IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-45069-6.html
   My bibliography  Save this article

Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes

Author

Listed:
  • Carlos Company

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Matthias Jürgen Schmitt

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Yuliia Dramaretska

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Michela Serresi

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Sonia Kertalli

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Ben Jiang

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

  • Jiang-An Yin

    (University Hospital Zurich)

  • Adriano Aguzzi

    (University Hospital Zurich)

  • Iros Barozzi

    (Medical University of Vienna
    Imperial College London)

  • Gaetano Gargiulo

    (Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association (MDC))

Abstract

Descriptive data are rapidly expanding in biomedical research. Instead, functional validation methods with sufficient complexity remain underdeveloped. Transcriptional reporters allow experimental characterization and manipulation of developmental and disease cell states, but their design lacks flexibility. Here, we report logical design of synthetic cis-regulatory DNA (LSD), a computational framework leveraging phenotypic biomarkers and trans-regulatory networks as input to design reporters marking the activity of selected cellular states and pathways. LSD uses bulk or single-cell biomarkers and a reference genome or custom cis-regulatory DNA datasets with user-defined boundary regions. By benchmarking validated reporters, we integrate LSD with a computational ranking of phenotypic specificity of putative cis-regulatory DNA. Experimentally, LSD-designed reporters targeting a wide range of cell states are functional without minimal promoters. Applied to broadly expressed genes from human and mouse tissues, LSD generates functional housekeeper-like sLCRs compatible with size constraints of AAV vectors for gene therapy applications. A mesenchymal glioblastoma reporter designed by LSD outperforms previously validated ones and canonical cell surface markers. In genome-scale CRISPRa screens, LSD facilitates the discovery of known and novel bona fide cell-state drivers. Thus, LSD captures core principles of cis-regulation and is broadly applicable to studying complex cell states and mechanisms of transcriptional regulation.

Suggested Citation

  • Carlos Company & Matthias Jürgen Schmitt & Yuliia Dramaretska & Michela Serresi & Sonia Kertalli & Ben Jiang & Jiang-An Yin & Adriano Aguzzi & Iros Barozzi & Gaetano Gargiulo, 2024. "Logical design of synthetic cis-regulatory DNA for genetic tracing of cell identities and state changes," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45069-6
    DOI: 10.1038/s41467-024-45069-6
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-45069-6
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-45069-6?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Hyejung Won & Luis de la Torre-Ubieta & Jason L. Stein & Neelroop N. Parikshak & Jerry Huang & Carli K. Opland & Michael J. Gandal & Gavin J. Sutton & Farhad Hormozdiari & Daning Lu & Changhoon Lee & , 2016. "Chromosome conformation elucidates regulatory relationships in developing human brain," Nature, Nature, vol. 538(7626), pages 523-527, October.
    2. Yuting Guan & Xiujie Liang & Ziyuan Ma & Hailong Hu & Hongbo Liu & Zhen Miao & Andreas Linkermann & Jacklyn N. Hellwege & Benjamin F. Voight & Katalin Susztak, 2021. "A single genetic locus controls both expression of DPEP1/CHMP1A and kidney disease development via ferroptosis," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    3. Elphège P. Nora & Bryan R. Lajoie & Edda G. Schulz & Luca Giorgetti & Ikuhiro Okamoto & Nicolas Servant & Tristan Piolot & Nynke L. van Berkum & Johannes Meisig & John Sedat & Joost Gribnau & Emmanuel, 2012. "Spatial partitioning of the regulatory landscape of the X-inactivation centre," Nature, Nature, vol. 485(7398), pages 381-385, May.
    4. Philippe Cloutier & Christian Poitras & Mathieu Durand & Omid Hekmat & Émilie Fiola-Masson & Annie Bouchard & Denis Faubert & Benoit Chabot & Benoit Coulombe, 2017. "R2TP/Prefoldin-like component RUVBL1/RUVBL2 directly interacts with ZNHIT2 to regulate assembly of U5 small nuclear ribonucleoprotein," Nature Communications, Nature, vol. 8(1), pages 1-14, August.
    5. Shane Neph & Jeff Vierstra & Andrew B. Stergachis & Alex P. Reynolds & Eric Haugen & Benjamin Vernot & Robert E. Thurman & Sam John & Richard Sandstrom & Audra K. Johnson & Matthew T. Maurano & Richar, 2012. "An expansive human regulatory lexicon encoded in transcription factor footprints," Nature, Nature, vol. 489(7414), pages 83-90, September.
    6. Xinchen Wang & Liang He & Sarah M. Goggin & Alham Saadat & Li Wang & Nasa Sinnott-Armstrong & Melina Claussnitzer & Manolis Kellis, 2018. "High-resolution genome-wide functional dissection of transcriptional regulatory regions and nucleotides in human," Nature Communications, Nature, vol. 9(1), pages 1-15, December.
    7. Sascha Jung & Evan Appleton & Muhammad Ali & George M. Church & Antonio del Sol, 2021. "A computer-guided design tool to increase the efficiency of cellular conversions," Nature Communications, Nature, vol. 12(1), pages 1-12, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Xuelong Yao & Zongyang Lu & Zhanying Feng & Lei Gao & Xin Zhou & Min Li & Suijuan Zhong & Qian Wu & Zhenbo Liu & Haofeng Zhang & Zeyuan Liu & Lizhi Yi & Tao Zhou & Xudong Zhao & Jun Zhang & Yong Wang , 2022. "Comparison of chromatin accessibility landscapes during early development of prefrontal cortex between rhesus macaque and human," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. Vinícius G. Contessoto & Olga Dudchenko & Erez Lieberman Aiden & Peter G. Wolynes & José N. Onuchic & Michele Pierro, 2023. "Interphase chromosomes of the Aedes aegypti mosquito are liquid crystalline and can sense mechanical cues," Nature Communications, Nature, vol. 14(1), pages 1-12, December.
    3. Yi Li & James Lee & Lu Bai, 2024. "DNA methylation-based high-resolution mapping of long-distance chromosomal interactions in nucleosome-depleted regions," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Hossein Salari & Geneviève Fourel & Daniel Jost, 2024. "Transcription regulates the spatio-temporal dynamics of genes through micro-compartmentalization," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    5. Alon Diament & Tamir Tuller, 2015. "Improving 3D Genome Reconstructions Using Orthologous and Functional Constraints," PLOS Computational Biology, Public Library of Science, vol. 11(5), pages 1-22, May.
    6. Sonali Narang & Yohana Ghebrechristos & Nikki A. Evensen & Nina Murrell & Sylwia Jasinski & Talia H. Ostrow & David T. Teachey & Elizabeth A. Raetz & Timothee Lionnet & Matthew Witkowski & Iannis Aifa, 2024. "Clonal evolution of the 3D chromatin landscape in patients with relapsed pediatric B-cell acute lymphoblastic leukemia," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    7. Mary-Ellen Lynall & Blagoje Soskic & James Hayhurst & Jeremy Schwartzentruber & Daniel F. Levey & Gita A. Pathak & Renato Polimanti & Joel Gelernter & Murray B. Stein & Gosia Trynka & Menna R. Clatwor, 2022. "Genetic variants associated with psychiatric disorders are enriched at epigenetically active sites in lymphoid cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Da Lin & Weize Xu & Ping Hong & Chengchao Wu & Zhihui Zhang & Siheng Zhang & Lingyu Xing & Bing Yang & Wei Zhou & Qin Xiao & Jinyue Wang & Cong Wang & Yu He & Xi Chen & Xiaojian Cao & Jiangwei Man & A, 2022. "Decoding the spatial chromatin organization and dynamic epigenetic landscapes of macrophage cells during differentiation and immune activation," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    9. Khalid H. Bhat & Saurabh Priyadarshi & Sarah Naiyer & Xinyan Qu & Hammad Farooq & Eden Kleiman & Jeffery Xu & Xue Lei & Jose F. Cantillo & Robert Wuerffel & Nicole Baumgarth & Jie Liang & Ann J. Feene, 2023. "An Igh distal enhancer modulates antigen receptor diversity by determining locus conformation," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Dafne Ibarra-Morales & Michael Rauer & Piergiuseppe Quarato & Leily Rabbani & Fides Zenk & Mariana Schulte-Sasse & Francesco Cardamone & Alejandro Gomez-Auli & Germano Cecere & Nicola Iovino, 2021. "Histone variant H2A.Z regulates zygotic genome activation," Nature Communications, Nature, vol. 12(1), pages 1-14, December.
    11. Julia Minderjahn & Alexander Fischer & Konstantin Maier & Karina Mendes & Margit Nuetzel & Johanna Raithel & Hanna Stanewsky & Ute Ackermann & Robert Månsson & Claudia Gebhard & Michael Rehli, 2022. "Postmitotic differentiation of human monocytes requires cohesin-structured chromatin," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    12. Wu Zuo & Guangming Chen & Zhimei Gao & Shuai Li & Yanyan Chen & Chenhui Huang & Juan Chen & Zhengjun Chen & Ming Lei & Qian Bian, 2021. "Stage-resolved Hi-C analyses reveal meiotic chromosome organizational features influencing homolog alignment," Nature Communications, Nature, vol. 12(1), pages 1-20, December.
    13. Li-Hsin Chang & Sourav Ghosh & Andrea Papale & Jennifer M. Luppino & Mélanie Miranda & Vincent Piras & Jéril Degrouard & Joanne Edouard & Mallory Poncelet & Nathan Lecouvreur & Sébastien Bloyer & Amél, 2023. "Multi-feature clustering of CTCF binding creates robustness for loop extrusion blocking and Topologically Associating Domain boundaries," Nature Communications, Nature, vol. 14(1), pages 1-19, December.
    14. Pedro Madrigal & Siwei Deng & Yuliang Feng & Stefania Militi & Kim Jee Goh & Reshma Nibhani & Rodrigo Grandy & Anna Osnato & Daniel Ortmann & Stephanie Brown & Siim Pauklin, 2023. "Epigenetic and transcriptional regulations prime cell fate before division during human pluripotent stem cell differentiation," Nature Communications, Nature, vol. 14(1), pages 1-23, December.
    15. Anat Kreimer & Tal Ashuach & Fumitaka Inoue & Alex Khodaverdian & Chengyu Deng & Nir Yosef & Nadav Ahituv, 2022. "Massively parallel reporter perturbation assays uncover temporal regulatory architecture during neural differentiation," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    16. Jia-Yong Zhong & Longjian Niu & Zhuo-Bin Lin & Xin Bai & Ying Chen & Feng Luo & Chunhui Hou & Chuan-Le Xiao, 2023. "High-throughput Pore-C reveals the single-allele topology and cell type-specificity of 3D genome folding," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    17. Jingxuan Xu & Xiang Xu & Dandan Huang & Yawen Luo & Lin Lin & Xuemei Bai & Yang Zheng & Qian Yang & Yu Cheng & An Huang & Jingyi Shi & Xiaochen Bo & Jin Gu & Hebing Chen, 2024. "A comprehensive benchmarking with interpretation and operational guidance for the hierarchy of topologically associating domains," Nature Communications, Nature, vol. 15(1), pages 1-19, December.
    18. Pengfei Liu & Jeromine Vigneau & Rory J. Craig & Josué Barrera-Redondo & Elena Avdievich & Claudia Martinho & Michael Borg & Fabian B. Haas & Chang Liu & Susana M. Coelho, 2024. "3D chromatin maps of a brown alga reveal U/V sex chromosome spatial organization," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    19. Theodore Sakellaropoulos & Catherine Do & Guimei Jiang & Giulia Cova & Peter Meyn & Dacia Dimartino & Sitharam Ramaswami & Adriana Heguy & Aristotelis Tsirigos & Jane A. Skok, 2024. "MethNet: a robust approach to identify regulatory hubs and their distal targets from cancer data," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    20. Lina Zheng & Wei Wang, 2022. "Regulation associated modules reflect 3D genome modularity associated with chromatin activity," Nature Communications, Nature, vol. 13(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-45069-6. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.