction and maintenance of naive human pluripotency are governed by distinct signaling requirements.

Published
2022

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