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1. Embryo model completes gastrulation to neurulation and organogenesis

Author

Amadei, Gianluca, Handford, Charlotte E., Qiu, Chengxiang, De Jonghe, Joachim, Greenfeld, Hannah, Tran, Martin, Martin, Beth K., Chen, Dong-Yuan, Aguilera-Castrejon, Alejandro, Hanna, Jacob H., Elowitz, Michael B., Hollfelder, Florian, Shendure, Jay, Glover, David M., Zernicka-Goetz, Magdalena, Handford, Charlotte E. [0000-0002-5245-8027], Qiu, Chengxiang [0000-0002-6346-8669], De Jonghe, Joachim [0000-0003-0584-8265], Martin, Beth K. [0000-0002-9661-014X], Chen, Dong-Yuan [0000-0003-2179-2847], Aguilera-Castrejon, Alejandro [0000-0002-1339-7778], Hanna, Jacob H. [0000-0003-2042-9974], Elowitz, Michael B. [0000-0002-1221-0967], Hollfelder, Florian [0000-0002-1367-6312], Shendure, Jay [0000-0002-1516-1865], Zernicka-Goetz, Magdalena [0000-0002-7004-2471], and Apollo - University of Cambridge Repository

Subjects
Neural Tube, PAX6 Transcription Factor, Organogenesis, 13/106, 13/109, 631/136/2060, 13, Models, Biological, 14/32, 14/1, Mice, 631/532/2117, 13/1, Prosencephalon, 13/100, Mesencephalon, Animals, Cell Lineage, 14/19, Neurulation, Embryonic Stem Cells, Endoderm, Gastrulation, article, 631/532/1360, Heart, Embryo, Mammalian, 631/136/2086/2126, 631/136/2086/2127, Somites, 13/51, 14/63
Abstract

Embryonic stem (ES) cells can undergo many aspects of mammalian embryogenesis in vitro1–5, but their developmental potential is substantially extended by interactions with extraembryonic stem cells, including trophoblast stem (TS) cells, extraembryonic endoderm stem (XEN) cells and inducible XEN (iXEN) cells6–11. Here we assembled stem cell-derived embryos in vitro from mouse ES cells, TS cells and iXEN cells and showed that they recapitulate the development of whole natural mouse embryo in utero up to day 8.5 post-fertilization. Our embryo model displays headfolds with defined forebrain and midbrain regions and develops a beating heart-like structure, a trunk comprising a neural tube and somites, a tail bud containing neuromesodermal progenitors, a gut tube, and primordial germ cells. This complete embryo model develops within an extraembryonic yolk sac that initiates blood island development. Notably, we demonstrate that the neurulating embryo model assembled from Pax6-knockout ES cells aggregated with wild-type TS cells and iXEN cells recapitulates the ventral domain expansion of the neural tube that occurs in natural, ubiquitous Pax6-knockout embryos. Thus, these complete embryoids are a powerful in vitro model for dissecting the roles of diverse cell lineages and genes in development. Our results demonstrate the self-organization ability of ES cells and two types of extraembryonic stem cells to reconstitute mammalian development through and beyond gastrulation to neurulation and early organogenesis.

Published
2022

2. Mouse fetal growth restriction through parental and fetal immune gene variation and intercellular communications cascade

Author

Kaur, Gurman, Porter, Caroline BM, Ashenberg, Orr, Lee, Jack, Riesenfeld, Samantha J, Hofree, Matan, Aggelakopoulou, Maria, Subramanian, Ayshwarya, Kuttikkatte, Subita Balaram, Attfield, Kathrine E, Desel, Christiane AE, Davies, Jessica L, Evans, Hayley G, Avraham-Davidi, Inbal, Nguyen, Lan T, Dionne, Danielle A, Neumann, Anna E, Jensen, Lise Torp, Barber, Thomas R, Soilleux, Elizabeth, Carrington, Mary, McVean, Gil, Rozenblatt-Rosen, Orit, Regev, Aviv, Fugger, Lars, Kaur, Gurman [0000-0001-7722-3956], Riesenfeld, Samantha J [0000-0001-9144-021X], Hofree, Matan [0000-0001-8368-0299], Subramanian, Ayshwarya [0000-0002-4134-7612], Attfield, Kathrine E [0000-0003-3387-521X], Desel, Christiane AE [0000-0003-2029-3851], Davies, Jessica L [0000-0002-8888-1441], Avraham-Davidi, Inbal [0000-0001-7118-9179], Neumann, Anna E [0000-0001-7115-8305], Soilleux, Elizabeth [0000-0002-4032-7249], Carrington, Mary [0000-0002-2692-2180], McVean, Gil [0000-0002-5012-4162], Rozenblatt-Rosen, Orit [0000-0001-6313-3570], Fugger, Lars [0000-0003-2883-3226], and Apollo - University of Cambridge Repository

Subjects
123, 631/250/2504, General Physics and Astronomy, Cell Communication, HLA-C Antigens, General Biochemistry, Genetics and Molecular Biology, 14/32, Mice, 13/1, Fetus, Pregnancy, Animals, 45/91, Fetal Growth Retardation, Multidisciplinary, 45, article, General Chemistry, 631/208/248, Trophoblasts, 692/4017, 13/31, 631/250/1619/382, 38/77, Female, 38/39, 64/60
Abstract

Fetal growth restriction (FGR) affects 5–10% of pregnancies, and can have serious consequences for both mother and child. Prevention and treatment are limited because FGR pathogenesis is poorly understood. Genetic studies implicateKIRandHLAgenes in FGR, however, linkage disequilibrium, genetic influence from both parents, and challenges with investigating human pregnancies make the risk alleles and their functional effects difficult to map. Here, we demonstrate that the interaction between the maternal KIR2DL1, expressed on uterine natural killer (NK) cells, and the paternally inherited HLA-C*0501, expressed on fetal trophoblast cells, leads to FGR in a humanized mouse model. We show that the KIR2DL1 and C*0501 interaction leads to pathogenic uterine arterial remodeling and modulation of uterine NK cell function. This initial effect cascades to altered transcriptional expression and intercellular communication at the maternal-fetal interface. These findings provide mechanistic insight into specific FGR risk alleles, and provide avenues of prevention and treatment.

Published
2022
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3. TRIM24 is an insulin-responsive regulator of P-bodies

Author

Wei, Wen, Chen, Qiaoli, Liu, Minjun, Sheng, Yang, OuYang, Qian, Feng, Weikuan, Yang, Xinyu, Ding, Longfei, Su, Shu, Zhang, Jingzi, Fang, Lei, Vidal-Puig, Antonio, Wang, Hong-Yu, Chen, Shuai, Fang, Lei [0000-0002-2582-4845], Vidal-Puig, Antonio [0000-0003-4220-9577], Chen, Shuai [0000-0002-8511-911X], and Apollo - University of Cambridge Repository

Subjects
631/443/319/2723, 45/70, Multidisciplinary, Ubiquitin-Protein Ligases, 692/699/1503/1607/2751, article, Nuclear Proteins, General Physics and Astronomy, General Chemistry, Processing Bodies, 631/45/275, General Biochemistry, Genetics and Molecular Biology, PPAR gamma, 14/32, Mice, 13/95, Animals, Insulin, 64/60, RNA, Messenger, 631/337/1645/2020, 631/80/86/2367, Transcription Factors
Abstract

Funder: to the Ministry of Science and Technology of China (Grant Nos. 2018YFA0801100 and 2021YFF0702100 to H.Y.W.), the National Natural Science Foundation of China (31971067 to H.Y.W., Funder: to the Ministry of Science and Technology of China (Grant Nos. 2018YFA0801100 and 2021YFF0702100 to S.C.), the National Natural Science Foundation of China (Grant Nos. 31970719 and 32025019 to S.C.), Insulin is a potent inducer of mRNA transcription and translation, contributing to metabolic regulation. Insulin has also been suggested to regulate mRNA stability through the processing body (P-body) molecular machinery. However, whether and how insulin regulates mRNA stability via P-bodies is not clear. Here we show that the E3-ligase TRIM24 is a critical factor linking insulin signalling to P-bodies. Upon insulin stimulation, protein kinase B (PKB, also known as Akt) phosphorylates TRIM24 and stimulates its shuttling from the nucleus into the cytoplasm. TRIM24 interacts with several critical components of P-bodies in the cytoplasm, promoting their polyubiquitylation, which consequently stabilises Pparγ mRNA. Inactivation of TRIM24 E3-ligase activity or prevention of its phosphorylation via knockin mutations in mice promotes hepatic Pparγ degradation via P-bodies. Consequently, both knockin mutations alleviate hepatosteatosis in mice fed on a high-fat diet. Our results demonstrate the critical role of TRIM24 in linking insulin signalling to P-bodies and have therapeutic implications for the treatment of hepatosteatosis.

Published
2022

4. Cell-type specialization is encoded by specific chromatin topologies

Author

Winick-Ng, Warren, Kukalev, Alexander, Harabula, Izabela, Zea-Redondo, Luna, Szab��, Dominik, Meijer, Mandy, Serebreni, Leonid, Zhang, Yingnan, Bianco, Simona, Chiariello, Andrea M, Irastorza-Azcarate, Ibai, Thieme, Christoph J, Sparks, Thomas M, Carvalho, S��lvia, Fiorillo, Luca, Musella, Francesco, Irani, Ehsan, Triglia, Elena Torlai, Kolodziejczyk, Aleksandra A, Abentung, Andreas, Apostolova, Galina, Paul, Eleanor J, Franke, Vedran, Kempfer, Rieke, Akalin, Altuna, Teichmann, Sarah, Dechant, Georg, Ungless, Mark A, Nicodemi, Mario, Welch, Lonnie, Castelo-Branco, Gon��alo, Pombo, Ana, Winick-Ng, Warren [0000-0002-8716-5558], Meijer, Mandy [0000-0003-3314-1224], Bianco, Simona [0000-0001-5819-060X], Chiariello, Andrea M [0000-0002-6112-0167], Thieme, Christoph J [0000-0002-1566-0971], Fiorillo, Luca [0000-0003-2967-0123], Triglia, Elena Torlai [0000-0002-6059-0116], Paul, Eleanor J [0000-0003-1183-9285], Franke, Vedran [0000-0003-3606-6792], Akalin, Altuna [0000-0002-0468-0117], Teichmann, Sarah [0000-0002-6294-6366], Castelo-Branco, Gonçalo [0000-0003-2247-9393], Pombo, Ana [0000-0002-7493-6288], Apollo - University of Cambridge Repository, UCIBIO - Applied Molecular Biosciences Unit, DCV - Departamento de Ciências da Vida, Winick-Ng, W., Kukalev, A., Harabula, I., Zea-Redondo, L., Szabo, D., Meijer, M., Serebreni, L., Zhang, Y., Bianco, S., Chiariello, A. M., Irastorza-Azcarate, I., Thieme, C. J., Sparks, T. M., Carvalho, S., Fiorillo, L., Musella, F., Irani, E., Triglia, E. T., Kolodziejczyk, A. A., Abentung, A., Apostolova, G., Paul, E. J., Franke, V., Kempfer, R., Akalin, A., Teichmann, S. A., Dechant, G., Ungless, M. A., Nicodemi, M., Welch, L., Castelo-Branco, G., Pombo, A., Torlai Triglia, Elena [0000-0002-6059-0116], and Teichmann, Sarah A [0000-0002-6294-6366]

Subjects
Male, Genetics of the nervous system, Cells, Molecular Conformation, 45/22, Nucleic Acid Denaturation, Chromosomes, 38/91, 14/32, Mice, 14/56, 13/100, 38/23, 631/208/200, Animals, 14/19, General, Neurons, Nuclear organization, Binding Sites, 45, article, Brain, polymer physics, Chromatin Assembly and Disassembly, Regulatory networks, Chromatin, Chromatin architecture, Gene regulation, Computer models of chromosome, 13/31, Gene Expression Regulation, Genes, 631/553/2711, Cardiovascular and Metabolic Diseases, Multigene Family, 14/63, 631/114/2401, 38/77, Data integration, 631/337/386, 64/60, Technology Platforms, 119, 631/378/2583, Transcription Factors
Abstract

The three-dimensional (3D) structure of chromatin is intrinsically associated with gene regulation and cell function1–3. Methods based on chromatin conformation capture have mapped chromatin structures in neuronal systems such as in vitro differentiated neurons, neurons isolated through fluorescence-activated cell sorting from cortical tissues pooled from different animals and from dissociated whole hippocampi4–6. However, changes in chromatin organization captured by imaging, such as the relocation of Bdnf away from the nuclear periphery after activation7, are invisible with such approaches8. Here we developed immunoGAM, an extension of genome architecture mapping (GAM)2,9, to map 3D chromatin topology genome-wide in specific brain cell types, without tissue disruption, from single animals. GAM is a ligation-free technology that maps genome topology by sequencing the DNA content from thin (about 220 nm) nuclear cryosections. Chromatin interactions are identified from the increased probability of co-segregation of contacting loci across a collection of nuclear slices. ImmunoGAM expands the scope of GAM to enable the selection of specific cell types using low cell numbers (approximately 1,000 cells) within a complex tissue and avoids tissue dissociation2,10. We report cell-type specialized 3D chromatin structures at multiple genomic scales that relate to patterns of gene expression. We discover extensive ‘melting’ of long genes when they are highly expressed and/or have high chromatin accessibility. The contacts most specific of neuron subtypes contain genes associated with specialized processes, such as addiction and synaptic plasticity, which harbour putative binding sites for neuronal transcription factors within accessible chromatin regions. Moreover, sensory receptor genes are preferentially found in heterochromatic compartments in brain cells, which establish strong contacts across tens of megabases. Our results demonstrate that highly specific chromatin conformations in brain cells are tightly related to gene regulation mechanisms and specialized functions., A new technique called immunoGAM, which combines genome architecture mapping (GAM) with immunoselection, enabled the discovery of specialized chromatin conformations linked to gene expression in specific cell populations from mouse brain tissues.

Published
2021

5. Cells of the human intestinal tract mapped across space and time

Author

Cecilia Domínguez Conde, Ni Huang, Omer Ali Bayraktar, Krishnaa T. Mahbubani, Holm H. Uhlig, Justin Engelbert, Steven Leonard, Emma Dann, Minal Patel, Aaron M. Fleming, Sara F. Vieira, C. Elizabeth Hook, Sarah A. Teichmann, Lia S. Campos, Emily Stephenson, Issac Goh Kai’En, Sophie Pritchard, Stijn van Dongen, Michael D Morgan, Kourosh Saeb-Parsy, Krzysztof Polanski, Rasa Elmentaite, Kenny Roberts, John C. Marioni, Thomas R. W. Oliver, Natsuhiko Kumasaka, Matthias Zilbauer, Roger A. Barker, Francesca Perrone, Kylie R. James, Kerstin B Meyer, Muzlifah Haniffa, Komal Nayak, Menna R. Clatworthy, Vitalii Kleshchevnikov, Steven Lisgo, Liam Bolt, Lira Mamanova, Xiaoling He, Monika Dabrowska, Rachel A. Botting, Matilda Katan, Hamish W King, Elmentaite, Rasa [0000-0001-7366-5466], Kumasaka, Natsuhiko [0000-0002-3557-0375], Roberts, Kenny [0000-0001-6155-0821], Dann, Emma [0000-0002-7400-7438], King, Hamish W. [0000-0001-5972-8926], Bolt, Liam [0000-0001-7293-0774], Vieira, Sara F. [0000-0002-1021-3021], Mamanova, Lira [0000-0003-1463-8622], Katan, Matilda [0000-0001-9992-8375], Oliver, Thomas R. W. [0000-0003-4306-0102], Domínguez Conde, Cecilia [0000-0002-8684-4655], Botting, Rachel A. [0000-0001-9595-4605], Polanski, Krzysztof [0000-0002-2586-9576], Morgan, Michael D. [0000-0003-0757-0711], Marioni, John C. [0000-0001-9092-0852], Bayraktar, Omer Ali [0000-0001-6055-277X], Meyer, Kerstin B. [0000-0001-5906-1498], Uhlig, Holm H. [0000-0002-6111-7355], Mahbubani, Krishnaa T. [0000-0002-1327-2334], Saeb-Parsy, Kourosh [0000-0002-0633-3696], Zilbauer, Matthias [0000-0002-7272-0547], Haniffa, Muzlifah [0000-0002-3927-2084], James, Kylie R. [0000-0002-7107-0650], Teichmann, Sarah A. [0000-0002-6294-6366], Apollo - University of Cambridge Repository, King, Hamish W [0000-0001-5972-8926], Vieira, Sara F [0000-0002-1021-3021], Oliver, Thomas RW [0000-0003-4306-0102], Botting, Rachel A [0000-0001-9595-4605], Morgan, Michael D [0000-0003-0757-0711], Marioni, John C [0000-0001-9092-0852], Meyer, Kerstin B [0000-0001-5906-1498], Uhlig, Holm H [0000-0002-6111-7355], Mahbubani, Krishnaa T [0000-0002-1327-2334], James, Kylie R [0000-0002-7107-0650], Teichmann, Sarah A [0000-0002-6294-6366], and Oliver, Thomas R W [0000-0003-4306-0102]

Subjects
Aging, Time Factors, Organogenesis, Cell, Datasets as Topic, Inflammatory bowel disease, 14, Enteric Nervous System, Mice, Crohn Disease, Child, 631/114/2391, health care economics and organizations, Crohn's disease, Multidisciplinary, article, humanities, Cell biology, Intestines, medicine.anatomical_structure, Health, Female, 38/39, medicine.symptom, 631/136, Signal Transduction, Adult, Cellular signalling networks, education, Inflammation, Biology, 38/91, 14/32, Immune system, Fetus, Spatio-Temporal Analysis, 692/699/1503/257/1402, Developmental biology, medicine, Animals, Humans, 45, Receptors, IgG, Epithelial Cells, medicine.disease, Embryonic stem cell, Gastrointestinal Microbiome, Mice, Inbred C57BL, Metagenome, Enteric nervous system, Lymph Nodes
Abstract

Funder: Medical Research Council, The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung's disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

Published
2021
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6. Maternal iron deficiency perturbs embryonic cardiovascular development in mice

Author

Dorota Szumska, Jack J. Miller, Magda Wolna, Aimée Jacquemot, Victor L. J. Tybulewicz, Michael Troup, Fabrice Prin, Eleni Giannoulatou, Helena Rodriguez-Caro, Eleanor M. Stuart, Emily Hardman, Jacob E Munro, Elizabeth M. C. Fisher, Samira Lakhal-Littleton, Nikita Ved, Sarah De Val, Eva Lana-Elola, Rifdat Aoidi, Jacinta I. Kalisch-Smith, Shelley Harris, Duncan B. Sparrow, Timothy J. Mohun, Kalisch-Smith, Jacinta I. [0000-0002-5071-3805], Munro, Jacob [0000-0002-2751-0989], Miller, Jack J. [0000-0002-6258-1299], Hardman, Emily [0000-0002-3073-0309], Fisher, Elizabeth M. C. [0000-0003-2850-9936], Tybulewicz, Victor L. J. [0000-0003-2439-0798], Sparrow, Duncan B. [0000-0002-1141-6613], Apollo - University of Cambridge Repository, Kalisch-Smith, Jacinta I [0000-0002-5071-3805], Miller, Jack J [0000-0002-6258-1299], Fisher, Elizabeth MC [0000-0003-2850-9936], Tybulewicz, Victor LJ [0000-0003-2439-0798], and Sparrow, Duncan B [0000-0002-1141-6613]

Subjects
0301 basic medicine, Heart disease, General Physics and Astronomy, Physiology, Aorta, Thoracic, Penetrance, 96/35, Cardiovascular System, 14, 38/1, 0302 clinical medicine, Pregnancy, Edema, Myocytes, Cardiac, Transgenes, 14/19, 692/308/1426, 64, Multidisciplinary, Stem Cells, article, food and beverages, Cell Differentiation, Iron deficiency, Iron Deficiencies, Coronary Vessels, humanities, 3. Good health, Experimental models of disease, Phenotype, In utero, Embryogenesis, Female, 64/60, 38/39, 82/1, 692/499, Signal Transduction, Down syndrome, Offspring, Science, Iron, Green Fluorescent Proteins, 631/136/2086, Embryonic Development, Tretinoin, General Biochemistry, Genetics and Molecular Biology, 38/91, 82/80, 14/1, 14/32, 03 medical and health sciences, 14/5, medicine, Genetic predisposition, Animals, 631/136/1425, Lymphatic Vessels, business.industry, Disease model, Gene Expression Profiling, Myocardium, General Chemistry, medicine.disease, Embryo, Mammalian, Teratology, Mice, Inbred C57BL, 030104 developmental biology, Risk factors, Dietary Supplements, 13/51, 14/63, 59/57, Gene-Environment Interaction, business, 030217 neurology & neurosurgery, Biomarkers
Abstract

Congenital heart disease (CHD) is the most common class of human birth defects, with a prevalence of 0.9% of births. However, two-thirds of cases have an unknown cause, and many of these are thought to be caused by in utero exposure to environmental teratogens. Here we identify a potential teratogen causing CHD in mice: maternal iron deficiency (ID). We show that maternal ID in mice causes severe cardiovascular defects in the offspring. These defects likely arise from increased retinoic acid signalling in ID embryos. The defects can be prevented by iron administration in early pregnancy. It has also been proposed that teratogen exposure may potentiate the effects of genetic predisposition to CHD through gene–environment interaction. Here we show that maternal ID increases the severity of heart and craniofacial defects in a mouse model of Down syndrome. It will be important to understand if the effects of maternal ID seen here in mice may have clinical implications for women., From mouse experiments, the authors link iron deficiency in mothers with cardiovascular defects and increased retinoic acid signalling in their offspring, and giving iron early in pregnancy can prevent most defects.

Published
2021
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7. Telomere damage promotes vascular smooth muscle cell senescence and immune cell recruitment after vessel injury

Author

Martin R. Bennett, Kirsty Foote, Helle F. Jørgensen, Anna K. Uryga, Dimitra Aravani, Abel Martin Garrido, Alison Finigan, Mandy O.J. Grootaert, Joel Chappell, Sebnem Oc, Francesca Rossiello, F. D'Adda Di Fagagna, Chappell, Joel [0000-0002-5834-4100], Jorgensen, Helle F [0000-0002-7909-2977], Bennett, Martin R [0000-0002-2565-1825], Apollo - University of Cambridge Repository, Jorgensen, Helle F. [0000-0002-7909-2977], and Bennett, Martin R. [0000-0002-2565-1825]

Subjects
Male, 0301 basic medicine, Life Sciences & Biomedicine - Other Topics, Vascular smooth muscle, NEOINTIMAL FORMATION, Cell, Muscle Proteins, Medicine (miscellaneous), Cell recruitment, 030204 cardiovascular system & hematology, Muscle, Smooth, Vascular, ACTIVATION, PATHWAY, 13/1, Mice, 13/44, 0302 clinical medicine, Telomeric Repeat Binding Protein 2, Biology (General), 14/19, Cells, Cultured, Cellular Senescence, Mice, Knockout, Microfilament Proteins, article, food and beverages, Telomere, musculoskeletal system, Cell biology, Multidisciplinary Sciences, Mechanisms of disease, medicine.anatomical_structure, 631/80/509, 38/77, cardiovascular system, Science & Technology - Other Topics, 64/60, 631/80/304, medicine.symptom, Cardiology and Cardiovascular Medicine, General Agricultural and Biological Sciences, tissues, Life Sciences & Biomedicine, Senescence, Neointima, QH301-705.5, DNA damage, Myocytes, Smooth Muscle, Inflammation, Biology, General Biochemistry, Genetics and Molecular Biology, 14/32, 03 medical and health sciences, Immune system, INFLAMMATION, medicine, Animals, Humans, Cell Proliferation, REPAIR, Science & Technology, Cell growth, Atherosclerosis, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, DNA-DAMAGE, ATHEROSCLEROSIS, ATM, 13/51, DNA Damage
Abstract

Accumulation of vascular smooth muscle cells (VSMCs) is a hallmark of multiple vascular pathologies, including following neointimal formation after injury and atherosclerosis. However, human VSMCs in advanced atherosclerotic lesions show reduced cell proliferation, extensive and persistent DNA damage, and features of premature cell senescence. Here, we report that stress-induced premature senescence (SIPS) and stable expression of a telomeric repeat-binding factor 2 protein mutant (TRF2T188A) induce senescence of human VSMCs, associated with persistent telomeric DNA damage. VSMC senescence is associated with formation of micronuclei, activation of cGAS-STING cytoplasmic sensing, and induction of multiple pro-inflammatory cytokines. VSMC-specific TRF2T188A expression in a multicolor clonal VSMC-tracking mouse model shows no change in VSMC clonal patches after injury, but an increase in neointima formation, outward remodeling, senescence and immune/inflammatory cell infiltration or retention. We suggest that persistent telomere damage in VSMCs inducing cell senescence has a major role in driving persistent inflammation in vascular disease., Anna Uryga and Mandy Grootaert et al. combine cell culture and animal models to examine how senescence of human vascular smooth muscle cells (VSMCs) and persistent telomere damage drive inflammation. Their results suggest that telomere injury can be the primary cause of premature senescence in VSMCs, and that DNA damage can be a major cause of persistent inflammation in vascular disease.

Published
2021

8. The double-stranded DNA-binding proteins TEBP-1 and TEBP-2 form a telomeric complex with POT-1

Author

Christian Renz, Miguel Vasconcelos Almeida, Emily Nischwitz, Jan Schreier, Albert Fradera-Sola, Nikenza Viceconte, Dennis Kappei, Helle D. Ulrich, Alejandro Ceron-Noriega, Falk Butter, René F. Ketting, Sabrina Dietz, Dietz, Sabrina [0000-0003-3227-9264], Almeida, Miguel Vasconcelos [0000-0002-4816-3111], Viceconte, Nikenza [0000-0002-5101-4125], Fradera-Sola, Albert [0000-0002-4780-9312], Kappei, Dennis [0000-0002-3582-2253], Ketting, René F [0000-0001-6161-5621], Butter, Falk [0000-0002-7197-7279], Apollo - University of Cambridge Repository, and Ketting, René F. [0000-0001-6161-5621]

Subjects
DNA damage, Science, Mutant, Telomere-Binding Proteins, Biology, 631/45/475, Double-stranded DNA binding, Germline, 38/70, 570 Life sciences, Animals, Genetically Modified, 82/80, 14/32, 38/23, 64/11, Animals, Protein Isoforms, 14/19, Caenorhabditis elegans, Caenorhabditis elegans Proteins, Mitosis, 82/83, Phylogeny, Binding Sites, Base Sequence, 82/58, article, DNA, 631/80/103/560, Telomere, Shelterin, Phenotype, Cell biology, DNA-Binding Proteins, Germ Cells, Microscopy, Fluorescence, Multiprotein Complexes, 38/35, Mutation, 14/63, 570 Biowissenschaften, Protein Binding, 82/111
Abstract

Telomeres are bound by dedicated protein complexes, like shelterin in mammals, which protect telomeres from DNA damage. In the nematodeCaenorhabditis elegans, a comprehensive understanding of the proteins interacting with the telomere sequence is lacking. Here, we harnessed a quantitative proteomics approach to screen for proteins binding toC. elegans telomeres, and identified TEBP-1 and TEBP-2, two paralogs that associate to telomeres in vitro and in vivo. TEBP-1 and TEBP-2 are expressed in the germline and during embryogenesis.tebp-1andtebp-2mutants display strikingly distinct phenotypes:tebp-1mutants have longer telomeres than wild-type animals, whiletebp-2mutants display shorter telomeres and a mortal germline, a phenotype characterized by transgenerational germline deterioration. Notably,tebp-1;tebp-2double mutant animals have synthetic sterility, with germlines showing signs of severe mitotic and meiotic arrest. TEBP-1 and TEBP-2 form a telomeric complex with the known single-stranded telomere-binding proteins POT-1, POT-2, and MRT-1. Furthermore, we find that POT-1 bridges the double- stranded binders TEBP-1 and TEBP-2, with the single-stranded binders POT-2 and MRT-1. These results describe the first telomere-binding complex inC. elegans, with TEBP-1 and TEBP-2, two double-stranded telomere binders required for fertility and that mediate opposite telomere dynamics.

Published
2021
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9. NASH limits anti-tumour surveillance in immunotherapy-treated HCC

Author

Stephan Spahn, Florian Müller, Revant Gupta, Dominik Pfister, Kornelius Schulze, Pierre Bedossa, Eleni Kotsiliti, Lars Zender, Mathias Heikenwalder, Nicolás Gonzalo Núñez, Peter Schirmacher, Axel Schulz, Jan Kosla, Adrian T. Billeter, Thomas Engleitner, Aleksandra Deczkowska, Danijela Heide, Donato Inverso, Susanne Roth, Olivier Govaere, Carla Montironi, Martha M. Kirstein, Dan G. Duda, Antonio D'Alessio, Jörn M. Schattenberg, Ekaterina Friebel, Tiziana Pressiani, F. Hucke, Jörg Trojan, Michael Bitzer, Suhail Yousuf, Bernhard Scheiner, Marina Ruiz de Galarreta, Markus Peck-Radosavljevic, Michael Allison, Nuh N. Rahbari, Simon Cockell, Brinda Emu, Ahmed Kaseb, David J. Pinato, Matthias P. Ebert, Joachim C. Mertens, Jean-François Dufour, Fabian Rössler, Achim Weber, Katharina Wolter, Thomas Decaens, Amaia Lujambio, Anja Moncsek, Daniela Lenggenhager, Katharina Pomej, Nisar P. Malek, Fabian Finkelmeier, Elisabetta Bugianesi, Valentina Leone, Ann K. Daly, Michael Dudek, Manfred Claassen, Zuzana Macek Jilkova, Henning Wege, Florian Castet, Marta Szydlowska, Beat P. Müller-Stich, Ramy Younes, Nicola Personeni, Philipp K. Haber, Marco Bueter, Manfred Jugold, Andrea Schietinger, Hiroto Kikuchi, Ido Amit, Sandra Koch, Dina Tiniakos, Ana Teijeiro, Jan-Philipp Mallm, Josep M. Llovet, Indrabahadur Singh, Percy A. Knolle, Sara De Dosso, Roland Rad, Arndt Vogel, Henrik E. Mei, Burkhard Becher, Nabil Djouder, Tom Luedde, Felix Meissner, Oliver Waidmann, Parice N. Marche, Viktor Umansky, Hellmut G. Augustin, Thomas U. Marron, Matthias Pinter, Mengjie Qiu, Arndt Weinmann, Ankit Sinha, Kristian Unger, Assaf Weiner, Vlad Ratziu, Quentin M. Anstee, Kristin Stirm, Yi Hsiang Huang, Alexander Siebenhüner, Fabian Kütting, Lorenza Rimassa, Dirk Waldschmidt, Masatoshi Kudo, Marc Ringelhan, Michele Vacca, Roser Pinyol, Fabio Marra, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Novo Nordisk A/S [Maløv, Denmark], Universität Zürich [Zürich] = University of Zurich (UZH), Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Universitat de Barcelona (UB), Newcastle University [Newcastle], Medizinische Universität Wien = Medical University of Vienna, University of Tübingen, UniversitätsKlinikum Heidelberg, Weizmann Institute of Science [Rehovot, Israël], Max Planck Institute of Biochemistry (MPIB), Max-Planck-Gesellschaft, Technical University of Munich (TUM), University hospital of Zurich [Zurich], Helmholtz-Zentrum München (HZM), Heidelberg University, Spanish National Cancer Research Center (CNIO), Icahn School of Medicine at Mount Sinai [New York] (MSSM), National and Kapodistrian University of Athens (NKUA), University of Turin, Addenbrooke's Hospital, Cambridge University NHS Trust, Università degli Studi di Firenze = University of Florence [Firenze] (UNIFI), University Medical Center [Mainz], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), Hôpital Beaujon [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Diderot - Paris 7 (UPD7), Istituto Clinico Humanitas [Milan] (IRCCS Milan), Humanitas University [Milan] (Hunimed), Hannover Medical School [Hannover] (MHH), University Medical Center of Schleswig–Holstein = Universitätsklinikum Schleswig-Holstein (UKSH), Kiel University, Klinikum Klagenfurt am Wörthersee, Universitätsklinikum Frankfurt, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), Oncology Institute of Southern Switzerland (IOSI), Heinrich Heine Universität Düsseldorf = Heinrich Heine University [Düsseldorf], Memorial Sloane Kettering Cancer Center [New York], Weill Medical College of Cornell University [New York], Heidelberg University Hospital [Heidelberg], Medical Faculty [Mannheim], Massachusetts General Hospital [Boston], University of Cologne, Deutsches Rheuma-ForschungsZentrum (DRFZ), Deutsches Rheuma-ForschungsZentrum, German Center for Infection Research, Partnersite Munich (DZIF), University Medical Center [Tubingen, Germany], Inselspital Bern, University of Bern, The University of Texas M.D. Anderson Cancer Center [Houston], Kindai University, National Yang Ming University (NYMU), Taipei Veterans General Hospital [Taiwan], Universitätsklinikum Tübingen - University Hospital of Tübingen, Eberhard Karls Universität Tübingen = Eberhard Karls University of Tuebingen, Eberhard Karls University [Tübingen, Germany], Université Grenoble Alpes (UGA), Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble) (IAB), Centre Hospitalier Universitaire [Grenoble] (CHU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Etablissement français du sang - Auvergne-Rhône-Alpes (EFS)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes (UGA), CHU Grenoble, Hammersmith Hospital NHS Imperial College Healthcare, Università degli Studi del Piemonte Orientale - Amedeo Avogadro (UPO), Institució Catalana de Recerca i Estudis Avançats (ICREA), Pfister, Dominik [0000-0002-0542-2638], Núñez, Nicolás Gonzalo [0000-0003-3837-270X], Govaere, Olivier [0000-0002-4426-6930], Szydlowska, Marta [0000-0002-4660-899X], Gupta, Revant [0000-0002-0881-5074], Deczkowska, Aleksandra [0000-0003-0844-4346], Friebel, Ekaterina [0000-0003-1419-2376], Lenggenhager, Daniela [0000-0002-5382-9854], Moncsek, Anja [0000-0002-1191-5842], Inverso, Donato [0000-0003-0987-3345], Vacca, Michele [0000-0002-1973-224X], Marra, Fabio [0000-0001-8629-0878], Allison, Michael [0000-0003-3677-3294], D'Alessio, Antonio [0000-0002-9164-3671], Personeni, Nicola [0000-0002-7995-272X], Rimassa, Lorenza [0000-0001-9957-3615], Pomej, Katharina [0000-0002-2807-3565], Peck-Radosavljevic, Markus [0000-0002-0597-2728], Mallm, Jan-Philipp [0000-0002-7059-4030], Schietinger, Andrea [0000-0003-3644-1687], Augustin, Hellmut G [0000-0002-7173-4242], Kikuchi, Hiroto [0000-0002-3601-8435], Duda, Dan G [0000-0001-7065-8797], Mei, Henrik E [0000-0003-0697-7755], Schulz, Axel Ronald [0000-0002-5106-0148], Ringelhan, Marc [0000-0003-3131-5657], Lujambio, Amaia [0000-0002-2798-1481], Dufour, Jean-Francois [0000-0002-8062-1346], Kudo, Masatoshi [0000-0002-4102-3474], Djouder, Nabil [0000-0001-8423-1030], Zender, Lars [0000-0001-7626-2849], Pinato, David J [0000-0002-3529-0103], Rad, Roland [0000-0002-6849-9659], Mertens, Joachim C [0000-0003-2007-0308], Weber, Achim [0000-0003-0073-3637], Meissner, Felix [0000-0003-1000-7989], Amit, Ido [0000-0003-2968-877X], Knolle, Percy [0000-0003-2983-0414], Becher, Burkhard [0000-0002-1541-7867], Llovet, Josep M [0000-0003-0547-2667], Heikenwalder, Mathias [0000-0002-3135-2274], Apollo - University of Cambridge Repository, Max-Planck-Institut für Biochemie = Max Planck Institute of Biochemistry (MPIB), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM), Helmholtz Zentrum München = German Research Center for Environmental Health, Università degli studi di Torino = University of Turin (UNITO), Università degli Studi di Firenze = University of Florence (UniFI), MARCHE, Patrice, D’Alessio, Antonio [0000-0002-9164-3671], Augustin, Hellmut G. [0000-0002-7173-4242], Duda, Dan G. [0000-0001-7065-8797], Mei, Henrik E. [0000-0003-0697-7755], Pinato, David J. [0000-0002-3529-0103], Mertens, Joachim C. [0000-0003-2007-0308], and Llovet, Josep M. [0000-0003-0547-2667]

Subjects
Male, Carcinogenesis, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Programmed Cell Death 1 Receptor, CD8-Positive T-Lymphocytes, B7-H1 Antigen, 13/2, 13/1, Mice, 0302 clinical medicine, Non-alcoholic Fatty Liver Disease, LIVER-CANCER, R PACKAGE, RNA-SEQ, 14/19, Cancer, 0303 health sciences, Multidisciplinary, NONALCOHOLIC STEATOHEPATITIS, Liver Neoplasms, article, ddc, 3. Good health, 13/31, Multidisciplinary Sciences, medicine.anatomical_structure, Liver, 030220 oncology & carcinogenesis, Hepatocellular carcinoma, Disease Progression, Science & Technology - Other Topics, [SDV.IMM]Life Sciences [q-bio]/Immunology, 64/60, Tumor necrosis factor alpha, Immunotherapy, Adjuvant, 631/67, Carcinoma, Hepatocellular, [SDV.IMM] Life Sciences [q-bio]/Immunology, T cell, 610 Medicine & health, [SDV.CAN]Life Sciences [q-bio]/Cancer, 14/32, 03 medical and health sciences, 14/34, 13/21, [SDV.CAN] Life Sciences [q-bio]/Cancer, ADVANCED HEPATOCELLULAR-CARCINOMA, NAFLD, medicine, Animals, Humans, 14/35, 030304 developmental biology, Science & Technology, Tumor Necrosis Factor-alpha, business.industry, 631/250/251, medicine.disease, PHASE-III, digestive system diseases, 13/51, 14/63, 59/57, T-CELLS, Cancer research, Steatohepatitis, business, CD8
Abstract

Hepatocellular carcinoma (HCC) can have viral or non-viral causes1–5. Non-alcoholic steatohepatitis (NASH) is an important driver of HCC. Immunotherapy has been approved for treating HCC, but biomarker-based stratification of patients for optimal response to therapy is an unmet need6,7. Here we report the progressive accumulation of exhausted, unconventionally activated CD8+PD1+ T cells in NASH-affected livers. In preclinical models of NASH-induced HCC, therapeutic immunotherapy targeted at programmed death-1 (PD1) expanded activated CD8+PD1+ T cells within tumours but did not lead to tumour regression, which indicates that tumour immune surveillance was impaired. When given prophylactically, anti-PD1 treatment led to an increase in the incidence of NASH–HCC and in the number and size of tumour nodules, which correlated with increased hepatic CD8+PD1+CXCR6+, TOX+, and TNF+ T cells. The increase in HCC triggered by anti-PD1 treatment was prevented by depletion of CD8+ T cells or TNF neutralization, suggesting that CD8+ T cells help to induce NASH–HCC, rather than invigorating or executing immune surveillance. We found similar phenotypic and functional profiles in hepatic CD8+PD1+ T cells from humans with NAFLD or NASH. A meta-analysis of three randomized phase III clinical trials that tested inhibitors of PDL1 (programmed death-ligand 1) or PD1 in more than 1,600 patients with advanced HCC revealed that immune therapy did not improve survival in patients with non-viral HCC. In two additional cohorts, patients with NASH-driven HCC who received anti-PD1 or anti-PDL1 treatment showed reduced overall survival compared to patients with other aetiologies. Collectively, these data show that non-viral HCC, and particularly NASH–HCC, might be less responsive to immunotherapy, probably owing to NASH-related aberrant T cell activation causing tissue damage that leads to impaired immune surveillance. Our data provide a rationale for stratification of patients with HCC according to underlying aetiology in studies of immunotherapy as a primary or adjuvant treatment., In hepatocellular carcinoma driven by non-alcoholic steatohepatitis, aberrant T cell activation and impaired immune surveillance seem to make hepatocellular carcinoma less responsive to anti-PD1 or anti-PDL1 immunotherapy.

Published
2021
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10. Secretin release after Roux-en-Y gastric bypass reveals a population of glucose-sensitive S cells in distal small intestine

Author

Kirstine N. Bojsen-Møller, Fiona M. Gribble, Sten Madsbad, Ida M. Modvig, Nicolai J. Wewer Albrechtsen, Bolette Hartmann, Daniel B. Andersen, Cathrine Ørskov, Rune E. Kuhre, Pierre Larraufie, Frank Reimann, Christoffer Martinussen, Kaare V. Grunddal, C. Christiansen, Jens J. Holst, Richard G. Kay, Modvig, Ida M. [0000-0002-6824-2802], Reimann, Frank [0000-0001-9399-6377], Holst, Jens J. [0000-0001-6853-3805], Apollo - University of Cambridge Repository, Department of Biomedical Sciences [Copenhagen], Faculty of Health and Medical Sciences, University of Copenhagen = Københavns Universitet (KU)-University of Copenhagen = Københavns Universitet (KU), Institute of Metabolic Science-Metabolic Research Laboratories, University of Cambridge [UK] (CAM), Modvig, Ida M [0000-0002-6824-2802], and Holst, Jens J [0000-0001-6853-3805]

Subjects
0301 basic medicine, Male, Endocrinology, Diabetes and Metabolism, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Medicine (miscellaneous), Secretin, fluids and secretions, 0302 clinical medicine, Intestine, Small, Gastrointestinal hormones, 0303 health sciences, education.field_of_study, Nutrition and Dietetics, Chemistry, Glucagon secretion, article, Endocrine system and metabolic diseases, Type 2 diabetes, 692/163/2743/393, [SDV.MHEP.EM]Life Sciences [q-bio]/Human health and pathology/Endocrinology and metabolism, Postprandial Period, medicine.anatomical_structure, Pancreas, hormones, hormone substitutes, and hormone antagonists, medicine.medical_specialty, Somatostatin secretion, Enteroendocrine Cells, Population, Gastric Bypass, 030209 endocrinology & metabolism, 631/45/776/198, Glucagon, digestive system, 692/163/2743/137/773, 38/91, 14/32, 03 medical and health sciences, Internal medicine, medicine, Animals, Obesity, 631/443/319, Rats, Wistar, education, 82/83, 030304 developmental biology, business.industry, Insulin, 82/58, nutritional and metabolic diseases, digestive system diseases, Small intestine, Rats, 030104 developmental biology, Metabolism, Glucose, Endocrinology, 692/163/2743, business, 82/51
Abstract

ObjectivesGastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the postoperative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release.MethodsA specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after, and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA sequencing, mass-spectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin, and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation.ResultsPlasma postprandial secretin was more than doubled in humans after RYGB (P P P = 0.2) nor glucagon (P = 0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and glucagon secretion increased (P = 0.04), while blood glucose peak time was delayed (from 15 to 45 min) and gastric emptying time prolonged (P = 0.004).ConclusionsGlucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S cells warrants further studies.

Published
2020
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11. Hybridization between subterranean tuco-tucos (Rodentia, Ctenomyidae) with contrasting phylogenetic positions

Author

Leonardo Trindade Leipnitz, Thales Renato Ochotorena de Freitas, Bruno Busnello Kubiak, Thamara Santos de Almeida, Malcolm A. Ferguson-Smith, Renan Maestri, Edivaldo Herculano Corrêa de Oliveira, Leandro Rodrigues Borges, Jorge C. Pereira, Daniel Galiano, Rafael Kretschmer, Kubiak, Bruno Busnello [0000-0002-3996-5411], Kretschmer, Rafael [0000-0002-6856-2152], Maestri, Renan [0000-0001-9134-2943], Galiano, Daniel [0000-0003-1428-8634], Pereira, Jorge C [0000-0002-1472-1613], Ferguson-Smith, Malcolm A [0000-0001-9372-1381], Apollo - University of Cambridge Repository, Pereira, Jorge C. [0000-0002-1472-1613], and Ferguson-Smith, Malcolm A. [0000-0001-9372-1381]

Subjects
0106 biological sciences, 0301 basic medicine, Male, lcsh:Medicine, Evolutionary biology, 01 natural sciences, Molecular cytogenetics, Animal physiology, 631/181/757, lcsh:Science, 631/208/182, Phylogeny, Multidisciplinary, Phylogenetic tree, Hibridiza??o Gen?tica, Roedores / anatomia & histologia, 45/77, Karyotype, Reproductive isolation, Phenotype, 13/31, Phylogenetics, Cytogenetic Analysis, Tuco-Tucos Subterr?neos, Female, medicine.medical_specialty, Reproductive Isolation, Genetic Speciation, 13/106, 45/23, Rodentia, Biology, 010603 evolutionary biology, DNA, Mitochondrial, Article, Chromosomes, Chromosome Painting, 14/32, 03 medical and health sciences, Cytogenetics, Species Specificity, medicine, Animals, Cromossomos / gen?tica, Hybrid, lcsh:R, Skull, 631/208/1405, 631/601/1737, biology.organism_classification, Ctenomys flamarioni, 030104 developmental biology, Karyotyping, 14/63, Cruzamentos Gen?ticos, Hybridization, Genetic, lcsh:Q, Cari?tipo, 631/337/103, Microsatellite Repeats
Abstract

Funder: Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (Brazilian Federal Agency for the Support and Evaluation of Graduate Education); doi: https://doi.org/10.13039/501100002322, Funder: Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), Reproductive compatibility usually decreases according to increasing genetic difference and the time of divergence between species. However, the amount of modification required to influence hybridization may vary in different species. Thus, it is extremely important to conduct studies that seek to understand what and how variables influence the reproductive isolation of species. We have explored a system involving two species of subterranean rodents that present morphological, karyotypic, and evolutionary history differences and are capable of generating hybrids. To gain insight into the karyotype organization of genus Ctenomys, we examined the chromosome evolution by classical and molecular cytogenetics of both parental species and hybrids. Furthermore, we have used different approaches to analyze the differences between the parental species and the hybrids, and determined the origin of the hybrids. The results of our work demonstrate unequivocally that some species that present extensive differences in chromosome organization, phenotype, evolutionary history, sperm morphology and genetic, which are usually associated with reproductive isolation, can generate natural hybrids. The results also demonstrate that females of both species are able to generate hybrids with males of the other species. In addition, the chromosome-specific probes prepared from Ctenomys flamarioni provide an invaluable tool for comparative cytogenetics in closely related species.

Published
2020

12. WWP2 regulates pathological cardiac fibrosis by modulating SMAD2 signaling

Author

Cristina Beltrami, Owen J. L. Rackham, Costanza Emanueli, Nithya Devapragash, Wei-Ping Yu, Xi-Ming Sun, Stuart A. Cook, Norbert Hubner, Francesco Pesce, Ee Ling Heng, Elisabeth Tan, Aida Moreno-Moral, Enrique Lara-Pezzi, Gianni D Angelini, Enrico Petretto, Huimei Chen, Paul J.R. Barton, Nathan Harmston, Michal Pravenec, Sebastian Schafer, Maxime Rotival, Nicole Tee, Massimilano Mancini, Leanne E. Felkin, Leonardo Bottolo, Prashant K. Srivastava, Kirill Shkura, Cardiovascular and Metabolic Disorders [Singapor] (cvmd), Duke-NUS Medical School [Singapore], Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro (UNIBA), Ospedale San Giovanni di Dio, Firenze, National Heart and Lung Institute [London] (NHLI), Imperial College London-Royal Brompton and Harefield NHS Foundation Trust, Génétique Evolutive Humaine - Human Evolutionary Genetics, Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS), Faculty of Medicine [London, UK], Imperial College London, Agency for science, technology and research [Singapore] (A*STAR), Institute of Molecular and Cell Biology, National University of Singapore (NUS)-Agency for science, technology and research [Singapore] (A*STAR), MRC London Institute of Medical Sciences (LMC), National Heart Centre Singapore (NHCS), Royal Brompton and Harefield NHS Foundation Trust, Cardiovascular Research Centre [London], Centro Nacional de Investigaciones Cardiovasculares Carlos III [Madrid, Spain] (CNIC), Instituto de Salud Carlos III [Madrid] (ISC), University of Bristol [Bristol], Institute of Physiology [Prague], Czech Academy of Sciences [Prague] (CAS), University of Cambridge [UK] (CAM), The Alan Turing Institute, MRC Biostatistics Unit [Cambridge, UK], Max Delbrück Center for Molecular Medicine [Berlin] (MDC), Helmholtz-Gemeinschaft = Helmholtz Association, German Center for Cardiovascular Research (DZHK), Berlin Institute of Health (BIH), Charité - UniversitätsMedizin = Charité - University Hospital [Berlin], The research was primarily supported by National Medical Research Council (NMRC) Singapore grant NMRC/CBRG/0106/2016 (to E.P.) and the British Heart Foundation (BHF) Ph.D. Studentship grant FS/11/25/28740 (to E.P). We acknowledge additional funding support from European Union FP7 CardioNeT-ITN-289600 (to E.L.-P., S.A.C., and P.J.R.B.), Heart Research UK (to P.J.R.B.), NIHR CV BRU of Royal Brompton and Harefield, NHS Foundation Trust (to S.A.C. and P.J.R.B.), BHF (to S.A.C.), Leducq Foundation (to S.A.C.), MRC UK (to S.A.C.), BHF Program Grant no. RG/15/5/31446 (to C.E. and E.P.). M.P. was supported by Praemium Academiae award of the Czech Academy of Sciences and grant 14-36804G from the Czech Science Foundation., We wish to thank Dr. Jacques Behmoaras for contributing critical and constructive comments to the manuscript., European Project: 289600,EC:FP7:PEOPLE,FP7-PEOPLE-2011-ITN,CARDIONET(2012), Moreno-Moral, Aida [0000-0002-8155-3146], Barton, Paul J. R. [0000-0002-1165-7767], Schafer, Sebastian [0000-0002-6909-8275], Bottolo, Leonardo [0000-0002-6381-2327], Cook, Stuart A. [0000-0001-6628-194X], Petretto, Enrico [0000-0003-2163-5921], Apollo - University of Cambridge Repository, National Medical Research Council (Singapur), British Heart Foundation, Unión Europea. Comisión Europea, National Institutes of Health (Estados Unidos), Czech Science Foundation, Fondation Leducq, NHS Foundation Trusth, University of Bari Aldo Moro (UNIBA), Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Leducq Foundation for Cardiovascular Research, Commission of the European Communities, Heart Research UK, Medical Research Council (MRC), Barton, Paul JR [0000-0002-1165-7767], and Cook, Stuart A [0000-0001-6628-194X]

Subjects
Male, 45/43, BLOOD-PRESSURE, 02 engineering and technology, MESH: Protein Isoforms, MESH: Heart Diseases / genetics, Mice, Transforming Growth Factor beta, 42/44, Fibrosis, Protein Isoforms, Medicine, MESH: Animals, lcsh:Science, MESH: Ubiquitin-Protein Ligases / genetics, MESH: Fibrosis / metabolism, MESH: Genetic Predisposition to Disease* / genetics, GENE-EXPRESSION, Regulation of gene expression, Extracellular Matrix Proteins, MESH: Middle Aged, MESH: Fibrosis / genetics, TGF-BETA, MESH: Heart Diseases / metabolism, MESH: Ubiquitin-Protein Ligases / metabolism, 3. Good health, Cell biology, Ubiquitin ligase, FIBROBLAST, MESH: Young Adult, Science & Technology - Other Topics, 64/60, Cardiomyopathies, 0210 nano-technology, Cardiac function curve, Science, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, REVEALS, Humans, Aged, MESH: Adolescent, Science & Technology, MESH: Humans, [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], IDENTIFICATION, MESH: Smad2 Protein / metabolism, MESH: Extracellular Matrix Proteins / metabolism, MESH: Adult, MESH: Cardiomyopathies / metabolism, medicine.disease, 030104 developmental biology, Cardiovascular and Metabolic Diseases, E3 UBIQUITIN LIGASE, RAT, DETERMINANT, lcsh:Q, Myocardial fibrosis, MESH: Female, 0301 basic medicine, Cardiac fibrosis, General Physics and Astronomy, Smad2 Protein, Gene Regulatory Networks, 13/89, MESH: Aged, MESH: Transforming Growth Factor beta / metabolism, Multidisciplinary, biology, MESH: Smad2 Protein / genetics, article, Middle Aged, MESH: Cardiomyopathies / genetics, 021001 nanoscience & nanotechnology, 692/4019/592/75/74, MESH: Gene Expression Regulation, Multidisciplinary Sciences, Centre for Surgical Research, HEART-FAILURE, Female, 38/39, Adult, Adolescent, Heart Diseases, MESH: Mice, Transgenic, Ubiquitin-Protein Ligases, Mice, Transgenic, 14/32, 82/80, Young Adult, Animals, Genetic Predisposition to Disease, 14/35, MESH: Mice, Pressure overload, business.industry, General Chemistry, MESH: Male, Gene Expression Regulation, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Ubiquitin ligases, Heart failure, 13/51, biology.protein, 631/45/474/2073, MESH: Gene Regulatory Networks, business
Abstract

Cardiac fibrosis is a final common pathology in inherited and acquired heart diseases that causes cardiac electrical and pump failure. Here, we use systems genetics to identify a pro-fibrotic gene network in the diseased heart and show that this network is regulated by the E3 ubiquitin ligase WWP2, specifically by the WWP2-N terminal isoform. Importantly, the WWP2-regulated pro-fibrotic gene network is conserved across different cardiac diseases characterized by fibrosis: human and murine dilated cardiomyopathy and repaired tetralogy of Fallot. Transgenic mice lacking the N-terminal region of the WWP2 protein show improved cardiac function and reduced myocardial fibrosis in response to pressure overload or myocardial infarction. In primary cardiac fibroblasts, WWP2 positively regulates the expression of pro-fibrotic markers and extracellular matrix genes. TGFβ1 stimulation promotes nuclear translocation of the WWP2 isoforms containing the N-terminal region and their interaction with SMAD2. WWP2 mediates the TGFβ1-induced nucleocytoplasmic shuttling and transcriptional activity of SMAD2., Pathological cardiac fibrosis is a hallmark of diseases leading to heart failure. Here, the authors used systems genetics to identify a pro-fibrotic gene network regulated by WWP2, a E3 ubiquitin ligase, which orchestrates the nucleocytoplasmic shuttling and transcriptional activity of SMAD2 in the diseased heart.

Published
2019
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13. Single-cell roadmap of human gonadal development

Author

Garcia-Alonso, Luz, Lorenzi, Valentina, Mazzeo, Cecilia Icoresi, Alves-Lopes, João Pedro, Roberts, Kenny, Sancho-Serra, Carmen, Engelbert, Justin, Marečková, Magda, Gruhn, Wolfram H, Botting, Rachel A, Li, Tong, Crespo, Berta, Van Dongen, Stijn, Kiselev, Vladimir Yu, Prigmore, Elena, Herbert, Mary, Moffett, Ashley, Chédotal, Alain, Bayraktar, Omer Ali, Surani, Azim, Haniffa, Muzlifah, Vento-Tormo, Roser, Lorenzi, Valentina [0000-0002-3111-4006], Roberts, Kenny [0000-0001-6155-0821], Marečková, Magda [0000-0002-4897-5013], Gruhn, Wolfram H [0000-0001-6072-1916], Botting, Rachel A [0000-0001-9595-4605], Li, Tong [0000-0002-8240-4476], Crespo, Berta [0000-0003-0006-009X], Prigmore, Elena [0000-0001-8870-0316], Moffett, Ashley [0000-0002-8388-9073], Chédotal, Alain [0000-0001-7577-3794], Bayraktar, Omer Ali [0000-0001-6055-277X], Vento-Tormo, Roser [0000-0002-9870-8474], Apollo - University of Cambridge Repository, and Surani, Azim [0000-0002-8640-4318]

Subjects
Male, Sex Differentiation, Immunoglobulins, 45/23, 38/91, 14/32, Mice, PAX8 Transcription Factor, Pregnancy, 631/136/142, Testis, Animals, Humans, Cell Lineage, Receptors, Immunologic, Granulosa Cells, Membrane Glycoproteins, Multidisciplinary, Macrophages, Ovary, article, Membrane Proteins, 45/15, Chromatin, Pregnancy Trimester, First, Germ Cells, Microscopy, Fluorescence, Pregnancy Trimester, Second, Female, 38/39, 64/60, Single-Cell Analysis, 631/80, Transcriptome
Abstract

Gonadal development is a complex process that involves sex determination followed by divergent maturation into either testes or ovaries1. Historically, limited tissue accessibility, a lack of reliable in vitro models and critical differences between humans and mice have hampered our knowledge of human gonadogenesis, despite its importance in gonadal conditions and infertility. Here, we generated a comprehensive map of first- and second-trimester human gonads using a combination of single-cell and spatial transcriptomics, chromatin accessibility assays and fluorescent microscopy. We extracted human-specific regulatory programmes that control the development of germline and somatic cell lineages by profiling equivalent developmental stages in mice. In both species, we define the somatic cell states present at the time of sex specification, including the bipotent early supporting population that, in males, upregulates the testis-determining factor SRY and sPAX8s, a gonadal lineage located at the gonadal–mesonephric interface. In females, we resolve the cellular and molecular events that give rise to the first and second waves of granulosa cells that compartmentalize the developing ovary to modulate germ cell differentiation. In males, we identify human SIGLEC15+ and TREM2+ fetal testicular macrophages, which signal to somatic cells outside and inside the developing testis cords, respectively. This study provides a comprehensive spatiotemporal map of human and mouse gonadal differentiation, which can guide in vitro gonadogenesis.

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