Understanding tissue complexity by Spatially resolved omics strategies

Marco Antonio MENDOZA, PhD / HDR; Chargé de recherche CNRS

Head of the team SysFate; Laboratory of Systems and Synthetic Biology (LiSSB); UMR8030, French National Sequencing Center Genoscope

Abstract

One of the current challenges of systems biology is the study of complex living systems by evaluation of the various gene programs that define organ/tissue architecture. Indeed, accessing the gene programs in tissues has, until recently, been performed by global (bulk) gene expression analyses but recent advances in single-cell transcriptomics has made it possible to move from an ‘‘average view’’ toward single-cell gene-program readouts (Birnbaum, 2018). However, cell dissociation by enzymatic methods, necessary for single-cell assays, tends to modify transcriptional patterns (van den Brink et al., 2017), it destroys at least a fraction of the cells that compose the tissue and does not conserve tissue architecture.

Recent developments in spatially resolved transcriptomics (SrT) (Liu et al., 2020; Rodriques et al., 2019; Stahl et al., 2016) have made it possible to circumvent the aforementioned technical issues related to single-cell assays, notably the capacity to conserve the spatial architecture, essential for heterogeneous tissue analysis.

During this seminar, I will provide an overview of the strategies available for studying tissue complexity, notably those based on the use of physical supports (DNA arrays or microfluidic channels ), then I will present our developments for properly Inferring biologically relevant molecular tissue substructures, and finally I will discuss our current developments of spatial omics strategies for capturing transcription signatures from multiple consecutive sections, as a way to generate 3-dimesional tissue maps, but also our recent progress in spatial epigenomics profiling, thanks to our in-house DNA arrays manufacturing platform.

Publications 

Publications (>2680 citations; h-index 19; i10-index: 26).

• Salim Megat, Christine Marques, Marina Hernan Godoy, Chantal Sellier, Geoffrey Stuart-Lopez, Sylvie Dirrig- Grosch, Charlotte Gorin, Aurore Brunet, Mathieu Fischer, Celine Keime, Pascal Kessler, Marco Antonio Mendoza-Parra, Sonja W Scholz, Luigi Ferrucci, Albert Ludolph, Bryan Traynor, Adriano Chio, Luc Dupuis, Caroline Rouaux; CREB3 gain of function variants protect against ALS; Preprint October 11th 2024; BioRxiv
• Maria B. Goncalves, Yue Wu, Earl Clarke, John Grist, Julien Moehlin, Marco Antonio Mendoza-Parra, Carl Hobbs, Barret Kalindjian, Henry Fok, Adrian Mander, Hana Hassanin, Daryl Bendel, J¨org T¨aubel, Tim Mant, Thomas Carlstedt, Julian Jack and Jonathan P. T. Corcoran. C286, an orally available retinoic acid receptor β agonist drug, regulates multiple pathways to achieve spinal cord injury repair. Frontiers Molecular NeuroScience. 2024; 20th August 2024.
• Koshy AM, Mendoza-Parra MA. Retinoids: Mechanisms of Action in Neuronal Cell Fate Acquisition. 2023; 13(12):2279. https://doi.org/10.3390/life13122279.
• Antoine Aubert, Maria Grazia Mendoza-Ferri, Aude Bramoulle, François Stüder, Bruno Maria Colombo, Marco Antonio Mendoza-Parra; PSEN1-M146V and PSEN1-A246E mutations associated with Alzheimer’s disease impair proper microglia differentiation; Preprint October 10, 2023; BioRxv.
• Gwendoline Lozachmeur, Aude Bramoulle, Antoine Aubert, François Stüder, Julien Moehlin, Lucie Madrange, Frank Yates, Jean-Philippe Deslys and Marco Antonio Mendoza-Parra; 3-dimensional molecular cartography of human cerebral organoids revealed by double-barcoded spatial transcriptomics; Cell Reports Methods; September 1 2023.
• Aysis Koshy, Elodie Mathieux, François Stüder, Aude Bramoulle, Michele Lieb, Bruno Maria Colombo, Hinrich Gronemeyer, Marco Antonio Mendoza-Parra; Synergistic activation of RARb and RARg nuclear receptors restores cell specialization during stem cell differentiation by hijacking RARa-controlled programs; Life Science Alliance; November 29 2022
• Huyghe, G. Furlan, J. Schroeder, E. Cascales, A. Trajkova, M. Ruel, F. Stüder, M. Larcombe, Y. Bo Yang Sun,

1. Mugnier, L. De Matteo, A. Baygin, J. Wang, Y Yu, N. Rama, B. Gibert, J. Kielbassa, L. Tonon, P. Wajda, N. Gadot, M. Brevet, M. Siouda, P. Mulligan, R. Dante, P. Liu, H. Gronemeyer, M. Mendoza-Parra, J.M. Polo and
2. Lavial; Comparative roadmaps of reprogramming and oncogenic transformation identify Bcl11b and Atoh8 as broad regulators of cellular plasticity; Nature Cell Biology; September 8 2022.

• Julien Moehlin, Bastien Mollet, Bruno Maria Colombo, Marco A. Mendoza-Parra. Inferring biologically relevant molecular tissue substructures by agglomerative clustering of digitized spatial transcriptomes with multilayer; Cell Systems; May 7 2021.
• Julien Moehlin, Aysis Koshy, François Stüder and Marco Antonio Mendoza-Parra; Protocol for using MULTILAYER to reveal molecular tissue substructures from digitized spatial transcriptomes; STAR Protocols; September 17 2021.
• Aubert, Antoine, François Stüder, Bruno M. Colombo, and Marco A. Mendoza-Parra; A Core Transcription Regulatory Circuitry Defining Microglia Cell Identity Inferred from the Reanalysis of Multiple Human Microglia Differentiation Protocols; Brain Sciences September 13 2021.
• Akinchan Kumar, Yasenya Kasikci, Alaa Badredine, Karim Azzag, Marie L Quintyn Ranty, Falek Zaidi, Nathalie Aragou, Catherine Mazerolles, Bernard Malavaud, Marco A Mendoza-Parra, Laurence Vandel, Hinrich Gronemeyer; Patient-matched analysis identifies deregulated networks in prostate cancer to guide personalized therapeutic intervention; Am J Cancer Res; Nov. 15 2021.
• François Stüder, Jean-Louis Petit, Stefan Engelen, Marco Antonio Mendoza-Parra. Real-time SARS-CoV-2 diagnostic and variants tracking over multiple candidates using nanopore DNA sequencing; Scientific Reports; 11; 15869; August 5 2021.
• Florent Colin, Kristine Schauer, Ali Hamiche, Pierre Martineau, Jean‐Paul Borg, Jan Bednar, Guilia Bertolin, Luc Camoin, Yves Collette, Stephan Dimitrov, Isabelle Fournier, Vincent Hyenne , Marco A. Mendoza‐Parra, Xavier Morelli, Philippe Rondé, Izabela Sumara, Marc Tramier, Patrick Schultz, Jacky G. Goetz, The NANOTUMOR consortium ‐ towards the Tumor Cell Atlas; Biology of the Cell; February 7 2021.
• Maha Siouda, Audrey D. Dujardin, Laetitia Barbollat-Boutrand, Marco A. Mendoza-Parra, Benjamin Gibert, Maria Ouzounova, Jebrane Bouaoud, Laurie Tonon, Marie Robert, Jean-Philippe Foy, Vincent Lavergne, Serge

2020. Manie, Alain Viari, Alain Puisieux, Gabriel Ichim, Hinrich Gronemeyer, Pierre Saintigny, Peter Mulligan. CDYL2 epigenetically regulates MIR124 to control NF-κB/STAT3-dependent breast cancer cell plasticity, iScience; May 6 2020.

• Blum M, Cholley PE, Malysheva V, Nicaise S, Moehlin J, Gronemeyer H, Mendoza-Parra MA. A comprehensive resource for retrieving, visualizing, and integrating functional genomics data. Life Sci Alliance. December 9 2019.
• Goncalves, B., Moehlin, J., Clarke, E., Grist, J., Hobbs, C., Carr, A.M., Jack,J., Mendoza-Parra, M.A., Corcoran, J.P.T, RARβ agonist drug (C286) demonstrates efficacy in a pre-clinical neuropathic pain model restoring multiple pathways via DNA repair mechanisms, iScience Nov 22 2019.
• Elodie Mathieux and Marco Antonio Mendoza-Parra; Systems Biology Perspectives for Studying Neurodevelopmental Events; Book chapter IntechOpen “Neurodevelopment and Neurodevelopmental Disorder”; April 26 2019.
• Lucas Fauquier, Karim Azzag, Marco Antonio Mendoza Parra, Aurélie Quillien, Manon Boulet, Sarah Diouf, Gilles Carnac, Lucas Waltzer, Hinrich Gronemeyer & Laurence Vandel; CBP and P300 regulate distinct gene networks required for human primary myoblast differentiation and muscle integrity; Scientific Reports; August 22 2018.
• Pierre-Etienne Cholley, Julien Moehlin, Alexia Rohmer, Vincent Zilliox, Samuel Nicaise, Hinrich Gronemeyer and Marco Antonio Mendoza-Parra; Modeling gene-regulatory networks to describe cell fate transitions and predict master regulators; Nature Syst. Biol. & App; August 2 2018.
• Shinya Fujii, Shuichi Mori, Hiroyuki Kagechika, Marco Antonio Mendoza Parra and Hinrich Gronemeyer; Development of biotin-retinoid conjugates as chemical probes for analysis of retinoid function; Bioorganic & Medicinal Chemistry Letters; June 6 2018.
• Maja Milanovic, Dorothy Y. Fan, Dimitri Belenki, J. Henry M. Däbritz, Zhen Zhao, Yong Yu, Jan R. Dörr, Lora Dimitrova, Dido Lenze, Ines A. Monteiro Barbosa, Marco A. Mendoza-Parra, Tamara Kanashova, Marlen Metzner, Katharina Pardon, Maurice Reimann, Andreas Trumpp, Bernd Dörken, Johannes Zuber, Hinrich Gronemeyer, Michael Hummel, Gunnar Dittmar, Soyoung Lee and Clemens A. Schmitt; Senescence- associated reprogramming promotes cancer stemness; Nature; Jan 4 2018.
• MAM Saleem, Marco Antonio Mendoza-Parra, PE Cholley, M Blum and Hinrich Gronemeyer; Epimetheus: a multi-profile normalizer for epigenomic sequencing data; BMC Bioinformatics; May 12 2017.
• Marco Antonio Mendoza-Parra, Valeriya Malysheva, Mohamed Ashick Mohamed Saleem, Michele Lieb, Aurelie Godel and Hinrich Gronemeyer; Reconstructed cell fate-regulatory programs in stem cells reveal hierarchies and key factors of neurogenesis; Genome Research; September 20 2016.
• Valeriya Malysheva, Marco Antonio Mendoza-Parra, Mohamed Ashick Mohamed Saleem and Hinrich Gronemeyer; Reconstructing gene regulatory networks of tumorigenesis; Genome Medicine; May 19 2016.
• Marco Antonio Mendoza-Parra, Matthias Blum, Valeriya Malysheva, Pierre-Etienne Cholley and Hinrich Gronemeyer; LOGIQA: A database dedicated to Long-range Genome Interactions Quality Assessment; BMC Genomics; May 16 2016.
• Marco A. Mendoza-Parra, Mohamed Saleem MA, Matthias Blum, Pierre-Etienne Cholley and Hinrich Gronemeyer; NGS-QC Generator: A Quality control system for ChIP-seq and related deep sequencing- generated datasets; Statistical Genomics: Methods and Protocols; Springer Book Series; March 24 2016.
• Marco Antonio Mendoza-Parra, Vincent Saravaki, Pierre-Etienne Cholley, Matthias Blum, Benjamin Billoré and Hinrich Gronemeyer; Antibody performance in ChIP-sequencing assays: From quality scores of public data sets to quantitative certification; F1000Research; January 12 2016.
• Marco Antonio Mendoza-Parra, and Hinrich Gronemeyer, Systems biology approaches to uncover the function of RAR and RXR subtypes and of selective ligands in gene regulation during cell lineage specification, The Retinoids: Biology, Biochemistry and Disease » (Wiley-Blackwell publisher Book Series); May 2015. pp 165-192.
• Ronan Chaligné, Tatiana Popova, Marco Antonio Mendoza Parra, Mohamed Ashick Mohamed Saleem, David Gentien, Kristen Ban, Tristan Piolot, Olivier Leroy, Odette Mariani, Hinrich Gronemeyer, Anne Vincent- Salomon, Marc-Henri Stern and Edith Heard ; The inactive X chromosome is epigenetically unstable and transcriptionally labile in breast cancer; Genome Research; April 25 2015.
• Marco A. Mendoza-Parra and Hinrich Gronemeyer; Assessing quality standards for ChIP-seq and related massive parallel sequencing-generated datasets: When rating goes beyond avoiding the crisis; Genomics Data; 2014.
• Jelena Vjetrovic, Pattabhiraman Shankaranarayanan, Marco Mendoza-Parra and Hinrich Gronemeyer; Senescence-secreted factors activate Myc and sensitize pretrasformed cells to TRAIL-induced apoptosis; Aging Cell; June 13 2014.
• Marco Antonio Mendoza-Parra, and Hinrich Gronemeyer, Integrative genomics to dissect retinoids functions, The Biochemistry of Retinoic Acid Receptors I: Structure, Activation and Function at the Molecular Level; Subceullar Biochemistry; Springer Book Series; June 25 2014.
• Marco Antonio Mendoza-Parra, Wouter Van Gool, Mohamed Saleem MA, Danilo Guillermo Ceschin and Hinrich Gronemeyer; A quality control system for profiles obtained by massive parallel sequencing; Nucleic Acid Research; November 1 2013. (PATENTED)
• Marco Antonio Mendoza-Parra, Malgorzata Nowicka, Wouter Van Gool and Hinrich Gronemeyer; Characterising ChIP-seq binding patterns by model-based peak shape deconvolution; BMC Genomics; November 26 2013.
• Marco Antonio Mendoza-Parra, and Hinrich Gronemeyer, Genome-wide studies of nuclear receptors in cell fate decisions, Review journal “Seminars in Cell and Developmental Biology”, Thematic issue: Nuclear receptors and cell differentiation, pluripotency, development and stem cells; December 24 2013.
• Pattabhiraman Shankaranarayanan*, Marco Antonio Mendoza-Parra*, Wouter Van Gool, Luisa M. Trindade and Hinrich Gronemeyer, Single-tube linear DNA amplification (LinDA) for genome-wide studies using a few thousand cells, Nature Protocols. Jan 26 2012 (*equal author’s contribution)
• Marco Antonio Mendoza-Parra, Martial Sankar, Mannu Walia and Hinrich Gronemeyer; POLYPHEMUS: R package for comparative analysis of RNA Polymerase II ChIP-seq profiles by non-linear normalization; Nucleic Acid Research. Feb. 2012.
• Marco Antonio Mendoza-Parra, Mannu Walia, Martial Sankar and Hinrich Gronemeyer; Dissecting the retinoic acid-induced differentiation of F9 mouse embryonal stem cells through integrative genomic analysis; Molecular Systems Biology; Oct 11 2011.
• Pattabhiraman Shankaranarayanan, Marco Antonio Mendoza-Parra, Mannu Walia, Li Wang, Ning Li, Luisa Trindade and Hinrich Gronemeyer, Single-tube linear DNA amplification (LinDA) for robust ChIP-seq, Nature Methods. Jun 5 2011.
• Silvia Panizza, Marco Antonio Mendoza, Marc Berlinger,Lingzhi Huang, Alain Nicolas, Katsuhiko Shirahige and Franz Klein, Spo11-accessory proteins link double-strand break sites to the chromosome axis in early meiotic recombination, August 5 2011.