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1. Supersymmetry on the lattice: Geometry, Topology, and Spin Liquids

Author

Roychowdhury, Krishanu, Attig, Jan, Trebst, Simon, and Lawler, Michael J.

Subjects
Condensed Matter - Strongly Correlated Electrons, Condensed Matter - Other Condensed Matter
Abstract

In quantum mechanics, supersymmetry (SUSY) posits an equivalence between two elementary degrees of freedom, bosons and fermions. Here we show how this fundamental concept can be applied to connect bosonic and fermionic lattice models in the realm of condensed matter physics, e.g., to identify a variety of (bosonic) phonon and magnon lattice models which admit topologically nontrivial free fermion models as superpartners. At the single-particle level, the bosonic and the fermionic models that are generated by the SUSY are isospectral except for zero modes, such as flat bands, whose existence is undergirded by the Witten index of the SUSY theory. We develop a unifying framework to formulate these SUSY connections in terms of general lattice graph correspondences and discuss further ramifications such as the definition of supersymmetric topological invariants for generic bosonic systems. Notably, a Hermitian form of the supercharge operator, the generator of the SUSY, can itself be interpreted as a hopping Hamiltonian on a bipartite lattice. This allows us to identify a wide class of interconnected lattices whose tight-binding Hamiltonians are superpartners of one another or can be derived via squaring or square-rooting their energy spectra all the while preserving band topology features. We introduce a five-fold way symmetry classification scheme of these SUSY lattice correspondences, including cases with a non-zero Witten index, based on a topological classification of the underlying Hermitian supercharge operator. These concepts are illustrated for various explicit examples including frustrated magnets, Kitaev spin liquids, and topological superconductors., Comment: 37 pages, 27 figures

Published
2022

2. Universal principles of moir\'e band structures

Author

Attig, Jan, Park, Jinhong, Scherer, Michael M., Trebst, Simon, Altland, Alexander, and Rosch, Achim

Subjects
Condensed Matter - Mesoscale and Nanoscale Physics
Abstract

Moir\'e materials provide a highly tunable environment for the realization of band structures with engineered physical properties. Specifically, moir\'e structures with Fermi surface flat bands - a synthetic environment for the realization of correlated phases - have moir\'e unit cells containing thousands of atoms and tantalizingly complex bands structures. In this paper we show that statistical principles go a long way in explaining universal physical properties of these systems. Our approach builds on three conceptual elements: the presence of quantum chaos caused by the effective irregularity of the atomic configurations on short length scales, Anderson localization in momentum space, and the presence of approximate crystalline symmetries. Which of these principles dominates depends on material parameters such as the extension of the Fermi surface or the strength of the moir\'e lattice potential. The phenomenological consequences of this competition are predictions for the characteristic group velocity of moir\'e bands, a primary indicator for their average flatness. In addition to these generic features, we identify structures outside the statistical context, notably almost flat bands close to the extrema of the unperturbed spectra, and the celebrated zero energy `magic angle' flat bands, where the latter require exceptionally fine tuned material parameters., Comment: 15 pages, 10 figures

Published
2021
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3. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author

Ng, Kevin W., Boumelha, Jesse, Enfield, Katey S. S., Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A., Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott T. C., Martínez-Ruiz, Carlos, Puttick, Clare, Black, James R. M., Watkins, Thomas B. K., Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia, Frankell, Alexander M., Al Bakir, Maise, Lim, Emilia L., Hill, Mark S., Wilson, Gareth A., Cook, Daniel E., Birkbak, Nicolai J., Behrens, Axel, Yousaf, Nadia, Popat, Sanjay, Hackshaw, Allan, Hiley, Crispin T., Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, and Kassiotis, George

Published
2023
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4. Topological Mechanics from Supersymmetry

Author

Attig, Jan, Roychowdhury, Krishanu, Lawler, Michael J., and Trebst, Simon

Subjects
Condensed Matter - Strongly Correlated Electrons, Condensed Matter - Mesoscale and Nanoscale Physics, Condensed Matter - Statistical Mechanics
Abstract

In topological mechanics, the identification of a mechanical system's rigidity matrix with an electronic tight-binding model allows to infer topological properties of the mechanical system, such as the occurrence of `floppy' boundary modes, from the associated electronic band structure. Here we introduce an approach to systematically construct topological mechanical systems by an exact supersymmetry (SUSY) that relates the bosonic (mechanical) and fermionic (e.g. electronic) degrees of freedom. As examples we discuss mechanical analogues of the Kitaev honeycomb model and of a second-order topological insulator with floppy corner modes. Our SUSY construction naturally defines hitherto unexplored topological invariants for bosonic (mechanical) systems, such as bosonic Wilson loop operators that are formulated in terms of a SUSY-related fermionic Berry curvature., Comment: 8 pages, 6 figures

Published
2018
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5. Two-stage multipolar ordering in Pr(TM)$_2$Al$_{20}$ Kondo materials

Author

Freyer, Frederic, Attig, Jan, Lee, SungBin, Paramekanti, Arun, Trebst, Simon, and Kim, Yong Baek

Subjects
Condensed Matter - Strongly Correlated Electrons
Abstract

Among heavy fermion materials, there is a set of rare-earth intermetallics with non-Kramers Pr$^{3+}$ $4f^2$ moments which exhibit a rich phase diagram with intertwined quadrupolar orders, superconductivity, and non-Fermi liquid behavior. However, more subtle broken symmetries such as multipolar orders in these Kondo materials remain poorly studied. Here, we argue that multi-spin interactions between local moments beyond the conventional two-spin exchange must play an important role in Kondo materials near the ordered to heavy Fermi liquid transition. We show that this drives a plethora of phases with coexisting multipolar orders and multiple thermal phase transitions, providing a natural framework for interpreting experiments on the Pr(TM)$_2$Al$_{20}$ class of compounds., Comment: 8 pages, 8 figures

Published
2017
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6. Classical Spin Spirals in Frustrated Magnets from Free-Fermion Band Topology

Author

Attig, Jan and Trebst, Simon

Subjects
Condensed Matter - Strongly Correlated Electrons, Condensed Matter - Statistical Mechanics
Abstract

The formation of coplanar spin spirals is a common motif in the magnetic ordering of many frustrated magnets. For classical antiferromagnets, geometric frustration can lead to a massively degenerate ground state manifold of spirals whose propagation vectors can be described, depending on the lattice geometry, by points (triangular), lines (fcc), surfaces (frustrated diamond) or completely flat bands (pyrochlore). Here we demonstrate an exact mathematical correspondence of these spiral manifolds of classical antiferromagnets with the Fermi surfaces of free-fermion band structures. We provide an explicit lattice construction relating the frustrated spin model to a corresponding free-fermion tight-binding model. Examples of this correspondence relate the 120$^\circ$ order of the triangular lattice antiferromagnet to the Dirac nodal structure of the honeycomb tight-binding model or the spiral line manifold of the fcc antiferromagnet to the Dirac nodal line of the diamond tight-binding model. We discuss implications of topological band structures in the fermionic system to the corresponding classical spin system., Comment: 16 pages, 20 figures

Published
2017
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12. Tumor beta2-microglobulin and HLA-A expression is increased by immunotherapy and can predict response to CIT in association with other biomarkers.

Author

Reis, Bernhard, Attig, Jan, Dziadek, Sebastian, Graefe, Nico, Heller, Astrid, Rieder, Natascha, and Gomes, Bruno

Subjects
IMMUNOTHERAPY, BIOMARKERS, ANTIGEN presentation
Abstract

Background: Downregulation of MHC class I expression and/or defects in the antigen presentation pathways are commonly reported in human cancers. Numerous studies previously have explored extensively the molecular mechanisms that underlie HLA-class I and Beta2-Microglobulin (B2M) downregulation. However, the techniques presently available to detect expression of MHC class I proteins lack the robustness, specificity and sensitivity needed for systematic integration and analysis in clinical trials. Furthermore, the dynamics of HLA-class I and B2M expression have not been comprehensively studied as a potential biomarker for immunotherapy. Methods: Using novel, validated, immunohistochemistry (IHC)-based methods for quantifying B2M and HLA-A in tumor samples from diverse cancer types, we have determined loss of B2M and HLA-A proteins in 336 archived, primary specimens and 329 biopsies from metastatic patients collected during Roche-sponsored Phase 1 clinical trials investigating novel immunotherapy candidates as monotherapy or in combination with CPI. Results: Up to 56% of cases with B2M or HLA-A loss were noted in the investigated tumor types. The frequency of loss was dependent on indication and stage of disease and revealed heterogeneous expression patterns across patients. B2M and HLA-A loss was increased in metastatic lesions compared to primary tumors, indicating selection of MHC class I low clones in metastatic and refractory tumor cells. High on-treatment B2M expression correlated with successful clinical outcome (RECIST), while high baseline B2M did not. A treatment-induced increase of B2M expression was noted in most of the patients with low B2M levels at baseline. The triple biomarker combination of B2M, CD8 and PDL1 strongly improved response prediction to cancer immunotherapy. Conclusion: Our results indicate that B2M and HLA-A loss occurs frequently in tumors and is reversed in most instances following immunotherapy which supports the conclusion that MHC class I loss is not the dominant resistance mechanism to CPI treatment. This investigation reveals a highly dynamic expression of HLA-A and B2M in tumors affected by indication, metastatic status, immunophenotype and immunotherapy treatment. Baseline expression levels of B2M on tumors may be of utility as a constituent of a biomarker panel used for selecting patients for immunotherapy clinical trials. [ABSTRACT FROM AUTHOR]

Published
2024
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13. P-006 SBCMA has utility for early response monitoring in the blood and is correlated with forimtamig pharmacodynamic activity, clinical response and MRD

Author

Dekhtiarenko, Iryna, primary, Attig, Jan, additional, Helms, Hans-Joachin, additional, Lelios, Iva, additional, Clausen, Inga, additional, Jacob, Wolfgang, additional, Schneider, Meike, additional, Weisser, Martin, additional, Carlo-Stella, Carmelo, additional, Manier, Salomon, additional, Harrison, Simon, additional, Popat, Rakesh, additional, Riley, Caroline Hasselbalch, additional, and Bröske, Ann-Marie, additional

Published
2023
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14. Human endogenous retrovirus onco-exaptation counters cancer cell senescence through calbindin

Author

Attig, Jan, primary, Pape, Judith, additional, Doglio, Laura, additional, Kazachenka, Anastasiya, additional, Ottina, Eleonora, additional, Young, George R., additional, Enfield, Katey S.S., additional, Aramburu, Iker Valle, additional, Ng, Kevin W., additional, Faulkner, Nikhil, additional, Bolland, William, additional, Papayannopoulos, Venizelos, additional, Swanton, Charles, additional, and Kassiotis, George, additional

Published
2023
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15. Cap-binding protein 4EHP effects translation silencing by microRNAs

Author

Chapat, Clément, Jafarnejad, Seyed Mehdi, Matta-Camacho, Edna, Hesketh, Geoffrey G., Gelbart, Idit A., Attig, Jan, Gkogkas, Christos G., Alain, Tommy, Stern-Ginossar, Noam, Fabian, Marc R., Gingras, Anne-Claude, Duchaine, Thomas F., and Sonenberg, Nahum

Published
2017

18. Antibodies against endogenous retroviruses promote lung cancer immunotherapy

Author

Ng, Kevin W, Boumelha, Jesse, Enfield, Katey SS, Almagro, Jorge, Cha, Hongui, Pich, Oriol, Karasaki, Takahiro, Moore, David A, Salgado, Roberto, Sivakumar, Monica, Young, George, Molina-Arcas, Miriam, de Carné Trécesson, Sophie, Anastasiou, Panayiotis, Fendler, Annika, Au, Lewis, Shepherd, Scott TC, Martínez-Ruiz, Carlos, Puttick, Clare, Black, James RM, Watkins, Thomas BK, Kim, Hyemin, Shim, Seohee, Faulkner, Nikhil, Attig, Jan, Veeriah, Selvaraju, Magno, Neil, Ward, Sophia, Frankell, Alexander M, Al Bakir, Maise, Lim, Emilia L, Hill, Mark S, Wilson, Gareth A, Cook, Daniel E, Birkbak, Nicolai J, Behrens, Axel, Yousaf, Nadia, Popat, Sanjay, Hackshaw, Allan, Consortium, TRACERx, Consortium, CAPTURE, Hiley, Crispin T, Litchfield, Kevin, McGranahan, Nicholas, Jamal-Hanjani, Mariam, Larkin, James, Lee, Se-Hoon, Turajlic, Samra, Swanton, Charles, Downward, Julian, and Kassiotis, George

Subjects
Model organisms, Lung Neoplasms, Immunology, Gene Expression, Adenocarcinoma of Lung, Infectious Disease, Antibodies, Cohort Studies, Mice, Signalling & Oncogenes, Ecology,Evolution & Ethology, Carcinoma, Non-Small-Cell Lung, Tumor Microenvironment, Animals, Humans, Lung, Computational & Systems Biology, Chemical Biology & High Throughput, B-Lymphocytes, Human Biology & Physiology, Stem Cells, FOS: Clinical medicine, Endogenous Retroviruses, Genome Integrity & Repair, Cell Biology, Tumour Biology, Disease Models, Animal, Cell Cycle & Chromosomes, Immunotherapy, Genetics & Genomics
Abstract

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS)1,2. Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive1,2. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma3. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response. ispartof: NATURE vol:616 issue:7957 ispartof: location:England status: Published online

Published
2023
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21. Intravenous and Subcutaneous Administration of RG6234, a Novel GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients with Relapsed/Refractory Multiple Myeloma (RRMM): Biomarker Results from a Phase I Study

Author

Dekhtiarenko, Iryna, primary, Lelios, Iva, additional, Attig, Jan, additional, Sleiman, Nassim, additional, Lazzaro, Domenico, additional, Schindler, Emilie, additional, Eckmann, Jan, additional, Umana, Pablo, additional, Jacob, Wolfgang, additional, Schneider, Meike, additional, Carlo-Stella, Carmelo, additional, Mazza, Rita, additional, Manier, Salomon, additional, Facon, Thierry, additional, Yoon, Sung-Soo, additional, Koh, Youngil, additional, Harrison, Simon J, additional, Er, Jeremy, additional, Pinto, Antonio, additional, Volzone, Francesco, additional, Perrone, Giulia, additional, Corradini, Paolo, additional, Cazaubiel, Titouan, additional, Hulin, Cyrille, additional, Touzeau, Cyrille, additional, Moreau, Philippe, additional, Ocio, Enrique M., additional, Montes Gaisan, Carmen Maria, additional, Popat, Rakesh, additional, Leong, Sarah, additional, Offner, Fritz, additional, Rodriguez Otero, Paula, additional, Alfonso-Pierola, Ana, additional, Hutchings, Martin, additional, Riley, Caroline Hasselbalch, additional, and Bröske, Ann-Marie E, additional

Published
2022
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23. Electronic Spectra: Topology, Supersymmetry, and Statistics

Author

Attig, Jan

Subjects
ddc:530
Abstract

The description of electronic behavior within solids is a major part of modern Condensed Matter Physics. It is well known that depending on the precise conditions, very diverse phenomena arise from the interacting electrons in the material. To make predictions, it is therefore crucial to understand the electronic structure in a material and to compute its electronic spectrum. This thesis discusses three different aspects of electronic spectra including their numerical solution, each highlighting a distinct approach. In a first part, this thesis presents a numerical solution of many-electron spectra on small clusters of IrO6 octahedra. Such clusters are relevant in the field of strongly coupled matter as they give rise to the elementary building blocks of many topological spin systems, localized j = 1/2 moments. Exact diagonalization of the full many-electron interaction Hamiltonian is utilized to compute multi-particle spectra with respective eigenstates. Subsequently, these eigenstates are further used for numerical calculations of resonant inelastic X-ray scattering (RIXS) amplitudes. The numerical approach is versatile enough to be applied to different examples in this thesis, covering single-site RIXS spectra as in Ba2CeIrO6, materials with local clusters like Ba3InIr2O9 and Ba3Ti3−xIrxO9 and Kitaev materials such as Na2IrO3 and α-RuCl3. In particular, interference effects in the RIXS amplitudes are shown to play a crucial role of determining the nature of delocalized eigenstates in these materials. In a second part, supersymmetry is used to link the spectra of electronic lattice models with bosonic counterparts. To this endeavor, an exact lattice construction is introduced, underlying the supersymmetric identification and providing a visual representation of the supersymmetric matching. As a first instance of the supersymmetric map, it will be shown that models of complex fermions and models of complex bosons are supersymmetrically related if they reside on the two sublattices of a bipartite lattice. Another similar identification is introduced for Majorana fermions on a bipartite lattice which can be related to real boson models on one of the sublattices, allowing for the explicit construction of related mechanical models. As examples of this classical construction, the Kitaev model and a second order topological insulator with floppy corner modes are discussed. In both examples, the supersymmetrically related mechanical model is shown to exhibit the same spectral properties as its quantum mechanical analogue and even inherit topologically protected localized corner modes. In a third part, the electronic spectra of general Moiré materials are investigated at the example of twisted bilayer graphene. This part demonstrates that statistical principles are best suited to describe the vast number of bands originating from the large Moiré unit cells. The statistical description reveals a localization mechanism in momentum space which is investigated and described. The mechanism does not only apply to all parts of the spectrum in twisted bilayer graphene but is also believed to apply to generic Moiré materials. Moreover, exceptions from this general mechanism in twisted bilayer graphene are discussed in detail which turn out to be described by harmonic oscillator states.

Published
2022

24. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author

Au, Lewis, Hatipoglu, Emine, Robert De Massy, Marc, Litchfield, Kevin, Beattie, Gordon, Rowan, Andrew, Schnidrig, Desiree, Thompson, Rachael, Byrne, Fiona, Horswell, Stuart, Fotiadis, Nicos, Hazell, Steve, Nicol, David, Shepherd, Scott TC, Fendler, Annika, Mason, Robert, Del Rosario, Lyra, Edmonds, Kim, Lingard, Karla, Sarker, Sarah, Mangwende, Mary, Carlyle, Eleanor, Attig, Jan, Joshi, Kroopa, Uddin, Imran, Becker, Pablo D, Sunderland, Mariana Werner, Akarca, Ayse, Puccio, Ignazio, Yang, William W, Lund, Tom, Dhillon, Kim, Vasquez, Marcos Duran, Ghorani, Ehsan, Xu, Hang, Spencer, Charlotte, López, José I, Green, Anna, Mahadeva, Ula, Borg, Elaine, Mitchison, Miriam, Moore, David A, Proctor, Ian, Falzon, Mary, Pickering, Lisa, Furness, Andrew JS, Reading, James L, Salgado, Roberto, Marafioti, Teresa, Jamal-Hanjani, Mariam, PEACE Consortium, Kassiotis, George, Chain, Benny, Larkin, James, Swanton, Charles, Quezada, Sergio A, Turajlic, Samra, TRACERx Renal Consortium, and Apollo - University of Cambridge Repository

Subjects
multiregion, Receptors, Antigen, T-Cell, clear cell renal cell carcinoma, CD8-Positive T-Lymphocytes, autopsy, Clinical Trials, Phase II as Topic, Exome Sequencing, Tumor Microenvironment, Humans, TCR clonal replacement, Prospective Studies, TCR clonal maintenance, Carcinoma, Renal Cell, Immune Checkpoint Inhibitors, nivolumab, Sequence Analysis, RNA, Gene Expression Profiling, Endogenous Retroviruses, Genomics, Kidney Neoplasms, human endogenous retrovirus, Drug Resistance, Neoplasm, anti-PD-1, Tumor Escape, T cell receptor, Single-Cell Analysis
Abstract

ADAPTeR is a prospective, phase II study of nivolumab (anti-PD-1) in 15 treatment-naive patients (115 multiregion tumor samples) with metastatic clear cell renal cell carcinoma (ccRCC) aiming to understand the mechanism underpinning therapeutic response. Genomic analyses show no correlation between tumor molecular features and response, whereas ccRCC-specific human endogenous retrovirus expression indirectly correlates with clinical response. T cell receptor (TCR) analysis reveals a significantly higher number of expanded TCR clones pre-treatment in responders suggesting pre-existing immunity. Maintenance of highly similar clusters of TCRs post-treatment predict response, suggesting ongoing antigen engagement and survival of families of T cells likely recognizing the same antigens. In responders, nivolumab-bound CD8+ T cells are expanded and express GZMK/B. Our data suggest nivolumab drives both maintenance and replacement of previously expanded T cell clones, but only maintenance correlates with response. We hypothesize that maintenance and boosting of a pre-existing response is a key element of anti-PD-1 mode of action.

Published
2021

25. Determinants of anti-PD-1 response and resistance in clear cell renal cell carcinoma

Author

Au, Lewis, primary, Hatipoglu, Emine, additional, Robert de Massy, Marc, additional, Litchfield, Kevin, additional, Beattie, Gordon, additional, Rowan, Andrew, additional, Schnidrig, Desiree, additional, Thompson, Rachael, additional, Byrne, Fiona, additional, Horswell, Stuart, additional, Fotiadis, Nicos, additional, Hazell, Steve, additional, Nicol, David, additional, Shepherd, Scott T.C., additional, Fendler, Annika, additional, Mason, Robert, additional, Del Rosario, Lyra, additional, Edmonds, Kim, additional, Lingard, Karla, additional, Sarker, Sarah, additional, Mangwende, Mary, additional, Carlyle, Eleanor, additional, Attig, Jan, additional, Joshi, Kroopa, additional, Uddin, Imran, additional, Becker, Pablo D., additional, Sunderland, Mariana Werner, additional, Akarca, Ayse, additional, Puccio, Ignazio, additional, Yang, William W., additional, Lund, Tom, additional, Dhillon, Kim, additional, Vasquez, Marcos Duran, additional, Ghorani, Ehsan, additional, Xu, Hang, additional, Spencer, Charlotte, additional, López, José I., additional, Green, Anna, additional, Mahadeva, Ula, additional, Borg, Elaine, additional, Mitchison, Miriam, additional, Moore, David A., additional, Proctor, Ian, additional, Falzon, Mary, additional, Pickering, Lisa, additional, Furness, Andrew J.S., additional, Reading, James L., additional, Salgado, Roberto, additional, Marafioti, Teresa, additional, Jamal-Hanjani, Mariam, additional, Kassiotis, George, additional, Chain, Benny, additional, Larkin, James, additional, Swanton, Charles, additional, Quezada, Sergio A., additional, Turajlic, Samra, additional, Abbosh, Chris, additional, Shiu, Kai-Keen, additional, Bridgewater, John, additional, Hochhauser, Daniel, additional, Forster, Martin, additional, Lee, Siow-Ming, additional, Ahmad, Tanya, additional, Papadatos-Pastos, Dionysis, additional, Janes, Sam, additional, Van Loo, Peter, additional, Enfield, Katey, additional, McGranahan, Nicholas, additional, Huebner, Ariana, additional, Beck, Stephan, additional, Parker, Peter, additional, Walczak, Henning, additional, Enver, Tariq, additional, Hynds, Rob, additional, Sinclair, Ron, additional, Lok, Chi-wah, additional, Rhodes, Zoe, additional, Moore, David, additional, Khiroya, Reena, additional, Trevisan, Giorgia, additional, Ellery, Peter, additional, Linch, Mark, additional, Brandner, Sebastian, additional, Hiley, Crispin, additional, Veeriah, Selvaraju, additional, Razaq, Maryam, additional, Shaw, Heather, additional, Attard, Gert, additional, Akther, Mita Afroza, additional, Naceur-Lombardelli, Cristina, additional, Manzano, Lizi, additional, Al-Bakir, Maise, additional, Summan, Simranpreet, additional, Kanu, Nnenna, additional, Ward, Sophie, additional, Asghar, Uzma, additional, Lim, Emilia, additional, Gishen, Faye, additional, Tookman, Adrian, additional, Stone, Paddy, additional, Stirling, Caroline, additional, Hunter, Nikki, additional, Vaughan, Sarah, additional, Spain, Lavinia, additional, Yan, Haixi, additional, Shum, Ben, additional, Yousaf, Nadia, additional, Popat, Sanjay, additional, Curtis, Olivia, additional, Stamp, Gordon, additional, Toncheva, Antonia, additional, Nye, Emma, additional, Murra, Aida, additional, Korteweg, Justine, additional, Josephs, Debra, additional, Chandra, Ashish, additional, Spicer, James, additional, Stewart, Ruby, additional, Iredale, Lara-Rose, additional, Mackay, Tina, additional, Deakin, Ben, additional, Enting, Debra, additional, Rudman, Sarah, additional, Ghosh, Sharmistha, additional, Karapagniotou, Lena, additional, Pintus, Elias, additional, Tutt, Andrew, additional, Howlett, Sarah, additional, Michalarea, Vasiliki, additional, Brenton, James, additional, Caldas, Carlos, additional, Fitzgerald, Rebecca, additional, Jimenez-Linan, Merche, additional, Provenzano, Elena, additional, Cluroe, Alison, additional, Stewart, Grant, additional, Watts, Colin, additional, Gilbertson, Richard, additional, McDermott, Ultan, additional, Tavare, Simon, additional, Beddowes, Emma, additional, Roxburgh, Patricia, additional, Biankin, Andrew, additional, Chalmers, Anthony, additional, Fraser, Sioban, additional, Oien, Karin, additional, Kidd, Andrew, additional, Blyth, Kevin, additional, Krebs, Matt, additional, Blackhall, Fiona, additional, Summers, Yvonne, additional, Dive, Caroline, additional, Marais, Richard, additional, Gomes, Fabio, additional, Carter, Mat, additional, Dransfield, Jo, additional, Le Quesne, John, additional, Fennell, Dean, additional, Shaw, Jacqui, additional, Naidu, Babu, additional, Baijal, Shobhit, additional, Tanchel, Bruce, additional, Langman, Gerald, additional, Robinson, Andrew, additional, Collard, Martin, additional, Cockcroft, Peter, additional, Ferris, Charlotte, additional, Bancroft, Hollie, additional, Kerr, Amy, additional, Middleton, Gary, additional, Webb, Joanne, additional, Kadiri, Salma, additional, Colloby, Peter, additional, Olisemeke, Bernard, additional, Wilson, Rodelaine, additional, Tomlinson, Ian, additional, Jogai, Sanjay, additional, Ottensmeier, Christian, additional, Harrison, David, additional, Loda, Massimo, additional, Flanagan, Adrienne, additional, McKenzie, Mairead, additional, Hackshaw, Allan, additional, Ledermann, Jonathan, additional, Chan, Kitty, additional, Sharp, Abby, additional, Farrelly, Laura, additional, Bridger, Hayley, additional, Challacombe, Ben, additional, Chowdhury, Simon, additional, Drake, William, additional, Fernando, Archana, additional, Harrison-Phipps, Karen, additional, Hill, Peter, additional, Horsfield, Catherine, additional, O'Brien, Tim, additional, Olsburgh, Jonathon, additional, Polson, Alexander, additional, Varia, Mary, additional, and Verma, Hema, additional

Published
2021
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26. Intergenic RNA mainly derives from nascent transcripts of known genes

Author

Zagalak Julian, Ule Jernej, Agostini Federico, Nicholas M. Luscombe, and Attig Jan

Subjects
Transcription, Genetic, QH301-705.5, Gene annotation, RNA polymerase II, Computational biology, QH426-470, Genome, Cell Line, 03 medical and health sciences, 0302 clinical medicine, Intergenic region, Transcription (biology), Genetics, Humans, RNA, Messenger, Biology (General), Gene, 030304 developmental biology, 0303 health sciences, biology, Research, RNA, Endonucleases, Chromatin, Genes, biology.protein, Human genome, DNA, Intergenic, RNA-seq, Transcription, 030217 neurology & neurosurgery
Abstract

Background Eukaryotic genomes undergo pervasive transcription, leading to the production of many types of stable and unstable RNAs. Transcription is not restricted to regions with annotated gene features but includes almost any genomic context. Currently, the source and function of most RNAs originating from intergenic regions in the human genome remain unclear. Results We hypothesize that many intergenic RNAs can be ascribed to the presence of as-yet unannotated genes or the “fuzzy” transcription of known genes that extends beyond the annotated boundaries. To elucidate the contributions of these two sources, we assemble a dataset of more than 2.5 billion publicly available RNA-seq reads across 5 human cell lines and multiple cellular compartments to annotate transcriptional units in the human genome. About 80% of transcripts from unannotated intergenic regions can be attributed to the fuzzy transcription of existing genes; the remaining transcripts originate mainly from putative long non-coding RNA loci that are rarely spliced. We validate the transcriptional activity of these intergenic RNAs using independent measurements, including transcriptional start sites, chromatin signatures, and genomic occupancies of RNA polymerase II in various phosphorylation states. We also analyze the nuclear localization and sensitivities of intergenic transcripts to nucleases to illustrate that they tend to be rapidly degraded either on-chromatin by XRN2 or off-chromatin by the exosome. Conclusions We provide a curated atlas of intergenic RNAs that distinguishes between alternative processing of well-annotated genes from independent transcriptional units based on the combined analysis of chromatin signatures, nuclear RNA localization, and degradation pathways.

Published
2021

28. Endogenous retroviruses promote homeostatic and inflammatory responses to the microbiota

Author

Lima-Junior, Djalma S., primary, Krishnamurthy, Siddharth R., additional, Bouladoux, Nicolas, additional, Collins, Nicholas, additional, Han, Seong-Ji, additional, Chen, Erin Y., additional, Constantinides, Michael G., additional, Link, Verena M., additional, Lim, Ai Ing, additional, Enamorado, Michel, additional, Cataisson, Christophe, additional, Gil, Louis, additional, Rao, Indira, additional, Farley, Taylor K., additional, Koroleva, Galina, additional, Attig, Jan, additional, Yuspa, Stuart H., additional, Fischbach, Michael A., additional, Kassiotis, George, additional, and Belkaid, Yasmine, additional

Published
2021
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31. Determinants of anti-PD1 response and resistance in clear cell renal cell carcinoma

Author

Au, Lewis, primary, Hatipoglu, Emine, additional, de Massy, Marc Robert, additional, Litchfield, Kevin, additional, Rowan, Andrew, additional, Thompson, Rachael, additional, Schnidrig, Desiree, additional, Byrne, Fiona, additional, Beattie, Gordon, additional, Horswell, Stuart, additional, Fotiadis, Nicos, additional, Hazell, Steve, additional, Nicol, David, additional, Shepherd, Scott Thomas Colville, additional, Fendler, Annika, additional, Mason, Robert, additional, Attig, Jan, additional, Joshi, Kroopa, additional, Uddin, Imran, additional, Becker, Pablo, additional, Sunderland, Mariana Werner, additional, Akarca, Ayse, additional, Puccio, Ignazio, additional, Yang, William, additional, Lund, Tom, additional, Dhillon, Kim, additional, Vasquez, Marcos Duran, additional, Ghorani, Ehsan, additional, Xu, Hang, additional, López, José Ignacio, additional, Green, Anna, additional, Mahadeva, Ula, additional, Borg, Elaine, additional, Mitchison, Miriam, additional, Moore, David, additional, Proctor, Ian, additional, Falzon, Mary, additional, Furness, Andrew, additional, Pickering, Lisa, additional, Reading, James L., additional, Salgado, Roberto, additional, Marafioti, Teresa, additional, Jamal-Hanjani, Mariam, additional, Kassiotis, George, additional, Chain, Benny, additional, Larkin, James, additional, Swanton, Charles, additional, Quezada, Sergio A, additional, and Turajlic, Samra, additional

Published
2021
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37. Heteromeric RNP assembly at LINEs controls lineage-specific RNA processing

Author

Attig, Jan, Agostini, Federico, Gooding, Clare, Chakrabarti, Anob M., Singh, Aarti, Haberman, Nejc, Zagalak, Julian A., Emmett, Warren, Smith, Christopher W.J., Luscombe, Nicholas M., Ule, Jernej, Smith, Chris [0000-0002-2753-3398], and Apollo - University of Cambridge Repository

Subjects
exonogenesis, RNA Splicing, PTBP1, Polyadenylation, Article, Heterogeneous-Nuclear Ribonucleoproteins, splicing, Mice, Nuclear Matrix-Associated Proteins, evolution, Protein Interaction Mapping, Animals, Humans, Nucleotide Motifs, Phylogeny, 11 Medical and Health Sciences, Binding Sites, alternative polyadenylation, CLIP, cryptic exons, RNA-Binding Proteins, Exons, multivalency, 06 Biological Sciences, LINE repeats, Introns, Alternative Splicing, MATR3, Long Interspersed Nucleotide Elements, Mutation, RNA, HeLa Cells, Polypyrimidine Tract-Binding Protein, Protein Binding, Developmental Biology
Abstract

Summary Long mammalian introns make it challenging for the RNA processing machinery to identify exons accurately. We find that LINE-derived sequences (LINEs) contribute to this selection by recruiting dozens of RNA-binding proteins (RBPs) to introns. This includes MATR3, which promotes binding of PTBP1 to multivalent binding sites within LINEs. Both RBPs repress splicing and 3′ end processing within and around LINEs. Notably, repressive RBPs preferentially bind to evolutionarily young LINEs, which are located far from exons. These RBPs insulate the LINEs and the surrounding intronic regions from RNA processing. Upon evolutionary divergence, changes in RNA motifs within LINEs lead to gradual loss of their insulation. Hence, older LINEs are located closer to exons, are a common source of tissue-specific exons, and increasingly bind to RBPs that enhance RNA processing. Thus, LINEs are hubs for the assembly of repressive RBPs and also contribute to the evolution of new, lineage-specific transcripts in mammals. Video Abstract, Graphical Abstract, Highlights • Multivalent binding sites in young LINEs mainly recruit repressive RBPs • PTBP1 and MATR3 co-bind and repress RNA processing within and around young LINEs • 1-kb exclusion zone of LINEs from vicinity of exons reflects their repressive effects • Sequence-driven RBP remodeling on old LINEs drives evolution of tissue-specific exons, LINE elements recruit RNA-binding proteins to mammalian introns, influencing splicing and playing a key role in the evolution of tissue-specific exons.

Published
2018

39. Nuclear matrix protein Matrin3 regulates alternative splicing and forms overlapping regulatory networks with PTB

Author

Coelho, Miguel B., Attig, Jan, Bellora Pereyra, Nicolás, König, Julian, Hallegger, Martina, Kayikci, Melis, Eyras Jiménez, Eduardo, Ule, Jernej, Smith, Christopher, W. J., Smith, Chris [0000-0002-2753-3398], and Apollo - University of Cambridge Repository

Subjects
Matrin 3, Matrin3, Reverse Transcriptase Polymerase Chain Reaction, Gene Expression Profiling, ADN, Computational Biology, RNA-Binding Proteins, Articles, Microarray Analysis, PTB, Alternative Splicing, HEK293 Cells, Nuclear Matrix-Associated Proteins, RNA, Humans, Electrophoresis, Polyacrylamide Gel, Gene Regulatory Networks, RNA Interference, RNA, Small Interfering, Alternative splicing, DNA Primers, HeLa Cells, Polypyrimidine Tract-Binding Protein
Abstract

Matrin3 is an RNA- and DNA-binding nuclear matrix protein found to be associated with neural and muscular degenerative diseases. A number of possible functions of Matrin3 have been suggested, but no widespread role in RNA metabolism has yet been clearly demonstrated. We identified Matrin3 by its interaction with the second RRM domain of the splicing regulator PTB. Using a combination of RNAi knockdown, transcriptome profiling and iCLIP, we find that Matrin3 is a regulator of hundreds of alternative splicing events, principally acting as a splicing repressor with only a small proportion of targeted events being co-regulated by PTB. In contrast to other splicing regulators, Matrin3 binds to an extended region within repressed exons and flanking introns with no sharply defined peaks. The identification of this clear molecular function of Matrin3 should help to clarify the molecular pathology of ALS and other diseases caused by mutations of Matrin3. This work was supported by Wellcome Trust programme grants to CWJS (077877 and 092900) and by grants to EE and NB BIO2011-23920 and RNAREG (CSD2009-00080) from the Spanish Government and by the Sandra Ibarra Foundation for Cancer (FSI 2013). JA was supported by a Boehringer Ingelheim Fonds studentship

Published
2015

40. Additional file 1: Figure S1. of Insights into the design and interpretation of iCLIP experiments

Author

Haberman, Nejc, Huppertz, Ina, Attig, Jan, König, Julian, Wang, Zhen, Hauer, Christian, Hentze, Matthias, Kulozik, Andreas, Hir, Hervé Le, Tomaž Curk, Sibley, Christopher, Zarnack, Kathi, and Ule, Jernej

Abstract

Quality control of the PTBP1 and eIF4A3 iCLIP. Figure S2. CL-motifs are enriched at cDNA deletions and cDNA-starts in U2AF2-iCLIP. Figure S3. Analysis of cDNA-starts and cDNA-ends at the start of Y-tracts. Figure S4. Constrained cDNA-ends in eIF4A3 iCLIP. Figure S5. The impact of cDNA-end constraints on cDNA-starts in eIF4A3 iCLIP. Figure S6. Distribution of cDNA sizes in the studied experiments. (PDF 5.42 mb)

Published
2017
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41. Heteromeric RNP Assembly at LINEs Controls Lineage-Specific RNA Processing

Author

Attig, Jan, primary, Agostini, Federico, additional, Gooding, Clare, additional, Chakrabarti, Anob M., additional, Singh, Aarti, additional, Haberman, Nejc, additional, Zagalak, Julian A., additional, Emmett, Warren, additional, Smith, Christopher W.J., additional, Luscombe, Nicholas M., additional, and Ule, Jernej, additional

Published
2018
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43. Translational control of ERK signaling through miRNA/4EHP-directed silencing

Author

Jafarnejad, Seyed Mehdi, primary, Chapat, Clément, additional, Matta-Camacho, Edna, additional, Gelbart, Idit Anna, additional, Hesketh, Geoffrey G, additional, Arguello, Meztli, additional, Garzia, Aitor, additional, Kim, Sung-Hoon, additional, Attig, Jan, additional, Shapiro, Maayan, additional, Morita, Masahiro, additional, Khoutorsky, Arkady, additional, Alain, Tommy, additional, Gkogkas, Christos, G, additional, Stern-Ginossar, Noam, additional, Tuschl, Thomas, additional, Gingras, Anne-Claude, additional, Duchaine, Thomas F, additional, and Sonenberg, Nahum, additional

Published
2018
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46. Erratum to: Insights into the design and interpretation of iCLIP experiments

Author

Haberman, Nejc, primary, Huppertz, Ina, additional, Attig, Jan, additional, König, Julian, additional, Wang, Zhen, additional, Hauer, Christian, additional, Hentze, Matthias W., additional, Kulozik, Andreas E., additional, Le Hir, Hervé, additional, Curk, Tomaž, additional, Sibley, Christopher R., additional, Zarnack, Kathi, additional, and Ule, Jernej, additional

Published
2017
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47. Insights into the design and interpretation of iCLIP experiments

Author

Haberman, Nejc, primary, Huppertz, Ina, additional, Attig, Jan, additional, König, Julian, additional, Wang, Zhen, additional, Hauer, Christian, additional, Hentze, Matthias W., additional, Kulozik, Andreas E., additional, Le Hir, Hervé, additional, Curk, Tomaž, additional, Sibley, Christopher R., additional, Zarnack, Kathi, additional, and Ule, Jernej, additional

Published
2017
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