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1. Hydroxymethylation profile of cell-free DNA is a biomarker for early colorectal cancer.

Author

Walker, Nicolas, Rashid, Mamunur, Yu, Shirong, Bignell, Helen, Lumby, Casper, Livi, Carmen, Howell, Kate, Morley, David, Morganella, Sandro, Barrell, Daniel, Caim, Shabhonam, Gosal, Walraj, Füllgrabe, Jens, Charlesworth, Thomas, Vasquez, Louella, Ahdesmäki, Miika, Eizenga, Jordan, Prabhat, Parul, Proutski, Vitali, Murat-Onana, Marie, Greenwood, Catherine, Kirkwood, Lisa, Maisuria-Armer, Meeta, Li, Mengjie, Coats, Emma, Winfield, Victoria, MacBean, Lachlan, Stock, Toby, Tomé-Fernandez, Alice, Chan, Yat, Sheikh, Nasir, Golder, Paula, Steward, Michael, Ost, Tobias, Stewart, Douglas, Vilella, Albert, Noursalehi, Mojtaba, Paten, Benedict, Lucarelli, Debora, Mason, Joanne, Ridge, Gareth, Mellad, Jason, Shirodkar, Suman, Balasubaramanian, Shankar, and Holbrook, Joanna

Subjects
Biomarkers, Tumor, Cell-Free Nucleic Acids, Colorectal Neoplasms, DNA, Early Detection of Cancer, Humans, Sensitivity and Specificity
Abstract

Early detection of cancer will improve survival rates. The blood biomarker 5-hydroxymethylcytosine has been shown to discriminate cancer. In a large covariate-controlled study of over two thousand individual blood samples, we created, tested and explored the properties of a 5-hydroxymethylcytosine-based classifier to detect colorectal cancer (CRC). In an independent validation sample set, the classifier discriminated CRC samples from controls with an area under the receiver operating characteristic curve (AUC) of 90% (95% CI [87, 93]). Sensitivity was 55% at 95% specificity. Performance was similar for early stage 1 (AUC 89%; 95% CI [83, 94]) and late stage 4 CRC (AUC 94%; 95% CI [89, 98]). The classifier could detect CRC even when the proportion of tumor DNA in blood was undetectable by other methods. Expanding the classifier to include information about cell-free DNA fragment size and abundance across the genome led to gains in sensitivity (63% at 95% specificity), with similar overall performance (AUC 91%; 95% CI [89, 94]). We confirm that 5-hydroxymethylcytosine can be used to detect CRC, even in early-stage disease. Therefore, the inclusion of 5-hydroxymethylcytosine in multianalyte testing could improve sensitivity for the detection of early-stage cancer.

Published
2022

2. PVT1 interacts with the polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma

Author

Nylund, Patrick, Garrido-Zabala, Berta, Atienza Párraga, Alba, Vasquez, Louella, Pyl, Paul Theodor, Harinck, George Mickhael, Ma, Anqi, Jin, Jian, Öberg, Fredrik, Kalushkova, Antonia, Jernberg Wiklund, Helena, Nylund, Patrick, Garrido-Zabala, Berta, Atienza Párraga, Alba, Vasquez, Louella, Pyl, Paul Theodor, Harinck, George Mickhael, Ma, Anqi, Jin, Jian, Öberg, Fredrik, Kalushkova, Antonia, and Jernberg Wiklund, Helena

Abstract

Multiple myeloma is a heterogeneous hematological disease that originates from the bone marrow and is characterized by the monoclonal expansion of malignant plasma cells. Despite novel therapies, multiple myeloma remains clinically challenging. A common feature among patients with poor prognosis is the increased activity of the epigenetic silencer EZH2, which is the catalytic subunit of the PRC2. Interestingly, the recruitment of PRC2 lacks sequence specificity and, to date, the molecular mechanisms that define which genomic locations are destined for PRC2-mediated silencing remain unknown. The presence of a long non-coding RNA (lncRNA)-binding pocket on EZH2 suggests that lncRNA could potentially mediate PRC2 recruitment to specific genomic regions. Here, we coupled RNA immunoprecipitation sequencing, RNA-sequencing and chromatin immunoprecipitation-sequencing analysis of human multiple myeloma primary cells and cell lines to identify potential lncRNA partners to EZH2. We found that the lncRNA plasmacytoma variant translocation 1 (PVT1) directly interacts with EZH2 and is overexpressed in patients with a poor prognosis. Moreover, genes predicted to be targets of PVT1 exhibited H3K27me3 enrichment and were associated with pro-apoptotic and tumor suppressor functions. In fact, PVT1 inhibition independently promotes the expression of the PRC2 target genes ZBTB7C, RNF144A and CCDC136. Altogether, our work suggests that PVT1 is an interacting partner in PRC2-mediated silencing of tumor suppressor and pro-apoptotic genes in multiple myeloma, making it a highly interesting potential therapeutic target.

Published
2024
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3. Multifractal finite-size-scaling and universality at the Anderson transition

Author

Rodriguez, Alberto, Vasquez, Louella J., Slevin, Keith, and Roemer, Rudolf A.

Subjects
Condensed Matter - Disordered Systems and Neural Networks
Abstract

We describe a new multifractal finite size scaling (MFSS) procedure and its application to the Anderson localization-delocalization transition. MFSS permits the simultaneous estimation of the critical parameters and the multifractal exponents. Simulations of system sizes up to L^3=120^3 and involving nearly 10^6 independent wavefunctions have yielded unprecedented precision for the critical disorder W_c=16.530 (16.524,16.536) and the critical exponent nu=1.590 (1.579,1.602). We find that the multifractal exponents Delta_q exhibit a previously predicted symmetry relation and we confirm the non-parabolic nature of their spectrum. We explain in detail the MFSS procedure first introduced in our Letter [Phys. Rev. Lett. 105, 046403 (2010)] and, in addition, we show how to take account of correlations in the simulation data. The MFSS procedure is applicable to any continuous phase transition exhibiting multifractal fluctuations in the vicinity of the critical point., Comment: 18 pages, 13 figures

Published
2011
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4. Critical parameters from generalised multifractal analysis at the Anderson transition

Author

Rodriguez, Alberto, Vasquez, Louella J., Slevin, Keith, and Römer, Rudolf A.

Subjects
Condensed Matter - Disordered Systems and Neural Networks
Abstract

We propose a generalization of multifractal analysis that is applicable to the critical regime of the Anderson localization-delocalization transition. The approach reveals that the behavior of the probability distribution of wavefunction amplitudes is sufficient to characterize the transition. In combination with finite-size scaling, this formalism permits the critical parameters to be estimated without the need for conductance or other transport measurements. Applying this method to high-precision data for wavefunction statistics obtained by exact diagonalization of the three-dimensional Anderson model, we estimate the critical exponent $\nu=1.58\pm 0.03$., Comment: 5 pages, 3 figures, 2 tables

Published
2010
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5. Genetic perturbation of PU.1 binding and chromatin looping at neutrophil enhancers associates with autoimmune disease

Author

Watt, Stephen, Vasquez, Louella, Walter, Klaudia, Mann, Alice L., Kundu, Kousik, Chen, Lu, Sims, Ying, Ecker, Simone, Burden, Frances, Farrow, Samantha, Farr, Ben, Iotchkova, Valentina, Elding, Heather, Mead, Daniel, Tardaguila, Manuel, Ponstingl, Hannes, Richardson, David, Datta, Avik, Flicek, Paul, Clarke, Laura, Downes, Kate, Pastinen, Tomi, Fraser, Peter, Frontini, Mattia, Javierre, Biola-Maria, Spivakov, Mikhail, and Soranzo, Nicole

Published
2021
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6. Quantification and Profiling of Early and Late Differentiation Stage T Cells in Mantle Cell Lymphoma Reveals Immunotherapeutic Targets in Subsets of Patients.

Author

Lokhande, Lavanya, Nilsson, Daniel, de Matos Rodrigues, Joana, Hassan, May, Olsson, Lina M., Pyl, Paul-Theodor, Vasquez, Louella, Porwit, Anna, Gerdtsson, Anna Sandström, Jerkeman, Mats, and Ek, Sara

Subjects
NON-Hodgkin's lymphoma, T cells, RESEARCH funding, CANCER patients, DESCRIPTIVE statistics, GENE expression, DEEP learning, PROTEOMICS, TUMOR classification, CELL differentiation, T helper cells, CELL receptors, IMMUNOSUPPRESSION
Abstract

Simple Summary: In our study, we investigated immune regulation in a subtype of lymphoma called mantle cell lymphoma (MCL). Our goal was to understand how different types of immune cells, specifically T cells, behave in MCL. To do this, we combined image analysis and a technology called digital spatial profiling. We looked at tumor tissue from 102 MCL patients and analyzed different T-cell subsets. Interestingly, we found that late-stage differentiated T cells (CD57+) were more common in tumor-rich areas. These T cells also showed an increased expression of immune suppressive markers. We identified potential targets for treatment, such as CD47, IDO1, and CTLA-4. Additionally, we found that patients with sparse T-cell infiltration had an increased amount of GITR, which tentatively can be therapeutically targeted. Our findings shed light on previously unknown features of T-cell behavior in MCL. With the aim to advance the understanding of immune regulation in MCL and to identify targetable T-cell subsets, we set out to combine image analysis and spatial omic technology focused on both early and late differentiation stages of T cells. MCL patient tissue (n = 102) was explored using image analysis and GeoMx spatial omics profiling of 69 proteins and 1812 mRNAs. Tumor cells, T helper (TH) cells and cytotoxic (TC) cells of early (CD57−) and late (CD57+) differentiation stage were analyzed. An image analysis workflow was developed based on fine-tuned Cellpose models for cell segmentation and classification. TC and CD57+ subsets of T cells were enriched in tumor-rich compared to tumor-sparse regions. Tumor-sparse regions had a higher expression of several key immune suppressive proteins, tentatively controlling T-cell expansion in regions close to the tumor. We revealed that T cells in late differentiation stages (CD57+) are enriched among MCL infiltrating T cells and are predictive of an increased expression of immune suppressive markers. CD47, IDO1 and CTLA-4 were identified as potential targets for patients with T-cell-rich MCL TIME, while GITR might be a feasible target for MCL patients with sparse T-cell infiltration. In subgroups of patients with a high degree of CD57+ TC-cell infiltration, several immune checkpoint inhibitors, including TIGIT, PD-L1 and LAG3 were increased, emphasizing the immune-suppressive features of this highly differentiated T-cell subset not previously described in MCL. [ABSTRACT FROM AUTHOR]

Published
2024
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7. Multifractal analysis with the probability density function at the three-dimensional Anderson transition

Author

Rodriguez, Alberto, Vasquez, Louella J., and Roemer, Rudolf A.

Subjects
Condensed Matter - Disordered Systems and Neural Networks
Abstract

The probability density function (PDF) for critical wavefunction amplitudes is studied in the three-dimensional Anderson model. We present a formal expression between the PDF and the multifractal spectrum f(alpha) in which the role of finite-size corrections is properly analyzed. We show the non-gaussian nature and the existence of a symmetry relation in the PDF. From the PDF, we extract information about f(alpha) at criticality such as the presence of negative fractal dimensions and we comment on the possible existence of termination points. A PDF-based multifractal analysis is hence shown to be a valid alternative to the standard approach based on the scaling of general inverse participation ratios., Comment: 4 pages, 7 figures

Published
2008
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8. Optimisation of multifractal analysis using box-size scaling

Author

Rodriguez, Alberto, Vasquez, Louella J., and Roemer, Rudolf A.

Subjects
Condensed Matter - Disordered Systems and Neural Networks
Abstract

We study various box-size scaling techniques to obtain the multifractal properties, in terms of the singularity spectrum f(alpha), of the critical eigenstates at the metal-insulator transition within the 3-D Anderson model of localisation. The typical and ensemble averaged scaling laws of the generalised inverse participation ratios are considered. In pursuit of a numerical optimisation of the box-scaling technique we discuss different box-partitioning schemes including cubic and non-cubic boxes, use of periodic boundary conditions to enlarge the system and single and multiple origins for the partitioning grid are also implemented. We show that the numerically most reliable method is to divide a system of linear size L equally into cubic boxes of size l for which L/l is an integer. This method is the least numerically expensive while having a good reliability., Comment: 6 pages, 4 figures

Published
2008
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9. Multifractal analysis of the metal-insulator transition in the 3D Anderson model I: Symmetry relation under typical averaging

Author

Vasquez, Louella J., Rodriguez, Alberto, and Roemer, Rudolf A.

Subjects
Condensed Matter - Disordered Systems and Neural Networks
Abstract

The multifractality of the critical eigenstate at the metal to insulator transition (MIT) in the three-dimensional Anderson model of localization is characterized by its associated singularity spectrum f(alpha). Recent works in 1D and 2D critical systems have suggested an exact symmetry relation in f(alpha). Here we show the validity of the symmetry at the Anderson MIT with high numerical accuracy and for very large system sizes. We discuss the necessary statistical analysis that supports this conclusion. We have obtained the f(alpha) from the box- and system-size scaling of the typical average of the generalized inverse participation ratios. We show that the best symmetry in f(alpha) for typical averaging is achieved by system-size scaling, following a strategy that emphasizes using larger system sizes even if this necessitates fewer disorder realizations., Comment: 10 pages, 12 figures

Published
2008
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10. Multifractal analysis of the metal-insulator transition in the 3D Anderson model II: Symmetry relation under ensemble averaging

Author

Rodriguez, Alberto, Vasquez, Louella J., and Roemer, Rudolf A.

Subjects
Condensed Matter - Disordered Systems and Neural Networks
Abstract

We study the multifractal analysis (MFA) of electronic wavefunctions at the localisation-delocalisation transition in the 3D Anderson model for very large system sizes up to $240^3$. The singularity spectrum $f(\alpha)$ is numerically obtained using the \textsl{ensemble average} of the scaling law for the generalized inverse participation ratios $P_q$, employing box-size and system-size scaling. The validity of a recently reported symmetry law [Phys. Rev. Lett. 97, 046803 (2006)] for the multifractal spectrum is carefully analysed at the metal-insulator transition (MIT). The results are compared to those obtained using different approaches, in particular the typical average of the scaling law. System-size scaling with ensemble average appears as the most adequate method to carry out the numerical MFA. Some conjectures about the true shape of $f(\alpha)$ in the thermodynamic limit are also made., Comment: 10 pages, 13 figures

Published
2008
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11. High precision multifractal analysis in the 3D Anderson model of localisation

Author

Vasquez, Louella J.

Subjects
530.15, QA Mathematics, QC Physics
Abstract

This work presents a large scale multifractal analysis of the electronic state in the vicinity of the localisation-delocalisation transition in the three-dimensional Anderson model of localisation using high-precision data and very large system sizes of up to L3 = 2403. The multifractal analysis is implemented using box- and system- size scaling of the generalized inverse participation ratios employing typical and ensemble averaging techniques. The statistical analysis in this study has shown that in the thermodynamic limit a proposed symmetry relation in the multifractal exponents is true for the 3D Anderson model in the orthogonal universality class. Better agreement with the symmetry is found when using system-size scaling with ensemble averaging in which a more complete picture of the multifractal spectrum f(α) is also obtained. A complete profile of f(α) has negative fractal dimensions and shows the contributions coming from the tails of the distribution. Various boxpartitioning approaches have been carefully studied such as the use of cubic and non-cubic boxes, periodic boundary conditions to enlarge the system, and single and multiple origins in the partitioning grid. The most reliable method is equal partitioning of a system into cubic boxes which has also been shown to be the least numerically expensive. Furthermore, this work gives an expression relating f(α) and the probability density function (PDF) of wavefunction intensities. The relation which contains a finite-size correction provides an alternative and simpler method to obtain f(α) directly from the PDF in which f(α) is interpreted as the scaleinvariant distribution at criticality. Finally, a generalization of standard multifractal analysis which is applicable to the critical regime and not just at the critical point is presented here. Using this generalization together with finite-size scaling analysis, estimates of critical disorder and critical exponent based on exact diagonalization have been obtained that are in excellent agreement, supporting for the first time previous results of transfer matrix calculations.

Published
2010

12. PVT1 interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma

Author

Nylund, Patrick, primary, Garrido-Zabala, Berta, additional, Párraga, Alba Atienza, additional, Vasquez, Louella, additional, Pyl, Paul Theodor, additional, Harinck, George Mickhael, additional, Ma, Anqi, additional, Jin, Jian, additional, Öberg, Fredrik, additional, Kalushkova, Antonia, additional, and Wiklund, Helena Jernberg, additional

Published
2023
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13. The Allelic Landscape of Human Blood Cell Trait Variation and Links to Common Complex Disease

Author

Astle, William J., Elding, Heather, Jiang, Tao, Allen, Dave, Ruklisa, Dace, Mann, Alice L., Mead, Daniel, Bouman, Heleen, Riveros-Mckay, Fernando, Kostadima, Myrto A., Lambourne, John J., Sivapalaratnam, Suthesh, Downes, Kate, Kundu, Kousik, Bomba, Lorenzo, Berentsen, Kim, Bradley, John R., Daugherty, Louise C., Delaneau, Olivier, Freson, Kathleen, Garner, Stephen F., Grassi, Luigi, Guerrero, Jose, Haimel, Matthias, Janssen-Megens, Eva M., Kaan, Anita, Kamat, Mihir, Kim, Bowon, Mandoli, Amit, Marchini, Jonathan, Martens, Joost H.A., Meacham, Stuart, Megy, Karyn, O’Connell, Jared, Petersen, Romina, Sharifi, Nilofar, Sheard, Simon M., Staley, James R., Tuna, Salih, van der Ent, Martijn, Walter, Klaudia, Wang, Shuang-Yin, Wheeler, Eleanor, Wilder, Steven P., Iotchkova, Valentina, Moore, Carmel, Sambrook, Jennifer, Stunnenberg, Hendrik G., Di Angelantonio, Emanuele, Kaptoge, Stephen, Kuijpers, Taco W., Carrillo-de-Santa-Pau, Enrique, Juan, David, Rico, Daniel, Valencia, Alfonso, Chen, Lu, Ge, Bing, Vasquez, Louella, Kwan, Tony, Garrido-Martín, Diego, Watt, Stephen, Yang, Ying, Guigo, Roderic, Beck, Stephan, Paul, Dirk S., Pastinen, Tomi, Bujold, David, Bourque, Guillaume, Frontini, Mattia, Danesh, John, Roberts, David J., Ouwehand, Willem H., Butterworth, Adam S., and Soranzo, Nicole

Published
2016
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14. Genetic Drivers of Epigenetic and Transcriptional Variation in Human Immune Cells

Author

Chen, Lu, Ge, Bing, Casale, Francesco Paolo, Vasquez, Louella, Kwan, Tony, Garrido-Martín, Diego, Watt, Stephen, Yan, Ying, Kundu, Kousik, Ecker, Simone, Datta, Avik, Richardson, David, Burden, Frances, Mead, Daniel, Mann, Alice L., Fernandez, Jose Maria, Rowlston, Sophia, Wilder, Steven P., Farrow, Samantha, Shao, Xiaojian, Lambourne, John J., Redensek, Adriana, Albers, Cornelis A., Amstislavskiy, Vyacheslav, Ashford, Sofie, Berentsen, Kim, Bomba, Lorenzo, Bourque, Guillaume, Bujold, David, Busche, Stephan, Caron, Maxime, Chen, Shu-Huang, Cheung, Warren, Delaneau, Oliver, Dermitzakis, Emmanouil T., Elding, Heather, Colgiu, Irina, Bagger, Frederik O., Flicek, Paul, Habibi, Ehsan, Iotchkova, Valentina, Janssen-Megens, Eva, Kim, Bowon, Lehrach, Hans, Lowy, Ernesto, Mandoli, Amit, Matarese, Filomena, Maurano, Matthew T., Morris, John A., Pancaldi, Vera, Pourfarzad, Farzin, Rehnstrom, Karola, Rendon, Augusto, Risch, Thomas, Sharifi, Nilofar, Simon, Marie-Michelle, Sultan, Marc, Valencia, Alfonso, Walter, Klaudia, Wang, Shuang-Yin, Frontini, Mattia, Antonarakis, Stylianos E., Clarke, Laura, Yaspo, Marie-Laure, Beck, Stephan, Guigo, Roderic, Rico, Daniel, Martens, Joost H.A., Ouwehand, Willem H., Kuijpers, Taco W., Paul, Dirk S., Stunnenberg, Hendrik G., Stegle, Oliver, Downes, Kate, Pastinen, Tomi, and Soranzo, Nicole

Published
2016
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15. Correction to: Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome

Author

Cheung, Warren A., Shao, Xiaojian, Morin, Andréanne, Siroux, Valérie, Kwan, Tony, Ge, Bing, Aïssi, Dylan, Chen, Lu, Vasquez, Louella, Allum, Fiona, Guénard, Frédéric, Bouzigon, Emmanuelle, Simon, Marie-Michelle, Boulier, Elodie, Redensek, Adriana, Watt, Stephen, Datta, Avik, Clarke, Laura, Flicek, Paul, Mead, Daniel, Paul, Dirk S., Beck, Stephan, Bourque, Guillaume, Lathrop, Mark, Tchernof, André, Vohl, Marie-Claude, Demenais, Florence, Pin, Isabelle, Downes, Kate, Stunnenberg, Hendrick G., Soranzo, Nicole, Pastinen, Tomi, and Grundberg, Elin

Published
2019
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17. Correction: Corrigendum: Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming

Author

Moreau, Thomas, Evans, Amanda L., Vasquez, Louella, Tijssen, Marloes R., Yan, Ying, Trotter, Matthew W., Howard, Daniel, Colzani, Maria, Arumugam, Meera, Wu, Wing Han, Dalby, Amanda, Lampela, Riina, Bouet, Guenaelle, Hobbs, Catherine M., Pask, Dean C., Payne, Holly, Ponomaryov, Tatyana, Brill, Alexander, Soranzo, Nicole, Ouwehand, Willem H., Pedersen, Roger A., and Ghevaert, Cedric

Published
2017
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18. Environmentally induced DNA methylation is inherited across generations in an aquatic keystone species

Author

Feiner, Nathalie, Radersma, Reinder, Vasquez, Louella, Ringner, Markus, Nystedt, Björn, Raine, Amanda, Tobi, Elmar W., Heijmans, Bastiaan T., Uller, Tobias, Feiner, Nathalie, Radersma, Reinder, Vasquez, Louella, Ringner, Markus, Nystedt, Björn, Raine, Amanda, Tobi, Elmar W., Heijmans, Bastiaan T., and Uller, Tobias

Abstract

Transgenerational inheritance of environmentally induced epigenetic marks can have significant impacts on eco-evolutionary dynamics, but the phenomenon remains controversial in ecological model systems. We used whole-genome bisulfite sequencing of individual water fleas (Daphnia magna) to assess whether environmentally induced DNA methylation is transgenerationally inherited. Genetically identical females were exposed to one of three natural stressors, or a de-methylating drug, and their offspring were propagated clonally for four generations under control conditions. We identified between 70 and 225 differentially methylated CpG positions (DMPs) in F1 individuals whose mothers were exposed to a natural stressor. Roughly half of these environmentally induced DMPs persisted until generation F4. In contrast, treatment with the drug demonstrated that pervasive hypomethylation upon exposure is reset almost completely after one generation. These results suggest that environmentally induced DNA methylation is non-random and stably inherited across generations in Daphnia, making epigenetic inheritance a putative factor in the eco-evolutionary dynamics of freshwater communities.

Published
2022
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20. Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome

Author

Cheung, Warren A., Shao, Xiaojian, Morin, Andréanne, Siroux, Valérie, Kwan, Tony, Ge, Bing, Aïssi, Dylan, Chen, Lu, Vasquez, Louella, Allum, Fiona, Guénard, Frédéric, Bouzigon, Emmanuelle, Simon, Marie-Michelle, Boulier, Elodie, Redensek, Adriana, Watt, Stephen, Datta, Avik, Clarke, Laura, Flicek, Paul, Mead, Daniel, Paul, Dirk S., Beck, Stephan, Bourque, Guillaume, Lathrop, Mark, Tchernof, André, Vohl, Marie-Claude, Demenais, Florence, Pin, Isabelle, Downes, Kate, Stunnenberg, Hendrick G., Soranzo, Nicole, Pastinen, Tomi, and Grundberg, Elin

Published
2017
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21. Environmentally induced DNA methylation is inherited across generations in water fleas (Daphnia magna)

Author

Feiner, Nathalie, Radersma, Reinder, Vasquez, Louella, Ringnér, Markus, Nystedt, Björn, Raine, Amanda, Tobi, Elmar W., Heijmans, Bastiaan T., Uller, Tobias, Feiner, Nathalie, Radersma, Reinder, Vasquez, Louella, Ringnér, Markus, Nystedt, Björn, Raine, Amanda, Tobi, Elmar W., Heijmans, Bastiaan T., and Uller, Tobias

Abstract

Environmental stress can result in epigenetic modifications that are passed down several generations. The transgenerational persistence of environmentally induced variation in DNA methylation remains controversial, and has so far been little investigated in invertebrates. Here, we show that four different environmental stressors are capable of inducing changes in DNA methylation that persist for at least four generations in the water flea Daphnia magna. Genetically identical females from the same brood were exposed to either a control treatment or one of four environmental stressors - high temperature, zinc, toxic cyanobacteria, and the methylation-inhibitor 5-azacytidine. Replicated and genetically identical lines from each of the stressed mothers were maintained under control conditions for four subsequent generations, and three individual Daphnia per group of generation F1, F2 and F4 were subjected to whole-genome bisulfite sequencing. We identified significant differences between F1 individuals from the environmentally stressed lines - exposed as germ cells - and the controls. As expected, 5-azacytidine caused extensive hypomethylation in the F1 generation, but nearly all of the de-methylated sites were re-methylated already in the F2 generation. Fewer differentially methylated sites were observed in the F1 of mothers exposed to high temperature, zinc, or toxic cyanobacteria. However, between 49% and 57% of these environmentally induced methylation variants in F1 persisted until the F4 generation. Both environmentally induced (maternal effects on F1) and transgenerational persistent (stable until F4) DMCs were predominantly found in exons. These results suggest that environmentally induced DNA methylation is non-random and persistent across generations, making it a putative factor in ecological and evolutionary change in water flea populations.

Published
2021

22. Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming

Author

Moreau, Thomas, Evans, Amanda L., Vasquez, Louella, Tijssen, Marloes R., Yan, Ying, Trotter, Matthew W., Howard, Daniel, Colzani, Maria, Arumugam, Meera, Wu, Wing Han, Dalby, Amanda, Lampela, Riina, Bouet, Guenaelle, Hobbs, Catherine M., Pask, Dean C., Payne, Holly, Ponomaryov, Tatyana, Brill, Alexander, Soranzo, Nicole, Ouwehand, Willem H., Pedersen, Roger A., Ghevaert, Cedric, Soranzo, Nicole [0000-0003-1095-3852], and Apollo - University of Cambridge Repository

Subjects
Blood Platelets, Pluripotent Stem Cells, Science, Genetic Vectors, Green Fluorescent Proteins, Cell Culture Techniques, Article, Genes, Reporter, Transduction, Genetic, Proto-Oncogene Proteins, Basic Helix-Loop-Helix Transcription Factors, Humans, GATA1 Transcription Factor, Transgenes, T-Cell Acute Lymphocytic Leukemia Protein 1, Cell Proliferation, Cryopreservation, Proto-Oncogene Protein c-fli-1, Lentivirus, Cell Differentiation, Cellular Reprogramming, Microarray Analysis, Corrigenda, Gene Expression Regulation, Megakaryocytes, Signal Transduction
Abstract

The production of megakaryocytes (MKs)—the precursors of blood platelets—from human pluripotent stem cells (hPSCs) offers exciting clinical opportunities for transfusion medicine. Here we describe an original approach for the large-scale generation of MKs in chemically defined conditions using a forward programming strategy relying on the concurrent exogenous expression of three transcription factors: GATA1, FLI1 and TAL1. The forward programmed MKs proliferate and differentiate in culture for several months with MK purity over 90% reaching up to 2 × 105 mature MKs per input hPSC. Functional platelets are generated throughout the culture allowing the prospective collection of several transfusion units from as few as 1 million starting hPSCs. The high cell purity and yield achieved by MK forward programming, combined with efficient cryopreservation and good manufacturing practice (GMP)-compatible culture, make this approach eminently suitable to both in vitro production of platelets for transfusion and basic research in MK and platelet biology., Platelets are blood circulating corpuscles generated from megakaryocytes that initiate wound healing. Here, Moreau et al. describe a way of producing large quantities of megakaryocytes from human pluripotent stem cells in the laboratory, moving us a step closer to manufacturing transfusion products.

Published
2016

23. Additional file 5: Figure S1. of Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome

Author

Cheung, Warren, Xiaojian Shao, Morin, Andréanne, Siroux, Valérie, Kwan, Tony, Ge, Bing, Aïssi, Dylan, Chen, Lu, Vasquez, Louella, Allum, Fiona, Guénard, Frédéric, Bouzigon, Emmanuelle, Marie-Michelle Simon, Boulier, Elodie, Redensek, Adriana, Watt, Stephen, Avik Datta, Clarke, Laura, Flicek, Paul, Mead, Daniel, Paul, Dirk, Beck, Stephan, Bourque, Guillaume, Lathrop, Mark, Tchernof, André, Marie-Claude Vohl, Demenais, Florence, Pin, Isabelle, Downes, Kate, Stunnenberg, Hendrick, Soranzo, Nicole, Pastinen, Tomi, and Grundberg, Elin

Abstract

Validation using 450 k array. Figure S2. Detailed description of samples per cell type. (PDF 440 kb)

Published
2017
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24. Additional file 9: of Functional variation in allelic methylomes underscores a strong genetic contribution and reveals novel epigenetic alterations in the human epigenome

Author

Cheung, Warren, Xiaojian Shao, Morin, Andréanne, Siroux, Valérie, Kwan, Tony, Ge, Bing, Aïssi, Dylan, Chen, Lu, Vasquez, Louella, Allum, Fiona, Guénard, Frédéric, Bouzigon, Emmanuelle, Marie-Michelle Simon, Boulier, Elodie, Redensek, Adriana, Watt, Stephen, Avik Datta, Clarke, Laura, Flicek, Paul, Mead, Daniel, Paul, Dirk, Beck, Stephan, Bourque, Guillaume, Lathrop, Mark, Tchernof, André, Marie-Claude Vohl, Demenais, Florence, Pin, Isabelle, Downes, Kate, Stunnenberg, Hendrick, Soranzo, Nicole, Pastinen, Tomi, and Grundberg, Elin

Abstract

ChromHMM state report. This file is the report generated after machine learning of the eight-state ChromHMM model. (PDF 261 kb)

Published
2017
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25. High precision multifractal analysis in the 3D Anderson model of localisation

Author

Vasquez, Louella J.

Subjects
QA, QC
Abstract

This work presents a large scale multifractal analysis of the electronic state\ud in the vicinity of the localisation-delocalisation transition in the three-dimensional\ud Anderson model of localisation using high-precision data and very large system\ud sizes of up to L3 = 2403. The multifractal analysis is implemented using box- and\ud system- size scaling of the generalized inverse participation ratios employing typical\ud and ensemble averaging techniques. The statistical analysis in this study has shown\ud that in the thermodynamic limit a proposed symmetry relation in the multifractal\ud exponents is true for the 3D Anderson model in the orthogonal universality class.\ud Better agreement with the symmetry is found when using system-size scaling with\ud ensemble averaging in which a more complete picture of the multifractal spectrum\ud f(α) is also obtained. A complete profile of f(α) has negative fractal dimensions\ud and shows the contributions coming from the tails of the distribution. Various boxpartitioning\ud approaches have been carefully studied such as the use of cubic and\ud non-cubic boxes, periodic boundary conditions to enlarge the system, and single\ud and multiple origins in the partitioning grid. The most reliable method is equal\ud partitioning of a system into cubic boxes which has also been shown to be the least\ud numerically expensive. Furthermore, this work gives an expression relating f(α)\ud and the probability density function (PDF) of wavefunction intensities. The relation\ud which contains a finite-size correction provides an alternative and simpler method\ud to obtain f(α) directly from the PDF in which f(α) is interpreted as the scaleinvariant\ud distribution at criticality. Finally, a generalization of standard multifractal\ud analysis which is applicable to the critical regime and not just at the critical point is\ud presented here. Using this generalization together with finite-size scaling analysis,\ud estimates of critical disorder and critical exponent based on exact diagonalization\ud have been obtained that are in excellent agreement, supporting for the first time\ud previous results of transfer matrix calculations.

26. Dual DNMT/EZH2 inhibition synergistically re-configures the epigenome and promotes anti-tumour effects in multiple myeloma

Author

Atienza Párraga, Alba, Nylund, Patrick, Diamanti, Klev, Garrido-Zabala, Berta, Vasquez, Louella, Pyl, Paul Theodor, Raykova, Doroteya, Skaftason, Aron, Ma, Anqi, Jin, Jian, Martín-Subero, José Ignacio, Öberg, Fredrik, Komorowski, Jan, Jernberg Wiklund, Helena, Kalushkova, Antonia, Atienza Párraga, Alba, Nylund, Patrick, Diamanti, Klev, Garrido-Zabala, Berta, Vasquez, Louella, Pyl, Paul Theodor, Raykova, Doroteya, Skaftason, Aron, Ma, Anqi, Jin, Jian, Martín-Subero, José Ignacio, Öberg, Fredrik, Komorowski, Jan, Jernberg Wiklund, Helena, and Kalushkova, Antonia

27. Dual targeting of G9a and DNMTs effectively induces tumour cell death in multiple myeloma

Author

Nylund, Patrick, Garrido-Zabala, Berta, Atienza Párraga, Alba, Vasquez, Louella, Jacob, Jim, Martín-Subero, José Ignacio, Öberg, Fredrik, Kalushkova, Antonia, Jernberg Wiklund, Helena, Nylund, Patrick, Garrido-Zabala, Berta, Atienza Párraga, Alba, Vasquez, Louella, Jacob, Jim, Martín-Subero, José Ignacio, Öberg, Fredrik, Kalushkova, Antonia, and Jernberg Wiklund, Helena

28. Corrigendum: Large-scale production of megakaryocytes from human pluripotent stem cells by chemically defined forward programming.

Author

Moreau, Thomas, Evans, Amanda L., Vasquez, Louella, Tijssen, Marloes R., Yan, Ying, Trotter, Matthew W., Howard, Daniel, Colzani, Maria, Arumugam, Meera, Wu, Wing Han, Dalby, Amanda, Lampela, Riina, Bouet, Guenaelle, Hobbs, Catherine M., Pask, Dean C., Payne, Holly, Ponomaryov, Tatyana, Brill, Alexander, Soranzo, Nicole, and Ouwehand, Willem H.

Abstract

This corrects the article DOI: 10.1038/ncomms11208 [ABSTRACT FROM AUTHOR]

Published
2017
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29. PVT1 interacts with polycomb repressive complex 2 to suppress genomic regions with pro-apoptotic and tumour suppressor functions in multiple myeloma.

Author

Nylund P, Garrido-Zabala B, Párraga AA, Vasquez L, Pyl PT, Harinck GM, Ma A, Jin J, Öberg F, Kalushkova A, and Wiklund HJ

Subjects
Humans, Polycomb Repressive Complex 2 genetics, Polycomb Repressive Complex 2 metabolism, Enhancer of Zeste Homolog 2 Protein genetics, Cell Line, Tumor, Genomics, Intracellular Signaling Peptides and Proteins, Multiple Myeloma drug therapy, RNA, Long Noncoding genetics
Abstract

Multiple myeloma is a heterogeneous hematological disease that originates from the bone marrow and is characterized by the monoclonal expansion of malignant plasma cells. Despite novel therapies, multiple myeloma remains clinically challenging. A common feature among patients with poor prognosis is the increased activity of the epigenetic silencer EZH2, which is the catalytic subunit of the PRC2. Interestingly, the recruitment of PRC2 lacks sequence specificity and, to date, the molecular mechanisms that define which genomic locations are destined for PRC2-mediated silencing remain unknown. The presence of a long non-coding RNA (lncRNA)-binding pocket on EZH2 suggests that lncRNA could potentially mediate PRC2 recruitment to specific genomic regions. Here, we coupled RNA immunoprecipitation sequencing, RNA-sequencing and chromatin immunoprecipitation-sequencing analysis of human multiple myeloma primary cells and cell lines to identify potential lncRNA partners to EZH2. We found that the lncRNA plasmacytoma variant translocation 1 (PVT1) directly interacts with EZH2 and is overexpressed in patients with a poor prognosis. Moreover, genes predicted to be targets of PVT1 exhibited H3K27me3 enrichment and were associated with pro-apoptotic and tumor suppressor functions. In fact, PVT1 inhibition independently promotes the expression of the PRC2 target genes ZBTB7C, RNF144A and CCDC136. Altogether, our work suggests that PVT1 is an interacting partner in PRC2-mediated silencing of tumor suppressor and pro-apoptotic genes in multiple myeloma, making it a highly interesting potential therapeutic target.

Published
2024
Full Text
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